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Zhang L, Lou W, Wang J. Advances in nucleic acid therapeutics: structures, delivery systems, and future perspectives in cancer treatment. Clin Exp Med 2024; 24:200. [PMID: 39196428 PMCID: PMC11358240 DOI: 10.1007/s10238-024-01463-4] [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: 06/19/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024]
Abstract
Cancer has emerged as a significant threat to human health. Nucleic acid therapeutics regulate the gene expression process by introducing exogenous nucleic acid fragments, offering new possibilities for tumor remission and even cure. Their mechanism of action and high specificity demonstrate great potential in cancer treatment. However, nucleic acid drugs face challenges such as low stability and limited ability to cross physiological barriers in vivo. To address these issues, various nucleic acid delivery vectors have been developed to enhance the stability and facilitate precise targeted delivery of nucleic acid drugs within the body. In this review article, we primarily introduce the structures and principles of nucleic acid drugs commonly used in cancer therapy, as well as their cellular uptake and intracellular transportation processes. We focus on the various vectors commonly employed in nucleic acid drug delivery, highlighting their research progress and applications in recent years. Furthermore, we propose potential trends and prospects of nucleic acid drugs and their carriers in the future.
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Affiliation(s)
- Leqi Zhang
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Wenting Lou
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Jianwei Wang
- Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, 2nd Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou, 310009, China.
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Zhang J, Wang P, Sun Y, Bai X, Zhong Y. Intraperitoneal Irrigation Chemotherapy with Lobaplatin in Locally Advanced Gastric Cancer: A Special Type of Abdominal Chemotherapy. Asian Pac J Cancer Prev 2024; 25:2409-2413. [PMID: 39068574 PMCID: PMC11480614 DOI: 10.31557/apjcp.2024.25.7.2409] [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: 02/28/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND This study evaluated the safety and efficiency of intraperitoneal irrigation chemotherapy with lobaplatin for the treatment of advanced gastric cancer (GC). METHODS A total of 56 locally advanced GC patients (experimental group) who received intraoperative intraperitoneal irrigation chemotherapy in addition to undergoing radical D2 surgery were matched 1:1 based on 8 covariates to 56 patients without drug treatment (control group). Clinical data were collected and analyzed. RESULT The two groups were well balanced in basic characteristics and had comparable clinical indices. All patients had similar time to first flatus (2.8 ± 0.3 vs. 2.9 ± 0.3 d, P = 0.076), time to first oral intake (3.5 ± 3.4 vs. 4.1 ± 4.6 d, P = 0.439), and duration of postoperative hospitalization (9.1 ± 3.2 vs. 9.6 ± 4.0 d, P = 0.446). There were no significant differences in postoperative complications including anastomotic and duodenal stump leakage, abdominal and anastomotic bleeding, seroperitoneum, and incision infection between the experimental and control groups (P > 0.05). The rates of chemotherapy-related side effects including allergic reaction, neurotoxicity, diarrhea, and nausea/vomiting were also similar between the two groups, and there were no abnormalities in leukocyte and platelet levels and liver and renal function during the first 5 days after surgery. CONCLUSION Intraperitoneal irrigation chemotherapy with lobaplatin is safe for patients with advanced gastric cancer.
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Affiliation(s)
- Jing Zhang
- Department of Surgery, Huanxing Cancer Hospital, Beijing, China.
| | - Peng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yuemin Sun
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xiaofeng Bai
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yuxin Zhong
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Liu BN, Gao XL, Piao Y. Mapping the intellectual structure and emerging trends for the application of nanomaterials in gastric cancer: A bibliometric study. World J Gastrointest Oncol 2024; 16:2181-2199. [PMID: 38764848 PMCID: PMC11099444 DOI: 10.4251/wjgo.v16.i5.2181] [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: 11/24/2023] [Revised: 02/11/2024] [Accepted: 03/21/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Recent reviews have outlined the main nanomaterials used in relation to gastrointestinal tumors and described the basic properties of these materials. However, the research hotspots and trends in the application of nanomaterials in gastric cancer (GC) remain obscure. AIM To demonstrate the knowledge structure and evolutionary trends of research into the application of nanomaterials in GC. METHODS Publications related to the application of nanomaterials in GC were retrieved from the Web of Science Core Collection for this systematic review and bibliometric study. VOSviewer and CiteSpace were used for bibliometric and visualization analyses. RESULTS From 2000 to 2022, the application of nanomaterials in GC developed rapidly. The keyword co-occurrence analysis showed that the related research topics were divided into three clusters: (1) The application of nanomaterials in GC treatment; (2) The application and toxicity of nanomaterials in GC diagnosis; and (3) The effects of nanomaterials on the biological behavior of GC cells. Complexes, silver nanoparticles, and green synthesis are the latest high-frequency keywords that represent promising future research directions. CONCLUSION The application of nanomaterials in GC diagnosis and treatment and the mechanisms of their effects on GC cells have been major themes in this field over the past 23 years.
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Affiliation(s)
- Bo-Na Liu
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110015, Liaoning Province, China
| | - Xiao-Li Gao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110015, Liaoning Province, China
| | - Ying Piao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang 110015, Liaoning Province, China
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Sikora A, Sullivan KM, Dineen S, Raoof M, Karolak A. Emerging therapeutic approaches for peritoneal metastases from gastrointestinal cancers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200767. [PMID: 38596287 PMCID: PMC10873742 DOI: 10.1016/j.omton.2024.200767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Peritoneal metastases from gastrointestinal malignancies present difficult management decisions, with options consisting primarily of systemic chemotherapy or major surgery with or without hyperthermic intraperitoneal chemotherapy. Current research is investigating expanding therapeutic modalities, and the aim of this review is to provide an overview of the existing and emerging therapies for the peritoneal metastases from gastrointestinal cancers, primarily through the recent literature (2015 and newer). These include the current data with systemic therapy and cytoreduction with hyperthermic intraperitoneal or pressurized intraperitoneal aerosol chemotherapy, as well as novel promising modalities under investigation, including dominating oncolytic viral therapy and adoptive cellular, biologic, and bacteria therapy, or nanotechnology. The novel diverse strategies, although preliminary and preclinical in murine models, individually and collectively contribute to the treatment of peritoneal metastases, offering hope for improved outcomes and quality of life. We foresee that these evolving treatment approaches will facilitate the transfer of knowledge and data among studies and advance discovery of new drugs and optimized treatments for patients with peritoneal metastases.
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Affiliation(s)
- Aleksandra Sikora
- Department of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Kevin M. Sullivan
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Sean Dineen
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Mustafa Raoof
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA
- Department of Cancer Genetics and Epigenetics, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Aleksandra Karolak
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Machine Learning, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
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Zhou X, Li D, Xia S, Ma X, Li R, Mu Y, Liu Z, Zhang L, Zhou Q, Zhuo W, Ding K, Lin A, Liu W, Liu X, Zhou T. RNA-based modulation of macrophage-mediated efferocytosis potentiates antitumor immunity in colorectal cancer. J Control Release 2024; 366:128-141. [PMID: 38104775 DOI: 10.1016/j.jconrel.2023.12.018] [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: 09/29/2023] [Revised: 11/28/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
Tumor-associated macrophages play pivotal roles in tumor progression and metastasis. Macrophage-mediated clearance of apoptotic cells (efferocytosis) supports inflammation resolution, contributing to immune evasion in colorectal cancers. To reverse this immunosuppressive process, we propose a readily translatable RNA therapy to selectively inhibit macrophage-mediated efferocytosis in tumor microenvironment. A clinically approved lipid nanoparticle platform (LNP) is employed to encapsulate siRNA for the phagocytic receptor MerTK (siMerTK), enabling selective MerTK inhibition in the diseased organ. Decreased MerTK expression in tumor-associated macrophages results in apoptotic cell accumulation and immune activation in tumor microenvironment, leading to suppressed tumor growth and better survival in both liver and peritoneal metastasis models of colorectal cancers. siMerTK delivery combined with PD-1 blockade further produces enhanced antimetastatic efficacy with reactivated intratumoral immune milieu. Collectively, LNP-based siMerTK delivery combined with immune checkpoint therapy may present a feasible modality for metastatic colorectal cancer therapy.
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Affiliation(s)
- Xuefei Zhou
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China.
| | - Dezhi Li
- Department of Oncology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China
| | - Shenglong Xia
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Xixi Ma
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China
| | - Rong Li
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yongli Mu
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zimo Liu
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Lu Zhang
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Quan Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Wei Zhuo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Kefeng Ding
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China
| | - Aifu Lin
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei Liu
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China
| | - Xiangrui Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Cancer Center, Zhejiang University, Hangzhou 310058, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China; Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China.
| | - Tianhua Zhou
- Cancer Center, Zhejiang University, Hangzhou 310058, China; Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, Zhejiang 310020, China.
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Yu Z, Wu J, Zhang L, Liu SY. Potential molecular target screening and bioinformatics analysis of cholangiocarcinoma based on GEO database. Shijie Huaren Xiaohua Zazhi 2022; 30:128-135. [DOI: 10.11569/wcjd.v30.i3.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma is a highly malignant tumor with a poor prognosis. Targeted therapy is important for the treatment of cholangiocarcinoma, and it is therefore of great clinical importance to identify novel molecular targets for targeted therapy of this malignancy.
AIM To identify potential molecular targets for the treatment of cholangiocarcinoma and identify the key genes involved in cholangiocarcinoma by bioinformatics analysis.
METHODS We downloaded two sets of cholangiocarcinoma expression profile data from GEO database. GEO2R online analysis tool was used to screen differentially expressed genes in cholangiocarcinoma tumor tissues and normal tissues, and we performed GO enrichment analysis, KEGG pathway analysis, and protein interaction network for differentially expressed genes. We used Cytoscape software to calculate key genes. The GEPIA database was used to verify the expression of hub genes in cholangiocarcinoma tissues.
RESULTS A total of 158 differentially expressed genes were identified. GO enrichment analysis showed that these differential genes were mainly involved in the cellular response to zinc ion, negative regulation of growth, cell adhesion, metabolic process, and protein homotetramerization. They were enriched in exosomes, extracellular spaces, elastic fibers, and organelle membranes. The main molecular functions are related to heparin binding, cysteine-type endopeptidase inhibitor activity, protein homodimerization activity, receptor binding, and pyridoxal phosphate binding. KEGG pathway analysis showed that differential genes are mainly involved in processes such as mineral absorption, carbon and propanoate metabolism, PPAR signaling pathway, and fatty acid degradation. A protein interaction network diagram was constructed based on the String database, and the CytoHubba plug-in of the Cytoscape software was used to calculate the key genes. The key genes were all up-regulated ones. GEPIA analysis verified that the expression of key genes in cholangiocarcinoma tissues was significantly higher than that in normal tissues.
CONCLUSION In this study, eight key genes related to cholangiocarcinoma were identified, including NUSAP1, TOP2A, RAD51AP1, MCM4, KIAA0101, CDCA5, TYMS, and ZWINT. These genes provide new ideas for in-depth study of the targeted therapy of cholangiocarcinoma, and are expected to become new molecular therapeutic targets.
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Affiliation(s)
- Zhen Yu
- Department of Laboratory Medicine, The Third Central Hospital of Tianjin; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
| | - Jing Wu
- Department of Laboratory Medicine, The Third Central Hospital of Tianjin; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
| | - Lei Zhang
- Department of Laboratory Medicine, The Third Central Hospital of Tianjin; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
| | - Shu-Ye Liu
- Department of Laboratory Medicine, The Third Central Hospital of Tianjin; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
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I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors. J Control Release 2021; 341:524-532. [PMID: 34896447 DOI: 10.1016/j.jconrel.2021.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/26/2021] [Accepted: 12/04/2021] [Indexed: 12/17/2022]
Abstract
Intraperitoneal (i.p) chemotherapy is an attractive approach to treat peritoneally disseminated cancers by delivering therapeutic agents directly to the peritoneal cavity where some disseminated tumors are located. Cationic liposomes (CLs) have been used as a viable delivery carrier for i.p. chemotherapy to improve the peritoneal retention of anticancer agents. However, there are no reports on the fate of CLs following i.p. administration to the peritoneal cavity in the presence of disseminated tumors. We prepared a tumor xenograft murine model of peritoneally disseminated gastric cancer by i.p. inoculation of human gastric cancer cells and followed the fate of either CLs or PEGylated CLs (PEG-CLs) after i.p. injection in the model. I.p.-injected CLs were retained in peritoneal cavity for at least 3 days post-injection as a result of clustering with ascites fluid proteins, mainly albumin, while i.p. PEG-CLs was rapidly cleared from the peritoneal cavity to the circulation within 3 h post-injection. Importantly, i.p. CLs efficiently accumulated in the targeted disseminated tumor cells, but not in other abdominal organs including liver, spleen, and kidney. The tumor selectivity upon i.p. administration of CLs may be associated with the lymphatic drainage system. A lipoplex formulation composed of CLs with short hairpin RNA (shRNA) against luciferase, a model therapeutic agent, suppressed luciferase activity in peritoneally disseminated tumors by 80%, with no cytokine secretion in serum. This suggests that i.p. CLs can efficiently deliver a therapeutic agent to peritoneally disseminated tumors with few systemic adverse events. These results suggest that i.p. treatment with CLs or non-PEGylated lipoplexes may be a promising approach for the treatment of peritoneally disseminated cancers through their ability to selectively deliver therapeutic agents to i.p. target sites with minimal systemic adverse events.
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Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model. Int J Biol Macromol 2021; 174:494-501. [PMID: 33545180 DOI: 10.1016/j.ijbiomac.2021.01.201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/23/2021] [Accepted: 01/29/2021] [Indexed: 12/31/2022]
Abstract
Nano-fibrillated bacterial cellulose (NFBC) is a safe, biocompatible material that can be prepared by culturing a cellulose-producing bacterium in a culture supplemented with carboxymethylcellulose (CMC) or hydroxypropylcellulose (HPC). CM-NFBC and HP-NFBC, prepared using CMC or HPC, show hydrophilicity and amphiphilicity, respectively, and thus they could be useful carriers for hydrophobic anticancer agents such as paclitaxel (PTX). In the present study, we prepared novel PTX formulations for intraperitoneal administration by associating PTX with either CM-NFBC or HP-NFBC and studied their therapeutic efficacy on peritoneally disseminated gastric cancer in a xenograft nude mouse model. Freeze-dried PTX formulations (PTX/CM-NFBC and PTX/HP-NFBC) were quickly reconstituted with saline without any foaming, compared to nanoparticle albumin-bound PTX (nab-PTX, Abraxane®). Both PTX/NFBC formulations extended the mean survival times in our xenograft murine models compared with either free PTX or nab-PTX. The PTX/NFBC formulations reduced systemic side effects of free PTX relating to weight loss. In our disseminated gastric peritoneal cancer model, the PTX/NFBC formulation increased the therapeutic index for PTX by increasing the therapeutic efficacy and decreasing toxicity. NFBCs should receive consideration as improved carriers for the clinical delivery of hydrophobic anticancer drugs such as PTX in malignancies in the abdominal cavity with peritoneal metastasis and dissemination.
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Ando H, Ishida T. An RNAi therapeutic, DFP-10825, for intraperitoneal and intrapleural malignant cancers. Adv Drug Deliv Rev 2020; 154-155:27-36. [PMID: 32781056 DOI: 10.1016/j.addr.2020.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/31/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022]
Abstract
RNA interference (RNAi), a potent post-transcriptional gene-silencing action, has received considerable attentions as a novel therapeutic tool to treat intractable cancers. In recent days, we have developed a novel RNAi-based therapeutic formulation, DFP-10825, for the treatment of intractable advanced cancers developed in coelomic cavities. DFP-10825 was composed of chemically synthesized short hairpin RNA (shRNA) against thymidylate synthase (TS), a key enzyme for cancer proliferation, and cationic liposomes, and achieved high therapeutic effect on the mouse models of peritoneally disseminated gastric and ovarian cancers and malignant pleural mesothelioma without severe side effects by intracoelomic direct treatment. We further designed a freeze-dried DFP-10825 formulation for mass industrial production. DFP-10825 is undergoing in pre-clinical phase and goes to clinical trials. This review introduces a DFP-10825 formulation, a potent novel RNAi-based therapeutic maximizing the benefit of RNAi molecule (shRNA).
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Ando H, Fukushima M, Eshima K, Hasui T, Shimizu T, Ishima Y, Huang CL, Wada H, Ishida T. A novel intraperitoneal therapy for gastric cancer with DFP-10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model. Cancer Med 2019; 8:7313-7321. [PMID: 31609087 PMCID: PMC6885878 DOI: 10.1002/cam4.2598] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/11/2019] [Accepted: 09/19/2019] [Indexed: 12/21/2022] Open
Abstract
Purpose In advanced gastric cancer, peritoneal dissemination is a life‐threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP‐10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP‐10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer–bearing mice via intraperitoneal administration. In this study, we expanded DFP‐10825 to the treatment of peritoneally disseminated gastric cancer. Methods DFP‐10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI‐N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence‐labeled DFP‐10825 was monitored in this MKN45 peritoneally disseminated mouse model. Results Intraperitoneal injection of DFP‐10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI‐N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP‐10825. Interestingly, after intraperitoneal injection, fluorescence‐labeled DFP‐10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Conclusions Intraperitoneal injection of DFP‐10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP‐10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.
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Affiliation(s)
- Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Masakazu Fukushima
- Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.,Delta-Fly Pharma Inc, Tokushima, Japan
| | | | - Taichi Hasui
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Taro Shimizu
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yu Ishima
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Cheng-Long Huang
- Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Hiromi Wada
- Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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