|
1
|
Sun J, Li HL, Zhou WJ, Ma ZX, Huang XP, Li C. Current status and recent progress of nanomaterials in transcatheter arterial chemoembolization therapy for hepatocellular carcinoma. World J Clin Oncol 2025; 16:104435. [DOI: 10.5306/wjco.v16.i4.104435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/06/2025] [Accepted: 03/05/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Transcatheter arterial chemoembolization has become a common treatment modality for some patients with unresectable advanced HCC. Since the introduction of nanomaterials in 1974, their use in various fields has evolved rapidly. In medical applications, nanomaterials can serve as carriers for the delivery of chemotherapeutic drugs to tumour tissues. Additionally, nanomaterials have potential for in vivo tumour imaging. This article covers the properties and uses of several kinds of nanomaterials, focusing on their use in transcatheter arterial chemoembolization for HCC treatment. This paper also discusses the limitations currently associated with the use of nanomaterials.
Collapse
Affiliation(s)
- Jia Sun
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| | - Hai-Liang Li
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| | - Wen-Jun Zhou
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| | - Zeng-Xin Ma
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| | - Xiao-Pei Huang
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| | - Cheng Li
- Department of Hepatobiliary Pancreatic Hernia Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, Guangdong Province, China
| |
Collapse
|
|
2
|
Chen YS, Jin E, Day PJ. Use of Drug Sensitisers to Improve Therapeutic Index in Cancer. Pharmaceutics 2024; 16:928. [PMID: 39065625 PMCID: PMC11279903 DOI: 10.3390/pharmaceutics16070928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
The clinical management of malignant tumours is challenging, often leading to severe adverse effects and death. Drug resistance (DR) antagonises the effectiveness of treatments, and increasing drug dosage can worsen the therapeutic index (TI). Current efforts to overcome DR predominantly involve the use of drug combinations, including applying multiple anti-cancerous drugs, employing drug sensitisers, which are chemical agents that enhance pharmacokinetics (PK), including the targeting of cellular pathways and regulating pertinent membrane transporters. While combining multiple compounds may lead to drug-drug interactions (DDI) or polypharmacy effect, the use of drug sensitisers permits rapid attainment of effective treatment dosages at the disease site to prevent early DR and minimise side effects and will reduce the chance of DDI as lower drug doses are required. This review highlights the essential use of TI in evaluating drug dosage for cancer treatment and discusses the lack of a unified standard for TI within the field. Commonly used benefit-risk assessment criteria are summarised, and the critical exploration of the current use of TI in the pharmaceutical industrial sector is included. Specifically, this review leads to the discussion of drug sensitisers to facilitate improved ratios of effective dose to toxic dose directly in humans. The combination of drug and sensitiser molecules might see additional benefits to rekindle those drugs that failed late-stage clinical trials by the removal of detrimental off-target activities through the use of lower drug doses. Drug combinations and employing drug sensitisers are potential means to combat DR. The evolution of drug combinations and polypharmacy on TI are reviewed. Notably, the novel binary weapon approach is introduced as a new opportunity to improve TI. This review emphasises the urgent need for a criterion to systematically evaluate drug safety and efficiency for practical implementation in the field.
Collapse
Affiliation(s)
- Yu-Shan Chen
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
| | - Enhui Jin
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
| | - Philip J. Day
- Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; (Y.-S.C.); (E.J.)
- Department of Medicine, University of Cape Town, Cape Town 7925, South Africa
| |
Collapse
|
|
3
|
Said AM, Mansour YE, Soliman RR, Islam R, Fatahala SS. Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors. Eur J Med Chem 2024; 273:116492. [PMID: 38762918 DOI: 10.1016/j.ejmech.2024.116492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/21/2024]
Abstract
Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC50 = 28 nM) and CYP3A4 (IC50 = 223 nM) inhibitory activities with low absorption potential (Papp (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.
Collapse
Affiliation(s)
- Ahmed M Said
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
| | - Yara E Mansour
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt
| | - Radwa R Soliman
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA
| | - Ridwan Islam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA
| | - Samar S Fatahala
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt.
| |
Collapse
|
|
4
|
Patel D, Sethi N, Patel P, Shah S, Patel K. Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review. Eur J Pharm Biopharm 2024; 198:114267. [PMID: 38514020 DOI: 10.1016/j.ejpb.2024.114267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.
Collapse
Affiliation(s)
- Dhvani Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Nutan Sethi
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Paresh Patel
- Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Shreeraj Shah
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India
| | - Kaushika Patel
- Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, L J University, Ahmedabad 382 210, India.
| |
Collapse
|
|
5
|
Long J, Hu W, Ren T, Wang X, Lu C, Pan X, Wu C, Peng T. Combating multidrug resistance of breast cancer with ginsenoside Rh2-irrigated nano-in-thermogel. Int J Pharm 2024; 650:123718. [PMID: 38104849 DOI: 10.1016/j.ijpharm.2023.123718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/26/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
The emergence of multidrug resistance (MDR) is the leading cause of mortality in patients with breast cancer. Overexpressed P-glycoprotein (P-gp) that can pump out chemotherapeutics from multidrug-resistant cancer cells is the main cause of chemotherapy failure. P-gp inhibitors are hence increasingly used to sensitize chemotherapy to breast cancer with MDR by reducing the efflux of drugs. However, representative P-gp inhibitors usually have severe side effects and the effect of their release behavior on chemotherapy are neglected in current studies. We constructed a nano-in-thermogel delivery system with the sequential release of ginsenoside Rh2 (GRh2) and a chemotherapeutic drug in the tumor microenvironment as a drug compounding "reservoir" to combat MDR in breast cancer. Briefly, paclitaxel (PTX) and GRh2 were encapsulated in solid lipid nanoparticles (SLNs) and dispersed in a poloxamer-based thermogel (SLNs-Gel). GRh2 was used as an innovative and safe P-gp inhibitor to lower P-gp expression and cellular adenosine triphosphate context, thereby sensitizing PTX-resistant breast cancer cells (MCF-7/PTX) to PTX. Pharmacodynamic and in vivo safety studies confirmed that intratumoral injection of SLNs-Gel significantly suppressed the proliferation of PTX-resistant breast cancer and alleviated the PTX-induced hematotoxicity. The GRh2-irrigated nano-in-thermogel delivery system shows great potential in combating multidrug-resistant cancer.
Collapse
Affiliation(s)
- Jieyu Long
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 511436, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Wanshan Hu
- College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China
| | - Tao Ren
- College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China
| | - Xuewen Wang
- College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China
| | - Chao Lu
- College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Chuanbin Wu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 511436, China; College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China
| | - Tingting Peng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 511436, China; College of Pharmacy, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 511436, China.
| |
Collapse
|
|
6
|
Eslami M, Memarsadeghi O, Davarpanah A, Arti A, Nayernia K, Behnam B. Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines 2024; 12:183. [PMID: 38255288 PMCID: PMC10812960 DOI: 10.3390/biomedicines12010183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/17/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
Collapse
Affiliation(s)
- Maryam Eslami
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Omid Memarsadeghi
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Ali Davarpanah
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Afshin Arti
- Department of Biomedical Engineering, Central Tehran Branch, Islamic Azad University, Tehran 1469669191, Iran;
| | - Karim Nayernia
- International Center for Personalized Medicine (P7Medicine), 40235 Dusseldorf, Germany
| | - Babak Behnam
- Department of Regulatory Affairs, Amarex Clinical Research, NSF International, Germantown, MD 20874, USA
| |
Collapse
|
|
7
|
Zhang Y, Liu X, He P, Tang B, Xiao C, Chen X. Thiol-Responsive Polypeptide Sulfur Dioxide Prodrug Nanoparticles for Effective Tumor Inhibition. Biomacromolecules 2023; 24:4316-4327. [PMID: 37611178 DOI: 10.1021/acs.biomac.3c00767] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Sulfur dioxide (SO2) based gas therapy has emerged as a novel anticancer therapeutic strategy because of its high therapeutic efficacy and biosafety. To precisely adjust the SO2 content and control gas release, herein, a thiol-responsive polypeptide SO2 prodrug mPEG-block-poly(2-amino-6-(2,4-dinitrophenylsulfonamido)hexanoic acid) (PEG-b-PLys-DNs) was designed and facilely synthesized by polymerization of a novel N-carboxyanhydride SO2-NCA. The anticancer potential of the self-assembled nanoparticles (SO2-NPs) was investigated in detail. First, PEG-b-PLys-DNs were synthesized by ring-opening polymerization of SO2-NCA, which self-assembled into NPs sized 88.4 nm in aqueous. Subsequently, SO2-NPs were endocytosed into 4T1 cells and quickly released SO2 under a high concentration of glutathione in tumor cells. This process depleted cellular glutathione, generated reactive oxygen species, and dramatically increased oxidative stress, which led to cancer cell apoptosis. Finally, the in vivo anticancer efficacy of SO2-NPs was verified in 4T1-tumor-bearing mice. Our results indicated that this novel SO2 polymeric prodrug has great potential in eradicating tumors.
Collapse
Affiliation(s)
- Yu Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Xinming Liu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Pan He
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, P. R. China
| | - Bingtong Tang
- School of Materials Science and Engineering, Changchun University of Science and Technology, Changchun 130022, P. R. China
| | - Chunsheng Xiao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| |
Collapse
|
|
8
|
Rahman H, Ware MJ, Sajid A, Lusvarghi S, Durell SR, Ambudkar SV. Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport. Cancers (Basel) 2023; 15:3459. [PMID: 37444569 DOI: 10.3390/cancers15133459] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
P-glycoprotein (P-gp, ABCB1) transports structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs, thus contributing to multidrug-resistant cancer. Cryo-EM structures of human P-gp revealed that TMHs 4 and 10 contribute to the formation of the drug-binding cavity and undergo conformational changes during drug transport. To assess the role of the conformational changes in TMH4 and TMH10 during drug transport, we generated two mutants (TMH4-7A and TMH10-7A), each containing seven alanine substitutions. Analysis of the drug efflux function of these mutants using 15 fluorescent substrates revealed that most of the substrates were transported, indicating that even seven mutations in an individual helix have no significant effect on transport function. We then designed the TMH4,10-14A mutant combining seven mutations in both TMHs 4 and 10. Interestingly, when the TMH4,10-14A mutant was tested with 15 substrates, there was no efflux observed for fourteen. The basal ATPase activity of the TMH4,10-14A mutant, similar to that of the WT protein, was inhibited by zosuquidar but was not stimulated by verapamil or rhodamine 6G. Molecular dynamics simulations indicated that the mutations cause TMHs 4 and 10 to pack tighter to their proximal helices, reducing their independent mobility. In aggregate, our findings demonstrate the critical role of the residues of homologous TMHs 4 and 10 for substrate transport, consistent with conformational changes observed in the structure of P-gp.
Collapse
Affiliation(s)
- Hadiar Rahman
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| | - Mark J Ware
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| | - Andaleeb Sajid
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| | - Sabrina Lusvarghi
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| | - Stewart R Durell
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| | - Suresh V Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA
| |
Collapse
|
|
9
|
Pardhi E, Yadav R, Chaurasiya A, Madan J, Guru SK, Singh SB, Mehra NK. Multifunctional targetable liposomal drug delivery system in the management of leukemia: Potential, opportunities, and emerging strategies. Life Sci 2023; 325:121771. [PMID: 37182551 DOI: 10.1016/j.lfs.2023.121771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/06/2023] [Accepted: 05/07/2023] [Indexed: 05/16/2023]
Abstract
The concern impeding the success of chemotherapy in leukemia treatment is descending efficacy of drugs because of multiple drug resistance (MDR). The previous failure of traditional treatment methods is primarily responsible for the present era of innovative agents to treat leukemia effectively. The treatment option is a chemotherapeutic agent in most available treatment strategies, which unfortunately leads to high unavoidable toxicities. As a result of the recent surge in marketed products, theranostic nanoparticles, i.e., multifunctional targetable liposomes (MFTL), have been approved for improved and more successful leukemia treatment that blends therapeutic and diagnostic characteristics. Since they broadly offer the required characteristics to get past the traditional/previous limitations, such as the absence of site-specific anti-cancer therapeutic delivery and ongoing real-time surveillance of the leukemia target sites while administering therapeutic activities. To prepare MFTL, suitable targeting ligands or tumor-specific antibodies are required to attach to the surface of the liposomes. This review exhaustively covered and summarized the liposomal-based formulation in leukemia treatment, emphasizing leukemia types; regulatory considerations, patents, and clinical portfolios to overcome clinical translation hurdles have all been explored.
Collapse
Affiliation(s)
- Ekta Pardhi
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, Telangana, India
| | - Rati Yadav
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, Telangana, India
| | - Akash Chaurasiya
- Department of Pharmaceutics, BITS-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, District. RR, Hyderabad, India
| | - Jitender Madan
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, Telangana, India
| | - Santosh Kumar Guru
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Shashi Bala Singh
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, Telangana, India
| | - Neelesh Kumar Mehra
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, Telangana, India.
| |
Collapse
|
|
10
|
Li X, Qin Z, Yuan Q, Song Y, Xu Q, Yang J, Deng X. Controllable release of self-assembled reduction-sensitive paclitaxel dimer prodrug and tetrandrine nanoparticles promotes synergistic therapy against multidrug-resistant cancer. Biochim Biophys Acta Gen Subj 2023; 1867:130362. [PMID: 37031808 DOI: 10.1016/j.bbagen.2023.130362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/28/2023] [Accepted: 04/04/2023] [Indexed: 04/11/2023]
Abstract
BACKGROUND Multidrug resistance (MDR) is the main reason for chemotherapy failure. Nanocarriers combined delivery of anti-cancer drugs and MDR inhibitors is an effective strategy to avoid MDR and improve the anti-cancer activity of drugs. METHODS Two paclitaxel (PTX) molecules are linked by disulfide bonds into PTX2. Then, the PTX2 and tetrandrine (TET) are coated together by mPEG-PLGA self-assembled NPs for combinational treatment. Microstructure, physiological stability, and cytotoxicity are characterized for the co-loaded NPs. RESULTS The NPs exhibit excellent suitability and blood safety for intravenous injection, specifically responsive to pH 6-7, and promptly initiate chemical degradation. Ex vivo fluorescence microscopy image studies indicate that co-loaded NPs increase drug penetration into cancer cells compared with free drugs. MTT assay demonstrates that co-loaded NPs have higher cytotoxicity against HeLa and the flow cytometric analysis shows that co-loaded NPs trigger more apoptosis than the free drugs. Reactive oxygen species (ROS) assay indicates that the drug-loaded NPs generated higher levels of ROS to accelerate apoptosis in HeLa cells. CONCLUSIONS TET can get desirable effects of inhibiting the MDR in advance by binding with the active site on P-gp, then the disulfide bond of PTX2 is broken by glutathione (GSH) in cancer cells and decomposed into PTX to inhibit cancer cell proliferation. GENERAL SIGNIFICANCE Our studies indicate that the co-loaded NPs can potentially overcome the MDR of conventional chemotherapeutic agents.
Collapse
Affiliation(s)
- Xing Li
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China.
| | - Zhen Qin
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China
| | - Qingmei Yuan
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China.
| | - Yadong Song
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China
| | - Qinming Xu
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China.
| | - Jingang Yang
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China
| | - Xiaocui Deng
- School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China.
| |
Collapse
|
|
11
|
Zeng R, Yang XM, Li HW, Li X, Guan Y, Yu T, Yan P, Yuan W, Niu SL, Gu J, Chen YC, Ouyang Q. Simplified Derivatives of Tetrandrine as Potent and Specific P-gp Inhibitors to Reverse Multidrug Resistance in Cancer Chemotherapy. J Med Chem 2023; 66:4086-4105. [PMID: 36892076 DOI: 10.1021/acs.jmedchem.2c02061] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023]
Abstract
Targeted inhibition of a drug efflux transporter P-glycoprotein (P-gp) is an important strategy to reverse multidrug resistance in cancer chemotherapy. In this study, a rationally structural simplification to natural tetrandrine was performed based on molecular dynamics simulation and fragment growth, leading to an easily prepared, novel, and simplified compound OY-101 with high reversal activity and low cytotoxicity. Its excellent synergistic anti-cancer effect with vincristine (VCR) against drug-resistant cells Eca109/VCR was confirmed by reversal activity assay, flow cytometry, plate clone formation assay, and drug synergism analysis (IC50 = 9.9 nM, RF = 690). Further mechanism study confirmed that the OY-101 was a specific and efficient P-gp inhibitor. Importantly, OY-101 increased VCR sensitization in vivo without obvious toxicity. Overall, our findings may provide an alternative strategy for the design of novel specific P-gp inhibitor as an anti-tumor chemotherapy sensitizer.
Collapse
Affiliation(s)
- Rong Zeng
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Xiu-Ming Yang
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Hong-Wei Li
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Xue Li
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Yu Guan
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Tao Yu
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Peng Yan
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Wen Yuan
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Sheng-Li Niu
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Jing Gu
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Ying-Chun Chen
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| | - Qin Ouyang
- Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China
| |
Collapse
|
|
12
|
Ibrahim MAA, Abdeljawaad KAA, Jaragh-Alhadad LA, Oraby HF, Atia MAM, Alzahrani OR, Mekhemer GAH, Moustafa MF, Shawky AM, Sidhom PA, Abdelrahman AHM. Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an in silico drug discovery study. J Biomol Struct Dyn 2023; 41:13977-13992. [PMID: 36883864 DOI: 10.1080/07391102.2023.2176360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 01/29/2023] [Indexed: 03/09/2023]
Abstract
The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.
Collapse
Affiliation(s)
- Mahmoud A A Ibrahim
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
- School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa
| | - Khlood A A Abdeljawaad
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| | | | - Hesham Farouk Oraby
- Deanship of Scientific Research, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohamed A M Atia
- Molecular Genetics and Genome Mapping Laboratory, Genome Mapping Department, Agricultural Genetic Engineering Research Institute (AGERI), ARC, Giza, Egypt
| | - Othman R Alzahrani
- Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Gamal A H Mekhemer
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| | - Mahmoud F Moustafa
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Department of Botany and Microbiology, Faculty of Science, South Valley University, Qena, Egypt
| | - Ahmed M Shawky
- Science and Technology Unit (STU), Umm Al-Qura University, Makkah, Saudi Arabia
| | - Peter A Sidhom
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Alaa H M Abdelrahman
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| |
Collapse
|
|
13
|
Xie MH, Fu ZL, Hua AL, Zhou JF, Chen Q, Li JB, Yao S, Cai XJ, Ge M, Zhou L, Wu J. A new core–shell-type nanoparticle loaded with paclitaxel/norcantharidin and modified with APRPG enhances anti-tumor effects in hepatocellular carcinoma. Front Oncol 2022; 12:932156. [PMID: 36185205 PMCID: PMC9515951 DOI: 10.3389/fonc.2022.932156] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/22/2022] [Indexed: 01/11/2023] Open
Abstract
Nanoparticle delivery systems have been shown to improve the therapeutic efficacy of anti-cancer drugs, including a variety of drugs for the treatment of hepatocellular carcinoma (HCC). However, the current systems show some limitations, and the delivery of more effective nanoparticle systems for anti-HCC drugs with better targeting ability are needed. Here, we created paclitaxel (PTX)/norcantharidin (NCTD)-loaded core–shell lipid nanoparticles modified with a tumor neovasculature-targeted peptide (Ala-Pro-Arg-Pro-Gly, APRPG) and investigated their anti-tumor effects in HCC. Core–shell-type lipid nanoparticles (PTX/NCTD-APRPG-NPs) were established by combining poly(lactic-co-glycolic acid) (PLGA)-wrapped PTX with phospholipid-wrapped NCTD, followed by modification with APRPG. For comparison, PTX-loaded PLGA nanoparticles (PTX-NPs) and PTX/NCTD-loaded core–shell-type nanoparticles without APRPG (PTX/NCTD-NPs) were prepared. The in vitro and in vivo anti-tumor effects were examined in HepG2 cells and tumor-bearing mice, respectively. Morphological and release characterization showed that PTX/NCTD-APRPG-NPs were prepared successfully and achieved up to 90% release of PTX in a sustained manner. Compared with PTX/NCTD-NPs, PTX/NCTD-APRPG-NPs significantly enhanced the uptake of PTX. Notably, the inhibition of proliferation and migration of hepatoma cells was significantly higher in the PTX/NCTD-APRPG-NP group than those in the PTX-NP and PTX/NCTD-NP groups, which reflected significantly greater anti-tumor properties as well. Furthermore, key molecules in cell proliferation and apoptosis signaling pathways were altered most in the PTX/NCTD-APRPG-NP group, compared with the PTX-NP and PTX/NCTD-NP groups. Collectively, PTX/NCTD-loaded core–shell lipid nanoparticles modified with APRPG enhance the effectiveness of anti-HCC drugs and may be an effective system for the delivery of anti-HCC drugs.
Collapse
Affiliation(s)
- Ming-Hua Xie
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Zai-Lin Fu
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Ai-Lian Hua
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Ji-Fang Zhou
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Qian Chen
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Jian-Bo Li
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Shen Yao
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Xin-Jun Cai
- Department of Pharmacy, Zhejiang Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, China
| | - Min Ge
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
| | - Li Zhou
- Department of Oncology, First People’s Hospital of Linping District, Hangzhou, China
| | - Jia Wu
- Department of Pharmacy, First People’s Hospital of Linping District, Hangzhou, China
- *Correspondence: Jia Wu,
| |
Collapse
|
|
14
|
Wang X, Wu C, Liu S, Peng D. Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives. Drug Deliv 2022; 29:1370-1383. [PMID: 35532094 PMCID: PMC9090367 DOI: 10.1080/10717544.2022.2069881] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people's lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs’ intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers’ based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.
Collapse
Affiliation(s)
- Xiande Wang
- Department of Neurosurgery, Hangzhou Medical College Affiliated Lin'an People's Hospital, The First People's Hospital of Hangzhou Lin'an District, Hangzhou, China
| | - Cheng Wu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Shiming Liu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| | - Deqing Peng
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China
| |
Collapse
|
|
15
|
Kim CH, Lee TH, Kim BD, Kim HK, Lyu MJ, Jung HM, Goo YT, Kang MJ, Lee S, Choi YW. Co-administration of tariquidar using functionalized nanostructured lipid carriers overcomes resistance to docetaxel in multidrug resistant MCF7/ADR cells. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
16
|
Chavda VP, Vihol D, Mehta B, Shah D, Patel M, Vora LK, Pereira-Silva M, Paiva-Santos AC. Phytochemical-loaded liposomes for anticancer therapy: an updated review. Nanomedicine (Lond) 2022; 17:547-568. [PMID: 35259920 DOI: 10.2217/nnm-2021-0463] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The major obstacles observed in current chemotherapy are severe adverse effects, narrow therapeutic indexes and multidrug resistance. Anticancer phytochemicals are extracted and purified from natural plants, providing alternative therapeutic approaches with recognized biomedical benefits. However, poor bioavailability, high dose requirements and non-specific targeting have made those molecules less effective. To tackle those issues, liposomal nanovesicles for phytochemical delivery are taken into consideration for improving the therapeutic effectiveness by increasing transportation across cell barriers and conferring attractive cancer-specific targeting capabilities. In the present review, the liposomal approaches of anticancer phytochemicals are discussed, and recent advances in these formulations applied to cancer phytotherapy are further reviewed by an informed approach.
Collapse
Affiliation(s)
- Vivek P Chavda
- Department of Pharmaceutics & Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, 380009, India
| | - Disha Vihol
- Pharmacy Section, L M College of Pharmacy, Ahmedabad, 380009, India
| | - Bhavya Mehta
- Pharmacy Section, L M College of Pharmacy, Ahmedabad, 380009, India
| | - Dhruvil Shah
- Pharmacy Section, L M College of Pharmacy, Ahmedabad, 380009, India
| | - Manan Patel
- Pharmacy Section, L M College of Pharmacy, Ahmedabad, 380009, India
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, UK
| | - Miguel Pereira-Silva
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, 3000-548, Portugal.,REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, 3000-548, Portugal
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, 3000-548, Portugal.,REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, 3000-548, Portugal
| |
Collapse
|
|
17
|
The Influence of Interaction between Cadmium with 17β-Estradiol, 2-Methoxyestradiol and 16α-Hydroxyestrone on Viability and p-Glycoprotein in Ovarian Cancer Cell Line. Int J Mol Sci 2022; 23:ijms23052628. [PMID: 35269769 PMCID: PMC8910160 DOI: 10.3390/ijms23052628] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/04/2022] Open
Abstract
Occupational and environmental exposure to xenoestrogens, a subgroup of endocrine disruptors (EDCs), can affect the endocrine system and increase the risk of cancer, primarily the hormone-dependent kind. This type of cancer includes ovarian cancer, which is the leading cause of death from gynecological tumors. The aim of this study was to assess the role of 17β-estradiol and its metabolites: 2-MeOE2, 16α-OHE1 in exposure to the metalloestrogen cadmium. The effect of interactions of cadmium with estrogens on the viability of cells in malignant ovarian cancer cells SKOV-3 was investigated, both in simultaneous action and in the pre-incubation model. There are no known interactions between estrogens and cadmium in ovarian cancer cells. Due to the frequent occurrence of multidrug resistance (MDR) in ovarian cancer, the effects of estrogens and cadmium on MDR in SKOV-3, measured as P-glycoprotein (P-gp), were assessed. An interaction study showed that E2 had an antagonistic effect on cadmium-induced cell damage, while 2-MeOE2 showed less of a protective effect in combination with CdCl2 than E2. There were two types of interaction: toxic synergism and beneficial antagonism. E2 and cadmium increased P-gp expression in SKOV-3 cells, while 2-MeOE2 decreased P-gp expression to a potentially beneficial effect on MDR prevention. The obtained results constitute an interesting starting point for further research in the field of interactions between estrogens and xenoestrogens in ovarian cancer.
Collapse
|
|
18
|
Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers. Drug Deliv Transl Res 2022; 12:2550-2560. [PMID: 35031972 DOI: 10.1007/s13346-021-01106-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7 nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.
Collapse
|
|
19
|
Gong Z, Zhou B, Liu X, Cao J, Hong Z, Wang J, Sun X, Yuan X, Tan H, Ji H, Bai J. Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy. ACS APPLIED MATERIALS & INTERFACES 2021; 13:55913-55927. [PMID: 34784165 DOI: 10.1021/acsami.1c17917] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.
Collapse
Affiliation(s)
- Zhongying Gong
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Baolong Zhou
- School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Xiaoying Liu
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Juanjuan Cao
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Zexin Hong
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Jingye Wang
- Department of Pathology, Weifang Maternal and Child Health Hospital, Weifang 261000, China
| | - Xirui Sun
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Xiaomeng Yuan
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Haining Tan
- National Glycoengineering Research Center, Shandong University, Jinan 250012, China
| | - Hongjie Ji
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| | - Jingkun Bai
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
| |
Collapse
|
|
20
|
Shi C, Huang H, Zhou X, Zhang Z, Ma H, Yao Q, Shao K, Sun W, Du J, Fan J, Liu B, Wang L, Peng X. Reversing Multidrug Resistance by Inducing Mitochondrial Dysfunction for Enhanced Chemo-Photodynamic Therapy in Tumor. ACS APPLIED MATERIALS & INTERFACES 2021; 13:45259-45268. [PMID: 34533937 DOI: 10.1021/acsami.1c12725] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Efficiency of standard chemotherapy is dramatically hindered by intrinsic multidrug resistance (MDR). Recently, to amplify therapeutic efficacy, photodynamic therapy (PDT)-induced mitochondrial dysfunction by decorating targeting moieties on nanocarriers has obtained considerable attention. Nevertheless, low targeting efficiency, complex synthesis routes, and difficulty in releasing contents become the major obstacles in further clinical application. Herein, an ingenious liposomal-based nanomedicine (L@BP) was fabricated by encapsulating a mitochondria-anchored photosensitizer (Cy-Br) and paclitaxel (PTX) for realizing enhanced cooperation therapy. At the cellular level, L@BP could hurdle endosomal traps to localize and implement PDT in mitochondria. Intriguingly, the PDT-induced in situ mitochondrial dysfunction led to intracellular ATP reduction, which triggered the downregulated P-glycoprotein transportation capacity and thus resulted in diminishing the efflux of chemotherapeutic agents and increasing drug uptake by drug-resistant cells. The prepared nanomedicine eminently accumulated in the tumor site and acquired enhanced therapeutic efficiency on PTX-resistant lung cancer cells, which possessed great potential in circumventing MDR tumors.
Collapse
Affiliation(s)
- Chao Shi
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Haiqiao Huang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Xiao Zhou
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Zhen Zhang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - He Ma
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Qichao Yao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Kun Shao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
| | - Wen Sun
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
- Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen 518057, P. R. China
| | - Jianjun Du
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
- Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen 518057, P. R. China
| | - Jiangli Fan
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
- Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen 518057, P. R. China
| | - Bin Liu
- State Key Laboratory of Fine Chemicals, Shenzhen University, Nanshan District, Shenzhen 518071, P. R. China
| | - Lei Wang
- State Key Laboratory of Fine Chemicals, Shenzhen University, Nanshan District, Shenzhen 518071, P. R. China
| | - Xiaojun Peng
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China
- Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen 518057, P. R. China
| |
Collapse
|
|
21
|
Lee JS, Oh H, Sung D, Lee JH, Choi WI. High Solubilization and Controlled Release of Paclitaxel Using Thermosponge Nanoparticles for Effective Cancer Therapy. Pharmaceutics 2021; 13:1150. [PMID: 34452111 PMCID: PMC8398058 DOI: 10.3390/pharmaceutics13081150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/19/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer, which is a leading cause of death, contributes significantly to reducing life expectancy worldwide. Even though paclitaxel (PTX) is known as one of the main anticancer drugs, it has several limitations, including low solubility in aqueous solutions, a limited dosage range, an insufficient release amount, and patient resistance. To overcome these limitations, we suggest the development of PTX-loaded thermosponge nanoparticles (PTX@TNP), which result in improved anticancer effects, via a simple nanoprecipitation method, which allows the preparation of PTX@TNPs with hydrophobic interactions without any chemical conjugation. Further, to improve the drug content and yield of the prepared complex, the co-organic solvent ratio was optimized. Thus, it was observed that the drug release rate increased as the drug capacity of PTX@TNPs increased. Furthermore, increasing PTX loading led to considerable anticancer activity against multidrug resistance (MDR)-related colorectal cancer cells (HCT 15), implying a synergistic anticancer effect. These results suggest that the solubilization of high drug amounts and the controlled release of poorly water-soluble PTX using TNPs could significantly improve its anticancer therapy, particularly in the treatment of MDR-p-glycoprotein-overexpressing cancers.
Collapse
Affiliation(s)
- Jin Sil Lee
- Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea; (J.S.L.); (H.O.); (D.S.); (J.H.L.)
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology, Cheomdan-gwagiro 123, Buk-gu, Gwangju 61005, Korea
| | - Hyeryeon Oh
- Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea; (J.S.L.); (H.O.); (D.S.); (J.H.L.)
- School of Materials Science and Engineering, Gwangju Institute of Science and Technology, Cheomdan-gwagiro 123, Buk-gu, Gwangju 61005, Korea
| | - Daekyung Sung
- Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea; (J.S.L.); (H.O.); (D.S.); (J.H.L.)
| | - Jin Hyung Lee
- Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea; (J.S.L.); (H.O.); (D.S.); (J.H.L.)
| | - Won Il Choi
- Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Korea; (J.S.L.); (H.O.); (D.S.); (J.H.L.)
| |
Collapse
|
|
22
|
Das T, Anand U, Pandey SK, Ashby CR, Assaraf YG, Chen ZS, Dey A. Therapeutic strategies to overcome taxane resistance in cancer. Drug Resist Updat 2021; 55:100754. [PMID: 33691261 DOI: 10.1016/j.drup.2021.100754] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/17/2022]
Abstract
One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and β-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.
Collapse
Affiliation(s)
- Tuyelee Das
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India
| | - Uttpal Anand
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Swaroop Kumar Pandey
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India.
| |
Collapse
|
|
23
|
Role of ABCB1 in mediating chemoresistance of triple-negative breast cancers. Biosci Rep 2021; 41:227788. [PMID: 33543229 PMCID: PMC7909869 DOI: 10.1042/bsr20204092] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/14/2021] [Accepted: 02/04/2021] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a group of breast cancers which neither express hormonal receptors nor human epidermal growth factor receptor. Hence, there is a lack of currently known targeted therapies and the only available line of systemic treatment option is chemotherapy or more recently immune therapy. However, in patients with relapsed disease after adjuvant or neoadjuvant therapy, resistance to chemotherapeutic agents has often developed, which results in poor treatment response. Multidrug resistance (MDR) has emerged as an important mechanism by which TNBCs mediate drug resistance and occurs primarily due to overexpression of ATP-binding cassette (ABC) transporter proteins such as P-glycoprotein (Pgp). Pgp overexpression had been linked to poor outcome, reduced survival rates and chemoresistance in patients. The aim of this mini-review is to provide a topical overview of the recent studies and to generate further interest in this critical research area, with the aim to develop an effective and safe approach for overcoming Pgp-mediated chemoresistance in TNBC.
Collapse
|
|
24
|
Anbazhagan R, Muthusamy G, Krishnamoorthi R, Kumaresan S, Rajendra Prasad N, Lai JY, Yang JM, Tsai HC. PAMAM G4.5 dendrimers for targeted delivery of ferulic acid and paclitaxel to overcome P-glycoprotein-mediated multidrug resistance. Biotechnol Bioeng 2020; 118:1213-1223. [PMID: 33289076 DOI: 10.1002/bit.27645] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/17/2020] [Accepted: 11/28/2020] [Indexed: 12/24/2022]
Abstract
In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared with PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells.
Collapse
Affiliation(s)
- Rajeshkumar Anbazhagan
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC
| | - Ganesan Muthusamy
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Rajakumari Krishnamoorthi
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC
| | - Swedha Kumaresan
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Department of Chemistry, Women's Christian College, Chennai, Tamil Nadu, India
| | - Nagarajan Rajendra Prasad
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Juin-Yih Lai
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Tao-Yuan, Taiwan, ROC
| | - Jen-Ming Yang
- Department of Chemical and Materials Engineering, Chang Gung University, Tao-Yuan, Taiwan, ROC.,Department of General Dentistry, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan, ROC
| | - Hsieh-Chih Tsai
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC.,R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Tao-Yuan, Taiwan, ROC
| |
Collapse
|
|
25
|
Zhong XC, Shi MH, Liu HN, Chen JJ, Wang TT, Lin MT, Zhang ZT, Zhou Y, Lu YY, Xu WH, Gao JQ, Xu DH, Han M, Chen YD. Mitochondrial targeted doxorubicin derivatives delivered by ROS-responsive nanocarriers to breast tumor for overcoming of multidrug resistance. Pharm Dev Technol 2020; 26:21-29. [PMID: 33070673 DOI: 10.1080/10837450.2020.1832116] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.
Collapse
Affiliation(s)
- Xin-Cheng Zhong
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Ming-Han Shi
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Hui-Na Liu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Jie-Jian Chen
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Tian-Tian Wang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Meng-Ting Lin
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Zhen-Tao Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Yi Zhou
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Yi-Ying Lu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Wen-Hong Xu
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jian-Qing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Dong-Hang Xu
- Department of Pharmacy, The 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic China
| | - Min Han
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China
| | - Yi-Ding Chen
- Department of Breast Surgery, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic China
| |
Collapse
|
|
26
|
Application of the Tumor Site Recognizable and Dual-Responsive Nanoparticles for Combinational Treatment of the Drug-Resistant Colorectal Cancer. Pharm Res 2020; 37:72. [PMID: 32215748 DOI: 10.1007/s11095-020-02791-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 02/20/2020] [Indexed: 02/05/2023]
Abstract
PURPOSE Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers. METHODS Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice. RESULTS The developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy.. CONCLUSION The results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer. Graphical Abstract Left: Targeting delivery of drug to tumor site by the tumor recognizable and dual-responsive nanoparticles and penetrating into tumor inner via the mediation of irradiation. Right: Nanoparticle distribution within tumor tissues with green represents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.
Collapse
|
|
27
|
Yu J, Hu F, Zhu Q, Li X, Ren H, Fan S, Qian B, Zhai B, Yang D. PD-L1 monoclonal antibody-decorated nanoliposomes loaded with Paclitaxel and P-gp transport inhibitor for the synergistic chemotherapy against multidrug resistant gastric cancers. NANOSCALE RESEARCH LETTERS 2020; 15:59. [PMID: 32166458 PMCID: PMC7067943 DOI: 10.1186/s11671-019-3228-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/15/2019] [Indexed: 06/10/2023]
Abstract
Multidrug resistance (MDR) based on ATP-dependent efflux transporters (p-glycoprotein (p-gp)) remains a major obstacle in successful chemotherapy treatment. Herein, we have investigated the potential of PD-L1 mAb-conjugated nanoliposome to serve as a targeted delivery platform for the co-delivery of paclitaxel (PTX) and p-gp specific transport inhibitor (TQD, tariquidar) in drug-resistant gastric cancers. Two drugs, PTX and TQD, were co-loaded in a single vehicle in a precise ratio to enhance the prospect of combination chemotherapeutic effect. Cellular uptake study indicated that PD-PTLP had higher internalization efficiency in PD-L1 receptor overexpressing SGC7901/ADR cells than non-targeted PTLP. Highest synergy was observed at a weight fraction of 1/0.5 (PTX/TQD) and the combination of PTX and TQD resulted in obvious synergistic effect compared to that of individual drugs alone. Our in vitro results showed that TQD was effective in reversing the multidrug resistance in SGC7901/ADR cells. The IC50 value of PD-PTLP was 0.76 μg/ml compared to 6.58 μg/ml and 7.64 μg/ml for PTX and TQD, respectively. PD-TPLP triggered significantly higher levels of reactive oxygen species (ROS) and cell apoptosis compared to that of free PTX or TQD. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of PD-PTLP displayed a significant inhibition of tumor burden of drug-resistant xenograft tumors with significantly higher terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Furthermore, free PTX resulted in significant increase in the levels of AST and ALT while PD-PTLP insignificantly different compared to that of control indicating the safety index. Overall, we believe that combination of anticancer drug with a p-gp inhibitor could provide a potential direction toward the treatment of drug-resistant gastric tumors.
Collapse
Affiliation(s)
- Jinling Yu
- Department of General Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Fengli Hu
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Qiankun Zhu
- Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Xiaodong Li
- Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Haiyang Ren
- Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Shengjie Fan
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Bo Qian
- Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Bo Zhai
- Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| | - Dongdong Yang
- Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001 China
| |
Collapse
|
|
28
|
Patel M, Nowsheen S, Maraboyina S, Xia F. The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: a review. Cell Biosci 2020; 10:35. [PMID: 32180937 PMCID: PMC7065339 DOI: 10.1186/s13578-020-00390-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/23/2020] [Indexed: 02/08/2023] Open
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors represent one of the successful novel approaches to targeted cancer treatment. Indeed, the US Food and Drug Administration (FDA) has recently approved PARP inhibitors for the treatment of breast and ovarian cancers. Despite the proven efficacy of these agents, certain challenges remain with their use. Among the most important are primary and secondary resistance. Here, we review the mechanism of action of PARP inhibitors and their ability to exploit certain inherent deficiencies among malignant cells to improve cell killing, with a focus on deficiencies in homologous recombination among cells with BRCA1 and BRCA2 mutations. Moreover, we discuss the different mechanisms of resistance including development of secondary resistance and strategies to overcome them. Finally, we discuss the limitations of novel therapeutic interventions and possible future studies to exploit biochemical pathways in order to improve therapeutic efficacy of PARP inhibitors.
Collapse
Affiliation(s)
- Mausam Patel
- 1Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham St., #771, Little Rock, AR 72205-7199 USA
| | - Somaira Nowsheen
- 2Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN USA
| | - Sanjay Maraboyina
- 1Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham St., #771, Little Rock, AR 72205-7199 USA
| | - Fen Xia
- 1Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham St., #771, Little Rock, AR 72205-7199 USA
| |
Collapse
|
|
29
|
Dallavalle S, Dobričić V, Lazzarato L, Gazzano E, Machuqueiro M, Pajeva I, Tsakovska I, Zidar N, Fruttero R. Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors. Drug Resist Updat 2020; 50:100682. [PMID: 32087558 DOI: 10.1016/j.drup.2020.100682] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/28/2020] [Accepted: 02/05/2020] [Indexed: 02/07/2023]
Abstract
Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.
Collapse
Affiliation(s)
- Sabrina Dallavalle
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Via Celoria 2, 20133 Milan, Italy
| | - Vladimir Dobričić
- Department of Pharmaceutical Chemistry, University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia
| | - Loretta Lazzarato
- Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Turin, Italy
| | - Elena Gazzano
- Department of Oncology, Università degli Studi di Torino, Via Santena 5/bis, 10126 Turin, Italy
| | - Miguel Machuqueiro
- BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, C8 Building, Campo Grande, 1749-016, Lisbon, Portugal; Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisbon, Portugal
| | - Ilza Pajeva
- QSAR and Molecular Modelling Department, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Block 105, 1113 Sofia, Bulgaria
| | - Ivanka Tsakovska
- QSAR and Molecular Modelling Department, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Block 105, 1113 Sofia, Bulgaria
| | - Nace Zidar
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
| | - Roberta Fruttero
- Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Turin, Italy.
| |
Collapse
|
|
30
|
Tonbul H, Sahin A, Tavukcuoglu E, Esendagli G, Capan Y. Combination drug delivery with actively-targeted PLGA nanoparticles to overcome multidrug resistance in breast cancer. J Drug Deliv Sci Technol 2019. [DOI: 10.1016/j.jddst.2019.101380] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
|
31
|
Levy A, Leynes C, Baig M, Chew SA. The Application of Biomaterials in the Treatment of Platinum‐Resistant Ovarian Cancer. ChemMedChem 2019; 14:1810-1827. [DOI: 10.1002/cmdc.201900450] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Indexed: 12/26/2022]
Affiliation(s)
- Arkene Levy
- Department of Pharmacology, College of Medical Sciences Nova Southeastern University 3200 South University Drive Davie FL 33328 USA
| | - Carolina Leynes
- Department Health and Biomedical Sciences University of Texas Rio Grande Valley One West University Boulevard Brownsville TX 78520 USA
| | - Mirza Baig
- Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University 3200 South University Drive Davie FL 33328 USA
| | - Sue Anne Chew
- Department Health and Biomedical Sciences University of Texas Rio Grande Valley One West University Boulevard Brownsville TX 78520 USA
| |
Collapse
|
|
32
|
Li S, Yin G, Pu X, Huang Z, Liao X, Chen X. A novel tumor-targeted thermosensitive liposomal cerasome used for thermally controlled drug release. Int J Pharm 2019; 570:118660. [PMID: 31491484 DOI: 10.1016/j.ijpharm.2019.118660] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 08/06/2019] [Accepted: 09/01/2019] [Indexed: 12/22/2022]
Abstract
Drug carriers with tumor targeting and controlled release have strong prospects for application in safe and efficient chemotherapy. Among various carriers, liposomes have good biocompatibility and can enhance the uptake of drugs by cancer cells. However, traditional liposomes have no specific targeting to cancer cells and are prone to insufficient stability, causing early leakage of the drug. Accordingly, organic-inorganic hybrid phospholipid and thermosensitive phospholipid are deliberately introduced into a liposome system to enhance the morphological and structural stability of the liposomes while realizing thermally controlled drug release. Furthermore, modification with a targeting ligand (WSG-peptide) can endow liposomes with active targeting to ovarian carcinoma cells. First, WSG-peptide was grafted onto the hydrophilic terminal of phospholipid molecules, and the organic-inorganic hybrid cerasome-forming lipid (CFL) was synthesized via a two-step chemical reaction. Then, the WSG-grafted thermosensitive liposomal cerasome (c-LIP-WSG) was prepared by thin-film hydration method. The results showed that the c-LIP-WSG had excellent structural stability both in storage and in a simulated circulation environment. In vitro drug release confirmed that the liposomes exhibited thermally controlled release. Cell uptake experiments and living fluorescence imaging of SKOV-3 tumor-bearing nude mice confirmed that the WSG-peptide modified liposomes were provided with specific targeting properties for ovarian carcinoma.
Collapse
Affiliation(s)
- Sixie Li
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China
| | - Guangfu Yin
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China.
| | - Ximing Pu
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China
| | - Zhongbin Huang
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China
| | - Xiaoming Liao
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China
| | - Xianchun Chen
- College of Materials Science and Engineering, Sichuan University, Chengdu 610065, PR China
| |
Collapse
|
|
33
|
Alam A, Kowal J, Broude E, Roninson I, Locher KP. Structural insight into substrate and inhibitor discrimination by human P-glycoprotein. Science 2019; 363:753-756. [PMID: 30765569 DOI: 10.1126/science.aav7102] [Citation(s) in RCA: 346] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/18/2019] [Indexed: 12/19/2022]
Abstract
ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.
Collapse
Affiliation(s)
- Amer Alam
- Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich, Switzerland
| | - Julia Kowal
- Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich, Switzerland
| | - Eugenia Broude
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA
| | - Igor Roninson
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA
| | - Kaspar P Locher
- Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich, Switzerland.
| |
Collapse
|
|
34
|
Xie X, Zhang Y, Li F, Lv T, Li Z, Chen H, Jia L, Gao Y. Challenges and Opportunities from Basic Cancer Biology for Nanomedicine for Targeted Drug Delivery. Curr Cancer Drug Targets 2019; 19:257-276. [DOI: 10.2174/1568009618666180628160211] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/15/2018] [Accepted: 06/22/2018] [Indexed: 12/11/2022]
Abstract
Background:Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment.Objective:Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers.Methods:We collected related information and data from articles.Results:In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment.Conclusion:The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.
Collapse
Affiliation(s)
- Xiaodong Xie
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yingying Zhang
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Fengqiao Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Tingting Lv
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Ziying Li
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Haijun Chen
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Lee Jia
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yu Gao
- Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry; Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian 350116, China
| |
Collapse
|
|
35
|
Jabri T, Imran M, Aziz A, Rao K, Kawish M, Irfan M, Malik MI, Simjee SU, Arfan M, Shah MR. Design and synthesis of mixed micellar system for enhanced anticancer efficacy of Paclitaxel through its co-delivery with Naringin. Drug Dev Ind Pharm 2019; 45:703-714. [PMID: 30557053 DOI: 10.1080/03639045.2018.1550091] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emergence of multidrug resistance (MDR) has limited the success of chemotherapeutic agents. Reversal of drugs efflux systems through combination therapy has got wider attention for increasing anticancer drugs efficacy. This study aims at co-encapsulation of Paclitaxel with Naringin in mixed polymeric micelles for enhanced anticancer activity of the drug. Drug-loaded micelles were prepared using two different amphiphilic block co-polymers and were characterized for morphology, size, zeta potential, drug encapsulation, in vitro release and stability using atomic force microscope (AFM), zetasizer, UV spectrophotometer, and FT-IR. MTT assay and fluorescence microscopy were used for in vitro cytotoxicity and cellular uptake studies. Nano-size micelles with spherical morphology and negative charge encapsulated 76.52 ± 0.94% and 32.87 0.61% Paclitaxel and Naringin, respectively. The micelles were thermally stable and retained 87.05 ± 0.69% and 92.88 ± 2.17% Paclitaxel and Naringin upon one-month storage. Maximum drug release was achieved at fourth hour of the study for both the loaded drugs. Paclitaxel co-encapsulation with Naringin synergistically improved its intracellular uptake and 65% in vitro cytotoxicity against breast cancer cells was achieved at its lower dose of 15 µg/mL. Results suggest that co-encapsulation of Paclitaxel with Naringin in mixed micelles is an effective strategy for achieving its higher anticancer activity.
Collapse
Affiliation(s)
- Tooba Jabri
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Imran
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Aisha Aziz
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Komal Rao
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Kawish
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Irfan
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Imran Malik
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Shabana Usman Simjee
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Arfan
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| | - Muhammad Raza Shah
- a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, Karachi University , Karachi , Pakistan
| |
Collapse
|
|
36
|
Sun JH, Ye C, Bai EH, Zhang LL, Huo SJ, Yu HH, Xiang SY, Yu SQ. Co-delivery nanoparticles of doxorubicin and chloroquine for improving the anti-cancer effect in vitro. NANOTECHNOLOGY 2019; 30:085101. [PMID: 30523865 DOI: 10.1088/1361-6528/aaf51b] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
To increase the efficacy of small molecule chemotherapeutic drug (SMCD) and reduce its toxic and side effects, we selected two model drugs doxorubicin (DOX) and chloroquine (CQ). DOX is a SMCD and CQis a chemosensitizer with autophagy inhibition. Poly(lactic-co-glycolic acid) (PLGA) and alpha-tocopherol polyethylene glycol 1000 succinate were chosen as delivery carriers to design and prepare a novel type of drug co-delivery single-nanoparticles by emulsification-solvent volatilisation, named NPDOX+CQ. The physicochemical properties of NPDOX+CQ were characterised. Then A549 cells and A549/Taxol cells were used for the in vitro anti-cancer effect study. At the same time, cellular uptake, intracellular migration and anti-cancer mechanism of nanoparticles were studied. The NPs showed a uniform spherical shape with good dispersibility, and both drugs had good encapsulation efficiency and loading capacity. In all formulations, NPDOX+CQ showed the highest in vitro cytotoxicity. The results showed that NPs could protect drugs from being recognised and excluded by P-glycoprotein (P-gp). Moreover, the results of the mechanistic study demonstrated that NPs were transported by autophagy process after being taken up by the cells. Therefore, during the migration of NPDOX+CQ, CQ could exert its efficacy and block autophagy so that DOX would not be hit by autophagy. Western Blot results showed that NPDOX+CQ had the best inhibition effect of autophagy. It can be concluded that the system can prevent the drug from being recognised and excluded by P-gp, and CQ blocks the process of autophagy so that the DOX is protected and more distributed to the nucleus of multidrug resistance (MDR) cell. The NPDOX+CQ constructed in this study provides a feasible strategy for reversing MDR in tumour cells.
Collapse
Affiliation(s)
- Jia-Hui Sun
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, People's Republic of China
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
|
|
38
|
Giri TK. Breaking the Barrier of Cancer Through Liposome Loaded with Phytochemicals. Curr Drug Deliv 2018; 16:3-17. [DOI: 10.2174/1567201815666180918112139] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 05/20/2018] [Accepted: 09/11/2018] [Indexed: 11/22/2022]
Abstract
Currently, the most important cause of death is cancer. To treat the cancer there are a number of drugs existing in the market but no drug is found to be completely safe and effective. The toxicity of the drugs is the key problem in the cancer chemotherapy. However, plants and plant derived bioactive molecule have proved safe and effective in the treatment of cancers. Phytochemicals that are found in fruits, vegetables, herbs, and plant extract have been usually used for treating cancer. It has been established that several herbal drug have a strong anticancer activity. However, their poor bioavailability, solubility, and stability have severely restricted their use. These problems can be overcome by incorporating the herbal drug in nanolipolomal vesicles. In last few decades, researcher have used herbal drug loaded nanoliposome for the treatment and management of a variety of cancers. Presently, a number of liposomal formulations are on the market for the treatment of cancer and many more are in pipe line. This review discusses about the tumor microenvironment, targeting mechanism of bioactive phytochemicals to the tumor tissue, background of nanoliposome, and the potential therapeutic applications of different bioactive phytochemicals loaded nanoliposome in cancer therapy.
Collapse
Affiliation(s)
- Tapan Kumar Giri
- NSHM College of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata Group of Institutions, 124 BL Saha Road, Kolkata-700053, West Bengal, India
| |
Collapse
|
|
39
|
Karpuz M, Silindir-Gunay M, Ozer AY. Current and Future Approaches for Effective Cancer Imaging and Treatment. Cancer Biother Radiopharm 2018; 33:39-51. [PMID: 29634415 DOI: 10.1089/cbr.2017.2378] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cancer poses a major health problem, not only due to cancer-related deaths but also because of treatment toxicities. This review discusses early diagnosis and strategies to overcome treatment difficulties, to facilitate recovery, and prevent deaths. Generally, noninvasive techniques such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission computed tomography (PET), and their hybrid systems, including SPECT/CT, PET/CT, and PET/MRI, are used in diagnosis of cancer. Cancer treatment in clinics still comprises conventional methods such as chemotherapy, radiotherapy, and surgery. However, these techniques and methods are often inadequate. Therefore, new approaches, including the formulation of actively and/or passively targeted nanosized drug delivery systems and combined treatment protocols, are being investigated. In this article, conventional cancer imaging and treatment are reviewed. In addition, the formulation of nanosized systems and their use in cancer treatment are discussed and combined diagnostic and therapeutic (theranostic) approach are proposed as additional cancer therapies.
Collapse
Affiliation(s)
- Merve Karpuz
- 1 Department of Radiopharmacy, Faculty of Pharmacy, Hacettepe University , Sihhiye, Ankara, Turkey .,2 Department of Radiopharmacy, Faculty of Pharmacy, Izmir Katip Celebi University , Cigli, Izmir, Turkey
| | - Mine Silindir-Gunay
- 1 Department of Radiopharmacy, Faculty of Pharmacy, Hacettepe University , Sihhiye, Ankara, Turkey
| | - Asuman Yekta Ozer
- 1 Department of Radiopharmacy, Faculty of Pharmacy, Hacettepe University , Sihhiye, Ankara, Turkey
| |
Collapse
|
|
40
|
Xia Y, Fang M, Dong J, Xu C, Liao Z, Ning P, Zeng Q. pH sensitive liposomes delivering tariquidar and doxorubicin to overcome multidrug resistance of resistant ovarian cancer cells. Colloids Surf B Biointerfaces 2018; 170:514-520. [PMID: 29960952 DOI: 10.1016/j.colsurfb.2018.06.055] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 05/03/2018] [Accepted: 06/25/2018] [Indexed: 11/16/2022]
Abstract
Multidrug resistance of tumour cells is one of the most important hurdles in tumour chemotherapy. To overcome the multidrug resistance, we constructed a pH-sensitive liposome formulation (pHSL) by loading tariquidar (TQR) and DOX simultaneously in this work. The formulation showed high stability at pH 7.4 and excellent sensitivity at acidic pH, which facilitated the delivery of TQR and DOX into cells. Cellular experiments demonstrated that the pHSL/TQR/DOX 0.05 could almost restore the drug sensitivity of OVCAR8/ADR cells. Therefore, the pH sensitive liposome formulation pHSL/TQR/DOX 0.05 was very promising in treating resistant tumours.
Collapse
Affiliation(s)
- Yuqiong Xia
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China.
| | - Mei Fang
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| | - Jingyu Dong
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| | - Chunzhong Xu
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| | - Zhen Liao
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| | - Pengbo Ning
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| | - Qi Zeng
- School of Life Science and Technology, Xidian University, Xi'an, Shaanxi, 710126, China
| |
Collapse
|
|
41
|
Pugliese E, Coentro JQ, Zeugolis DI. Advancements and Challenges in Multidomain Multicargo Delivery Vehicles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2018; 30:e1704324. [PMID: 29446161 DOI: 10.1002/adma.201704324] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/05/2017] [Indexed: 06/08/2023]
Abstract
Reparative and regenerative processes are well-orchestrated temporal and spatial events that are governed by multiple cells, molecules, signaling pathways, and interactions thereof. Yet again, currently available implantable devices fail largely to recapitulate nature's complexity and sophistication in this regard. Herein, success stories and challenges in the field of layer-by-layer, composite, self-assembly, and core-shell technologies are discussed for the development of multidomain/multicargo delivery vehicles.
Collapse
Affiliation(s)
- Eugenia Pugliese
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
- Science Foundation Ireland (SFI), Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
| | - João Q Coentro
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
- Science Foundation Ireland (SFI), Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
| | - Dimitrios I Zeugolis
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
- Science Foundation Ireland (SFI), Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Ireland
| |
Collapse
|
|
42
|
β-casein nanovehicles for oral delivery of chemotherapeutic Drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells. Oncotarget 2018; 7:23322-34. [PMID: 26989076 PMCID: PMC5029629 DOI: 10.18632/oncotarget.8019] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/21/2016] [Indexed: 02/02/2023] Open
Abstract
Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that β-casein (β-CN) micelles (β-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on β-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within β-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by β-CN, suppressing drug crystallization. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to β-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. Oral delivery of β-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer.
Collapse
|
|
43
|
Rezazadeh M, Akbari V, Amuaghae E, Emami J. Preparation and characterization of an injectable thermosensitive hydrogel for simultaneous delivery of paclitaxel and doxorubicin. Res Pharm Sci 2018; 13:181-191. [PMID: 29853928 PMCID: PMC5921399 DOI: 10.4103/1735-5362.228918] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In the current study, we aimed to develop a novel injectable thermosensitive hydrogel for simultaneous intra-tumoral administration of paclitaxel (PTX) and doxorubicin hydrochloride (DOX). At first, mixed micelles composed of Pluronic F127 and α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was loaded with PTX and their physicochemical properties including particle size, zeta potential, drug loading content, entrapment efficiency, and the drug release were investigated in details. In the second step, the optimized PTX-loaded micelles prepared in the first step were incorporated into the thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel containing fixed amount of DOX. Gel formation temperature, rheological properties, injectability, degradation rates of the hydrogel, and the release rate of PTX and DOX from the hydrogel were examined. The mean particle sizes and zeta potentials of the PTX-loaded micelles were 157.5 ± 20.1 nm and -9.6 ± 1.1 mV, respectively. The entrapment efficiency of the formulation was about 51%. The hydrogel containing PTX-loaded micelles and DOX existed as a solution with low viscosity at 4 °C converted to a semisolid upon increasing the temperature to 35 °C. DOX was completely released from the hydrogel within 12 h, while 40-80% of PTX could be released from the different formulations during 3 days. This novel thermosensitive hydrogel prepared in the current study could be efficiently used for co-delivery of PTX and DOX in solid tumor types.
Collapse
Affiliation(s)
- Mahboubeh Rezazadeh
- Department of Pharmaceutics and Novel Drug Delivery System Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Vajihe Akbari
- Department of pharmaceutical biotechnology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Elham Amuaghae
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Jaber Emami
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| |
Collapse
|
|
44
|
Qi SS, Sun JH, Yu HH, Yu SQ. Co-delivery nanoparticles of anti-cancer drugs for improving chemotherapy efficacy. Drug Deliv 2017; 24:1909-1926. [PMID: 29191057 PMCID: PMC8241150 DOI: 10.1080/10717544.2017.1410256] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/17/2017] [Accepted: 11/23/2017] [Indexed: 12/20/2022] Open
Abstract
To achieve superior therapeutic efficacy, the combination chemotherapy using two or more anticancer drugs in clinical practice has been generally accepted as a feasible strategy. On account of the concept of combination chemotherapy, co-delivery of anticancer drugs with nanotechnology gradually becomes a desired strategy and one of the research frontiers on modern drug delivery. In recent years, nano drug co-delivery system (NDCDS), which loads at least two anticancer drugs with different physicochemical and pharmacological properties into a combination delivery system, has achieved rapid development. NDCDS synergistically inhibited the growth of the tumor compared with the free drugs. In this review, we highlighted the current state of co-delivery nanoparticles and the most commonly used nanomaterial, discussed challenges and strategies, and prospect future development.
Collapse
Affiliation(s)
- Shan-Shan Qi
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, The People’s Republic of China
- Cancer Pharmacology Crown Bioscience Inc, Taicang, The People’s Republic of China
| | - Jia-Hui Sun
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, The People’s Republic of China
| | - Hao-Han Yu
- Nanjing DeBioChem Inc, Nanjing, The People’s Republic of China
| | - Shu-Qin Yu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, The People’s Republic of China
| |
Collapse
|
|
45
|
Khan AR, Liu M, Khan MW, Zhai G. Progress in brain targeting drug delivery system by nasal route. J Control Release 2017; 268:364-389. [PMID: 28887135 DOI: 10.1016/j.jconrel.2017.09.001] [Citation(s) in RCA: 226] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/31/2017] [Accepted: 09/01/2017] [Indexed: 12/13/2022]
Abstract
The blood-brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct targeting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery technologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs via nasal administration. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE Carbopol 934p (PubChem CID: 6581) Carboxy methylcellulose (PubChem CID: 24748) Penetratin (PubChem CID: 101111470) Poly lactic-co-glycolic acid (PubChem CID: 23111554) Tween 80 (PubChem CID: 5284448).
Collapse
Affiliation(s)
- Abdur Rauf Khan
- Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Mengrui Liu
- Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Muhammad Wasim Khan
- Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China
| | - Guangxi Zhai
- Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China.
| |
Collapse
|
|
46
|
Zheng T, Wang A, Hu D, Wang Y. Tumor-targeting templated silica nanoparticles as a dual-drug delivery system for anti-angiogenic ovarian cancer therapy. Exp Ther Med 2017; 14:2162-2170. [PMID: 28962137 PMCID: PMC5609177 DOI: 10.3892/etm.2017.4777] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 05/05/2017] [Indexed: 01/14/2023] Open
Abstract
The present study indicated the successful construction of a silica nanoparticle (SLN)-based drug delivery system (DDS) for the tumor-targeted co-delivery of two anti-angiogenic drugs, candesartan (CD) and trastuzumab (Tra), for ovarian cancer therapy via different anti-angiogenic mechanisms using hyaluronic acid (HA)/Tra/CD/SLNs. In vitro and in vivo anti-angiogenic assays indicated that CD and Tra exert beneficial functions on suppressing cancer angiogenesis, and exhibited significantly enhanced effects compared with the angiotensin stimulated group (P<0.01). CD and Tra co-delivery also significantly increased the anti-angiogenic effect compared with applying either drug alone (P<0.01). Furthermore, HA on the surface of the DDS was demonstrated to reduce the cytotoxicity of the DDS and also endowed the particles with an advanced tumor-homing property in vitro and in vivo. The present results revealed that HA/Tra/CD/SLNs may be a preferable formulation for anti-angiogenic ovarian cancer therapy.
Collapse
Affiliation(s)
- Tianying Zheng
- Cancer Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Aijun Wang
- Cancer Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Dongyan Hu
- Cancer Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Yonggang Wang
- Cancer Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| |
Collapse
|
|
47
|
Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG. Int J Pharm 2017; 532:149-156. [PMID: 28844900 DOI: 10.1016/j.ijpharm.2017.08.095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/05/2017] [Accepted: 08/20/2017] [Indexed: 01/27/2023]
Abstract
Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80-90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination.
Collapse
|
|
48
|
Singh MS, Tammam SN, Shetab Boushehri MA, Lamprecht A. MDR in cancer: Addressing the underlying cellular alterations with the use of nanocarriers. Pharmacol Res 2017; 126:2-30. [PMID: 28760489 DOI: 10.1016/j.phrs.2017.07.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/29/2017] [Accepted: 07/26/2017] [Indexed: 01/02/2023]
Abstract
Multidrug resistance (MDR) is associated with a wide range of pathological changes at different cellular and intracellular levels. Nanoparticles (NPs) have been extensively exploited as the carriers of MDR reversing payloads to resistant tumor cells. However, when properly formulated in terms of chemical composition and physicochemical properties, NPs can serve as beyond delivery systems and help overcome MDR even without carrying a load of chemosensitizers or MDR reversing molecular cargos. Whether serving as drug carriers or beyond, a wise design of the nanoparticulate systems to overcome the cellular and intracellular alterations underlying the resistance is imperative. Within the current review, we will initially discuss the cellular changes occurring in resistant cells and how such changes lead to chemotherapy failure and cancer cell survival. We will then focus on different mechanisms through which nanosystems with appropriate chemical composition and physicochemical properties can serve as MDR reversing units at different cellular and intracellular levels according to the changes that underlie the resistance. Finally, we will conclude by discussing logical grounds for a wise and rational design of MDR reversing nanoparticulate systems to improve the cancer therapeutic approaches.
Collapse
Affiliation(s)
- Manu S Singh
- Department of Pharmaceutical Technology and Biopharmceutics, University of Bonn, Germany
| | - Salma N Tammam
- Department of Pharmaceutical Technology and Biopharmceutics, University of Bonn, Germany; Department of Pharmaceutical Technology, German University of Cairo, Egypt
| | | | - Alf Lamprecht
- Department of Pharmaceutical Technology and Biopharmceutics, University of Bonn, Germany; Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France.
| |
Collapse
|
|
49
|
Johnson R, Sabnis N, Sun X, Ahluwalia R, Lacko AG. SR-B1-targeted nanodelivery of anti-cancer agents: a promising new approach to treat triple-negative breast cancer. BREAST CANCER-TARGETS AND THERAPY 2017; 9:383-392. [PMID: 28670138 PMCID: PMC5479299 DOI: 10.2147/bctt.s131038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Patients with triple-negative breast cancer (TNBC) have a considerably less favorable prognosis than those with hormone-positive breast cancers. TNBC patients do not respond to current endocrine treatment and have a 5-year survival prognosis of <30%. The research presented here is intended to fill a void toward the much needed development of improved treatment strategies for metastatic TNBC. The overall goal of this research was to evaluate the effectiveness of reconstituted high-density lipoprotein (rHDL) nanoparticles (NPs) as delivery agents for anti-TNBC drugs. Using lapatinib and valrubicin as components of the rHDL/drug complexes resulted in a significantly better performance of the NP-transported drugs compared with their free (unencapsulated) counterparts. The enhancement of the therapeutic effect and the protection of normal cells (cardiomyocytes) achieved via the rHDL NPs were likely due to the overexpression of the high-density lipoprotein (HDL) (scavenger receptor class B type 1 [SR-B1]) receptor by the TNBC cells.
Collapse
Affiliation(s)
| | - Nirupama Sabnis
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center
| | | | | | - Andras G Lacko
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center.,Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX, USA
| |
Collapse
|
|
50
|
Lanthanide-integrated supramolecular polymeric nanoassembly with multiple regulation characteristics for multidrug-resistant cancer therapy. Biomaterials 2017; 129:83-97. [DOI: 10.1016/j.biomaterials.2017.03.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/12/2017] [Accepted: 03/13/2017] [Indexed: 11/18/2022]
|