The excessive extracellular matrix (ECM) in solid tumors significantly inhibits the deep penetration and homogeneous distribution of nanodrugs, which greatly reduces the therapeutic efficacy. In the present work, an injectable polyelectrolyte hydrogel (CD@IPH) containing collagenase and doxorubicin-loaded polyacrylic acid@polyaniline nanoparticles (DOX@NP) were developed for improved photothermal and chemotherapy. The collagenase is released quickly from the polyelectrolyte hydrogel in the first 12 h, effectively degrading ECM and enhancing the deep penetration and evenly distribution of DOX@NP in tumor tissues. Then, the tumor microenvironment-triggered release of DOX from DOX@NP exhibits improved photothermal and chemotherapeutic efficiency. Owing to the excellent photoacoustic and photothermal properties of polyaniline inner cores of DOX@NP, the drug penetration process can be monitored to enable the image-guided cancer therapy. Both in vitro and in vivo assays prove the superior therapeutic efficacy of collagenase-enhanced photothermal and chemotherapy. The designed nanocomposite hydrogel therefore provides a versatile drug delivery system for deep tumor synergistic therapies.

Chemotherapy serves as the primary treatment for cancers, facing challenges due to the emergence of drug resistance. Combination therapy has been developed to combat cancer drug resistance, yet it still suffers from lack of specific targeting of cancer cells and poor accumulation at the tumor site. Consequently, targeted administration of chemotherapy medications has been employed in cancer treatment. Doxorubicin (DOX) is one of the most frequently used chemotherapeutics, functioning by inhibiting topoisomerase activity. Enhancing the anti-cancer effects of DOX and overcoming drug resistance can be accomplished via delivery by nanoparticles. This review will focus on the development of peptide-DOX conjugates, the functionalization of nanoparticles with peptides, the co-delivery of DOX and peptides, as well as the theranostic use of peptide-modified nanoparticles in cancer treatment. The peptide-DOX conjugates have been designed to enhance the targeted delivery to cancer cells by interacting with receptors that are overexpressed on tumor surfaces. Moreover, nanoparticles can be modified with peptides to improve their uptake in tumor cells via endocytosis. Nanoparticles have the ability to co-deliver DOX along with therapeutic peptides for enhanced cancer treatment. Finally, nanoparticles modified with peptides can offer theranostic capabilities by facilitating both imaging and the delivery of DOX (chemotherapy).

The aim of this study is to synthesize the cobalt iron oxide (CoFe) and doxorubicin (Dox)-loaded chitosan bilirubin (ChiBil) nanoparticles and to investigate the anticancer therapeutic effect of the synthesized nanoparticles under magnetic guidance in a colon cancer.

ChiBil-CoFe-Dox nanoparticles were synthesized by conjugating CoFe and Dox and then loaded onto ChiBil nanoparticles. Synthesis were characterized using thermogravimetric (TGA) analysis, inductive coupled plasma (ICP) analysis, dynamic light scattering (DLS), zeta potential and field emission-transmission electron microscopy (FE-TEM). Cellular uptake and cytotoxicity studies were conducted in vitro. Biodistribution and tumor inhibition study was done in vivo CT-26 colon cancer model.

The ChiBil-CoFe-Dox nanoparticles were successfully synthesized in this study. The in vitro cytotoxicity study showed that the ChiBil-CoFe-Dox nanoparticle had a toxic effect on cancer cells. The accumulation of ChiBil-CoFe-Dox nanoparticles was enhanced under magnetic guidance, as observed by in vivo. Tumor inhibition study showed that the ChiBil-CoFe-Dox nanoparticle effectively reduced tumor size in vivo mice colon cancer model, especially when combined with magnetic guidance.

This study showed that ChiBil-CoFe-Dox nanoparticle was successfully synthesized and effectively reduced tumor size, especially when combined with magnetic guidance. The in vitro and in vivo results suggested that the ROS stimuli responsive ChiBil-CoFe-Dox nanoparticles may be a potent therapeutic option for treating colon cancer.

Multiple myeloma (MM) poses a significant therapeutic challenge due to its persistent progression and low survival rate. Although the proteasome inhibitor bortezomib has revolutionized MM treatment, MM aggressiveness and drug resistance remain critical concerns. To tackle this problem, we developed AMD3100-targeted Bortezomib Liposomes (ATBL) designed for the targeted delivery of bortezomib to MM cells. Uptake of ATBL into MM cells was dependent on CXCR4 and was enhanced compared to nontargeted liposomes, both in vitro and in vivo. Treating MM-bearing mice with ATBL achieved superior therapeutic efficacy compared to treatment with free bortezomib or nontargeted bortezomib-loaded liposomes. Notably, the therapeutic activity of ATBL was limited in mice inoculated with CXCR4-knockdown MM cells, highlighting CXCR4 as a potential biomarker for ATBL response. Importantly, ATBL was effective against an aggressive and bortezomib-resistant MM clone both in vitro and in vivo. Toxicity and biodistribution profiles demonstrated the safety and bone marrow-targeting ability of ATBL. Collectively, this study highlights ATBL as a promising next-generation proteasome inhibitor-based therapy that incorporates bone marrow-targeting ability and sensitizing elements to overcome drug resistance in MM.

Proteolysis targeting chimeras (PROTACs) technology is a promising strategy for degrading proteins of interest. Traditional PROTACs, however, often face challenges such as poor solubility, low stability, and off-target toxicity. To address these challenges, we integrated nanotechnology to enhance the delivery of target-protein degraders to the tumor sites, thereby improving their properties. Here, we report silica-based nano-PROTACs (SiPROTACs) that feature multiple ligands on the surface to target and degrade the transmembrane protein epidermal growth factor receptor (EGFR). SiPROTACs, with a diameter of approximately 50 nm, can efficiently bind to EGFR, recruit cereblon (CRBN) to induce EGFR ubiquitination, and facilitate their degradation by proteasomes. In HCC-827 and PC-9 cell lines, SiPROTACs initiated EGFR degradation at a notably low concentration of 50 nM, demonstrating greater efficiency compared to traditional PROTACs. In HCC-827 xenograft tumor-bearing mice, SiPROTACs accumulated at tumor site for at least 48 h and exhibited significant anti-tumor effects in vivo without causing noticeable side effects. These findings suggest a novel approach for the application of PROTACs highlighting their therapeutic potential for the treatment of non-small cell lung cancer (NSCLC).

Nanomedicine offers fresh approaches for breast cancer treatment, countering traditional limitations. The nanodrug delivery system's precision and biocompatibility hold promise, yet integration hurdles remain. This study reviews nano delivery systems in breast cancer therapy from 2013 to 2023, guiding future research directions.

In this study, we conducted a comprehensive search on Web of Science database (Guilin Medical University purchase edition) and downloaded literature related to the field published between 2013 and 2023. We analyzed these publications using R software, VOSviewer, and CiteSpace software.

This study reviewed 2632 documents, showing a steady publication increase from 2013 to 2023, peaking at 408 in 2022. China, USA, India, and Iran were prominent in publishing. The Chinese Academy of Sciences and Tabriz University of Medical Science were key collaboration centers. Notably, the Journal of Controlled Release and Biomaterials ranked among the top 10 journals for publications and citations, establishing their field representation. Key terms like "breast cancer," "nanoparticles," "drug delivery," "in-vitro," and "delivery" were widely used. Research focused on optimizing drug targeting, utilizing the tumor microenvironment for drug delivery, and improving delivery efficiency.

The nanodrug delivery system, as an innovative drug delivery approach, offers numerous advantages and has garnered global attention from researchers. This study provides an analysis of the status and hotspots in nano delivery systems within the realm of breast cancer therapy, offering valuable insights for future research in this domain.

The use of bismuth and its compounds in biomedicine has developed rapidly in recent years. Due to their unique properties, there are great opportunities for the development of new non-invasive strategies for the early diagnosis and effective treatment of cancers. This perspective highlights key fabrication methods to generate well-defined and clinically relevant bismuth materials of varying characteristics. On the one hand, this opens up a wide range of possibilities for unimodal and multimodal imaging. On the other hand, effective treatment strategies, which are increasingly based on combinatorial therapies, are given a great deal of attention. One of the biggest challenges remains the selective tumour targeting, whether active or passive. Here we present an overview on new developments of bismuth based materials moving forward from a simple enrichment at the tumour site via uptake by the mononuclear phagocytic system (MPS) to a more active tumour specific targeting via covalent modification with tumour-seeking molecules based on either small or antibody-derived molecules.

This review focuses on recent advancements in the effective use of mesoporous bioactive glasses (MBG) in the treatment of bone cancer, focusing on Osteosarcoma (OS). Bone cancers are rare but are associated with significant morbidity and mortality; often, aggressive treatment is required. Conventional treatments such as surgery, radiation, and chemotherapy are often not enough. This is because surgery cannot completely remove the tumor, without creating a critical size which are defects larger than 2 cm that cannot be repaired by physiological mechanisms. As a result, patients often face the additional burden of radiation and chemotherapy. Scientists have been exploring new treatments, including hyperthermia-targeted therapy, polymeric nanoparticles, and stem cell therapy. This could potentially negatively impact healthy tissues and organs. MBG offers a promising alternative to chemotherapeutic agents and ions for disease treatment as it acts as a multifunctional drug delivery system (DDS). In addition, MBG can also be engineered into scaffolds to facilitate local delivery of growth factors and drugs, thus promoting the efficiency of bone healing and restoration. Therefore, the current review highlights various MBG types reported in the past decade and explores potential future paths to enhance their use in bone cancer treatment while also giving insight on the already commercially available BGs that are used in different bone-related disease.

Cardiovascular disease remains a leading cause of global mortality, with many unresolved issues in current clinical treatment strategies despite years of extensive research. Due to the great progress in nanotechnology and gene therapy in recent years, the emerging gene therapy based on nanocarriers has provided a promising therapeutic alternative for cardiovascular diseases. This review outlines the status of nanocarriers as vectors in gene therapy for cardiovascular diseases, including coronary heart disease, pulmonary hypertension, hypertension, and valvular heart disease. It discusses challenges and future prospects, aiming to support emerging clinical treatments. This review is the first to summarize gene therapy using nanocarriers for valvular heart disease, highlighting their potential in targeting challenging tissues.

Molecular recognition is of crucial importance in several healthcare applications, such as sensing, drug delivery, and therapeutics. Molecularly imprinted polymers (MIPs) present an interesting alternative to biological receptors (e.g., antibodies, enzymes) for this purpose since synthetic receptors overcome the limited robustness, flexibility, high-cost, and potential for inhibition that comes with natural recognition elements. However, off the shelf MIP products remain limited, which is likely due to the lack of a scalable production approach that can manufacture these materials in high yields and narrow and defined size distributions to have full control over their properties. In this Perspective, we will confer how breakthroughs in the automation of MIP design, manufacturing, and evaluation of performance will accelerate the (commercial) implementation of MIPs in healthcare technology. In addition, we will discuss how prediction of the in vivo behavior of MIPs with animal-free technologies (e.g., 3D tissue models) will be critical to assess their clinical potential.

Platinum(II) complexes prevail as first-line treatment for many cancers but are associated with serious side effects and resistance development. Picoplatin emerged as a promising alternative to circumvent GSH-induced tumor resistance by introducing a bulky 2-picoline ligand. Although clinical studies were encouraging, picoplatin did not receive approval. Interestingly, the anticancer potential of prodrugs based on picoplatin is widely underexplored, and even less so the respective tumor-targeting approaches. We synthesized two new "hybrid" picoplatin(II) derivatives with an oxalate or cyclobutane dicarboxylate leaving group and their corresponding platinum(IV) prodrugs with an albumin-targeting maleimide moiety or a succinimide as reference. Picoplatin(II) and its derivatives indeed reacted much slower with GSH compared to the respective analogs cisplatin, carboplatin, or oxaliplatin. While PicoCarbo(IV) and PicoOxali(IV) were reduced slowly in the presence of ascorbic acid, picoplatin(IV) was extremely unstable. All three prodrugs were widely inactive in the MTT assays. The platinum(IV)-maleimide complexes rapidly bound to albumin with stable conjugates for >25 h. Albumin-binding resulted in elevated platinum plasma levels, prolonged blood circulation, and enhanced tumor accumulation of the prodrugs in mice bearing CT26 tumors. However, only maleimide-functionalized PicoCarbo(IV) and picoplatin(II) significantly inhibited tumor growth. One possible explanation is that for albumin-binding platinum(IV) prodrugs, the bulky 2-picoline moiety prevents sufficient activation/reduction to unlock their full anticancer potential.

Poly(lactide-co-glycolide) (PLG) nanoparticles loaded with doxorubicin have reached phase-I clinical trials for treating advanced solid tumors. This study explores cell hitchhiking, where nanoparticles associate with blood cells and investigates the impact on pharmacokinetics and tumor migration. Previous findings highlighted the early post-injection phase dominated by nonspecific nanoparticle-cell interactions and burst release. In contrast, this study examines the subsequent phase of tumor invasion, emphasizing the role of immune cells, mostly neutrophils, in redistributing the carrier to the tumor site via blood cell hitchhiking. We provide a detailed investigation of nanoparticle extravasation kinetics and mechanisms, showing qualitative and quantitative evidence of increased nanoparticle association with immune cells over time. By 30 min post-injection, approximately 15 % of monocytes and 15-19 % of neutrophils tested positive for nanoparticles, with significant differences observed between ex vivo and in vivo experiments, and between healthy and tumor-bearing animals. This study underscores the ambiguous role of immune cell-mediated tumor targeting. While the total accumulation of the carrier rises, this fraction is partially trapped in immune cells without any chance to escape.

Liver cancer is a highly lethal malignant tumor with a high incidence worldwide. Therefore, its treatment has long been a focus of medical research. Although traditional treatment methods such as surgery, radiotherapy, and chemotherapy have increased the survival rate of patients, their efficacy remains unsatisfactory owing to the nonspecific distribution of drugs, high toxicity, and drug resistance of tumor tissues. In recent years, the application of nanotechnology in the medical field has opened a new avenue for the treatment of liver cancer. Among these treatment methods, photothermal therapy (PTT) based on nanoliposomes has attracted wide attention owing to its unique targeting and high efficiency. This article reviews the latest preclinical research progress of nanoliposome-based PTT for liver cancer and its metastasis, discusses the preclinical challenges in this field, and proposes directions for improvement, with the aim of improving the effectiveness of liver cancer treatment.

Liposomal nanomedicines have emerged as a pivotal approach for the treatment of various diseases, notably cancer and infectious diseases. This manuscript provides an in-depth review of recent advancements in liposomal formulations, highlighting their composition, targeted delivery strategies, and mechanisms of action. We explore the evolution of liposomal products currently in clinical trials, emphasizing their potential in addressing diverse medical challenges. The integration of immunotherapeutic agents within liposomes marks a paradigm shift, enabling the design of 'immuno-modulatory hubs' capable of orchestrating precise immune responses while facilitating theranostic applications. The recent COVID-19 pandemic has accelerated research in liposomal-based vaccines and antiviral therapies, underscoring the need for improved delivery mechanisms to overcome challenges like rapid clearance and organ toxicity. Furthermore, we discuss the potential of "smart" liposomes, which can respond to specific disease microenvironments, enhancing treatment efficacy and precision. The integration of artificial intelligence and machine learning in optimizing liposomal designs promises to revolutionize personalized medicine, paving the way for innovative strategies in disease detection and therapeutic interventions. This comprehensive review underscores the significance of ongoing research in liposomal technologies, with implications for future clinical applications and enhanced patient outcomes.

Zwitterionic polymers exhibit strong hydration, high biocompatibility, and antifouling properties. Dendrimers are regularly branched polymers, which are used in the drug delivery system (DDS). In this study, we synthesized zwitterionic monomer- and polymer-conjugated dendrimers as a biocompatible nanoparticle to investigate the relation between the hydration property and biodistribution. A sulfobetaine monomer (SBM) was conjugated at the termini of the polyamidoamine (PAMAM) dendrimer. Polysulfobetaines (PSBs) were produced by reversible addition-fragmentation chain transfer polymerization and were also conjugated at the termini. Intermediate water, that is, water molecules loosely bound to the material, can be estimated from the melting peaks at less than 0 °C in differential scanning calorimetry (DSC) measurement. Our DSC results showed that the PSB-conjugated dendrimers (PSM-dens) contained more intermediate water than the SBM-conjugated dendrimer (SBM-den). PSB-dens accumulated in the tumor after intravenous administration, but SBM-den did not. These suggested that the amount of intermediate water, that is, the hydration property, was related to the biodistribution of the zwitterionic dendrimers. This relation is a possible design criterion for drug carriers. PSB-dens accumulated in the tumor even after the second injection, possibly overcoming the accelerated blood clearance observed with poly(ethylene glycol)-modified nanoparticles. Thus, this kind of zwitterionic polymer-conjugated dendrimer is useful for the DDS in cancer treatment.

Essentially, the blood-brain barrier (BBB) serves as a line of demarcation between neural tissues and the bloodstream. A unique and protective characteristic of the blood-brain barrier is its ability to maintain cerebral homeostasis by regulating the flux of molecules and ions. The inability to uphold proper functioning in any of these constituents leads to the disruption of this specialized multicellular arrangement, consequently fostering neuroinflammation and neurodegeneration. Recent advancements in nanomedicine have been regarded as a promising avenue for improving the delivery of drugs to the central nervous system in the modern era. A major benefit of this innovation is that it allows drugs to accumulate selectively within the cerebral area by circumventing the blood-brain barrier. Although brain-targeted nanomedicines have demonstrated impressive achievements, certain limitations in targeting specificity still exist. In this examination, we scrutinize the distinctive physical and chemical attributes of nanoparticles (NPs) contributing to their facilitation in BBB traversal. We explore the various mechanisms governing NP passage over the BBB, encompassing paracellular conveyance, mediated transport, as well as adsorptive- and receptor-mediated transcytosis. The therapeutic success of NPs for the treatment of brain tumors has been extensively investigated through the use of various categories of NPs. Among these are polymeric nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, metallic nanoparticles, quantum dots, and nanogels. The potential utility of nanoparticles goes beyond their ability to transport pharmaceuticals. They can serve as adept imaging contrast agents, capable of being linked with imaging probes. This will facilitate tumor visualization, delineate lesion boundaries and margins, and monitor drug delivery and treatment response. Versatile nanoparticles can be engineered to effectively target neoplastic lesions, serving dual roles in diagnostic imaging and therapeutic interventions. Subsequently, this discourse explores the constraints associated with nanoparticles in the context of treating brain tumors.

The blood-brain barrier (BBB) remains a major obstacle for effective delivery of therapeutics to treat central nervous system (CNS) disorders. Although transferrin receptor (TfR)-mediated transcytosis is widely employed for brain drug delivery, the inefficient release of therapeutic payload hinders their efficacy from crossing the BBB. Here, we developed a pH-responsive anti-polyethylene glycol (PEG) × anti-TfR bispecific antibody (pH-PEG engagerTfR) that can complex with PEGylated nanomedicine at physiological pH to trigger TfR-mediated transcytosis in the brain microvascular endothelial cells, while rapidly dissociating from PEGylated nanomedicine at acidic endosomes for efficient release of PEGylated nanomedicine to cross the BBB. The pH-PEG engagerTfR significantly increased the accumulation of PEGylated nanomedicine in the mouse brain compared to wild-type PEG engagerTfR (WT-PEG engagerTfR). pH-PEG engagerTfR-decorated PEGylated liposomal doxorubicin exhibited an enhanced antitumor effect and extended survival in a human glioblastoma (GBM) orthotopic xenograft mice model. Conditional release of PEGylated nanomedicine during BBB-related receptor-mediated transcytosis by pH-PEG engagerTfR is promising for enhanced brain drug delivery to treat CNS disorders.

Protein hydrolysis targeted chimeras (PROTACs) represent a different therapeutic approach, particularly relevant for overcoming challenges associated with traditional small molecule inhibitors. These challenges include targeting difficult proteins that are often deemed "undruggable" and addressing issues of acquired resistance. PROTACs employ the body's own E3 ubiquitin ligases to induce the degradation of specific proteins of interest (POIs) through the ubiquitin-proteasome pathway. This process is cyclical, allowing for broad applicability, potent protein degradation, and selective targeting. Despite their effectiveness, PROTACs can inadvertently target and degrade nonspecific proteins, potentially resulting in significant side effects and off-target toxicity. To address this concern, researchers have created stimuli-activated PROTACs that enhance targeted protein degradation while minimizing potential harm to healthy cells. These advanced PROTACs aim to improve the precision of degradation in both time and space. This article reviews the strategies for in situ activated PROTACs, highlighting key compounds and research advancements associated with various mechanisms of action. The insights presented here aim to guide further exploration in the field of activated PROTACs.

Nanomedicines, by significantly enhancing the solubility, stability, and targeted delivery of therapeutic agents, have emerged as transformative tools in light-induced therapies, particularly in the context of oncology. These advancements are attributed to their ability to mediate autophagy through light activation, thereby revolutionizing cancer treatment paradigms. This review provides a comprehensive analysis of the state-of-the-art integration of nanomedicines with phototherapy techniques, emphasizing their role in modulating autophagy within cancer cells. It delineates the potential of light-responsive nanomaterials to induce selective tumor cell death by precisely regulating over-activated autophagy pathways. Additionally, it discusses innovative strategies for combining nanomedicines with phototherapy and other clinical modalities for tumor treatment, as well as integrating autophagy with various forms of programmed cell death to address challenges related to drug resistance and therapeutic efficacy. By synthesizing recent advancements and delineating future research directions, this review offers a thorough perspective on the optimization of light-induced autophagy through nanomedicines, highlighting novel strategies for enhancing cancer treatment efficacy.

pH sensitivity of chitosan allows for precise phase transitions in acidic environments, controlling swelling and shrinking, making chitosan suitable for drug delivery systems. pH transitions are modulated by the presence of cross-linkers by the functionalization of the chitosan chain. This review relays a summary of chitosan functionalization and tailoring to optimize drug release. The potential to customize chitosan for different environments and therapeutic uses introduces opportunities for drug encapsulation and release. The focus on improving drug encapsulation and sustained release in specific tissues is an advanced interpretation, reflecting the evolving role of chitosan in achieving targeted and more efficient therapeutic outcomes. This review describes strategies to improve solubility and stability and ensure the controlled release of encapsulated drugs. The discussion on optimizing factors like cross-linking density, particle size, and pH for controlled drug release introduces a deeper understanding of how to achieve specific therapeutic effects. These strategies represent a refined approach to designing chitosan-based systems, pushing the boundaries of sustained release technologies and offering new avenues for precise drug delivery profiles.

About 50% of all cancers carry a mutation in p53 that impairs its tumor suppressor function. The p53 missense mutation p53R175H (p53R172H in mice) is a hotspot mutation in various cancer types. Therefore, monoclonal antibodies selectively targeting clinically relevant mutations like p53R175H could prove immensely value. We aimed to evaluate the in vitro and in vivo binding properties of two novel anti-p53R175H monoclonal antibodies and to assess their performance as agents for molecular imaging. In vitro, 125I-4H5 and 125I-7B9 demonstrated long shelf life and antigen-specific binding. Our in vivo study design allowed head-to-head comparison of the antibodies in a double tumor model using repeated SPECT/CT imaging, followed by biodistribution and autoradiography. Both tracers performed similarly, with marginally faster blood clearance for 125I-7B9. Repeated molecular imaging demonstrated suitable imaging characteristics for both antibodies, with the best contrast images occurring at 48 h post-injection. Significantly higher uptake was detected in the mut-p53-expressing tumors, confirmed by ex vivo autoradiography. We conclude that molecular imaging with an anti-p53R175H tracer could be a promising approach for cancer diagnostics and could be further applied for patient stratification and treatment response monitoring of mutant p53-targeted therapeutics.

Triple negative breast cancers (TNBCs) lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) on their cell surfaces are highly aggressive, difficult-to-treat and often relapse. Herein, we report on the self-assembled lipid nanoparticles (LNPs) of two new pegylated lipopeptides for killing TNBCs (MDA-MB-231). The pegylated lipopeptides were synthesized by conjugating an n-hexadecyl hydrophobic tail to one end of a (PEG)27 unit the other distal end of which was covalently grafted with two previously reported tumor targeting RGDK- and CGKRK- peptides. The SEM images of the self-assembled LNPs formed upon dissolution of the pegylated lipopeptides in aqueous medium revealed formation of spherical aggregates. The degree of cellular uptake for the self-assembled LNPs formed by the pegylated CGKRK-lipopeptide were found to be significantly higher than that for the self-assembled LNPs formed by the pegylated RGDK-lipopeptide in MCF-7, MDA-MB-231, HEK-293 and HFF cells. Notably, about 60 % TNBCs (MDA-MB-231 cells) were killed upon treatment with commercially available potent JAK2 inhibitor (WP 1066) loaded LNPs of the pegylated RGDK-lipopeptide. Contrastingly, the same treatment killed only about 20 % non-cancerous HEK-293 cells. The self-assembled pegylated LNPs described herein open the door for undertaking preclinical studies in animal models for TNBCs.

Cancer is among the leading causes of mortality worldwide. Natural bioactive compounds like Meniran (Phyllanthus niruri L.) have been the focus of extensive research due to their potent anticancer properties. Nevertheless, drug delivery strategies may be necessary to encapsulate bioactive compounds, thereby reducing their toxicity and enhancing their stability. Herein, we successfully synthesized Meniran extract incorporated zeolitic imidazolate framework (ZIF-8) nanoparticles for anticancer therapy. Meniran-incorporated ZIF-8 nanoparticles possess unique advantages including well-distributed nanoparticles with rhombic dodecahedrons and excellent pH-responsiveness. In vitro analysis showed that Meniran-incorporated ZIF-8 nanoparticles have anticancer activity towards HeLa cells. Interestingly, computational simulations offer valuable insights into the molecular-level interaction mechanisms between ZIF-8 and specific proteins under cancer cells. As far as we are aware, this is the first report of natural bioactive compounds derived from Meniran encapsulated into nanoparticles as a drug delivery system, marking a significant advancement in the development of novel biomaterials for cancer treatment.

The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed starPEG40kDa with or without talazoparib (TLZ), a potent PARP inhibitor, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four copis of TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous (s.c.) xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared with CT26, a known EPR-high cell line. MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545 and moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 s.c. xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in s.c. and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.

P60, a Foxp3 inhibitory peptide, can hinder the regulatory T cell (Treg) activity and impair tumor proliferation. However, low systemic stability and poor specificity have led to daily dosing to achieve therapeutic effect. Therefore, this study aims to improve P60 stability and specific delivery through its encapsulation in liposomes targeting CD25, constitutively expressed in Tregs. P60 liposomes formulated with DSPE-PEG750 or DSPE-PEG2000 were incubated with DSPE-PEG2000-Maleimide micelles conjugated to Fab' fragments of anti-CD25 to develop two targeted formulations or immunoliposomes (IL): IL-P602000 (DSPE-PEG2000 only) and IL-P60750 (combining DSPE-PEG750 and DSPE-PEG2000). P60 encapsulation efficiency was 50%-60% irrespective of PEG chain length. Treg uptake was 2.5 and 14 times higher for IL-PEG750 compared with IL-PEG2000 and non-targeted liposomes, respectively, in in-vitro assays. In fact, IL-P60750 allowed CD8+  T cells ex-vivo proliferation in presence of Treg at doses 10-20 times lower than for free P60. Antitumor response of P60 and IL-P60750 in monotherapy and combined with anti-PD-1 was evaluated in MC38 and LLCOVA tumor bearing mice. In MC38 model, IL-P60750 monotherapy induced total tumor regression in 40% of mice reaching 100% for anti-PD-1 combination. This effect was associated with a significant increase in activated CD8+ T cells in tumors. Notably, IL-P60750 also inhibited human Treg in ex-vivo assay, showing the translational capability of this formulation. In conclusion, IL-P60750 formulated with different PEG chain lengths, has demonstrated antitumor efficacy by selective inhibition of Treg activity and enhances the effect of anti-PD1. Altogether, this novel IL represents a promising nanoplatform for cancer immunotherapies.

Recently, we developed AT101, an IgM-class mouse monoclonal antibody directed against glypican-1 (GPC1), a proteoglycan that can be considered as useful target for glioblastoma multiforme (GBM) treatment being specifically and highly expressed on GBM cell surface. Here, we proposed the use of AT101 as targeting agent in a drug delivery nanoplatfom to effectively deliver chitosan nanobubbles (NBs) for GBM treatment.

Chitosan NBs were prepared and conjugated with AT101 or left unconjugated as control.

The ability of AT101 to bind the GPC1 protein was demonstrated by flow cytometry and immunofluorescence analysis in the "GBM-like" GPC1-expressing cell lines U-87 MG and T98G. AT101 was shown to bind GPC1-expressing GBM tumor samples by immunofluorescence. In-vivo experiments in the U-87 MG xenograft model showed that AT101 was able to bind GPC1 on cell surface and accumulate in U-87 MG tumor masses (p = 0.0002 respect to control). Moreover, in-vivo experiments showed that AT101 is able to target GPC1 when conjugated to chitosan NBs, thus increasing their specific deliver to GPC1-expressing cells of U-87 MG tumor, as compared to chitosan NBs not conjugated to AT101 (p = 0.02).

AT101 is an useful targeting agent for the development of drug delivery nanoplatforms for GBM treatment.

Background/Objectives: Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa®, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts. Here, we sought to evaluate whether a liposomal formulation of HCQ could effectively modulate autophagy in vivo and augment treatment outcomes in the same tumor model. Methods: We developed two liposomal formulations of HCQ: a pH-loaded formulation and a formulation based on copper complexation. The pharmacokinetics of each formulation was evaluated in CD1 mice following intravenous administration. An efficacy study was performed in immunocompromised mice bearing established JIMT-1tumors. Autophagy markers in tumor tissue harvested after four weeks of treatment were assessed by Western blot. Results: The liposomal formulations engendered ~850-fold increases in total drug exposure over time relative to the free drug. Both liposomal and free HCQ in combination with gefitinib provided comparable therapeutic benefits (p > 0.05). An analysis of JIMT-1 tumor tissue indicated that the liposomal HCQ and gefitinib combination augmented the inhibition of autophagy in vivo compared to the free HCQ and gefitinib combination as demonstrated by increased LC3-II and p62/SQSTM1 (p62) protein levels. Conclusions: The results suggest that liposomal HCQ has a greater potential to modulate autophagy in vivo compared to free HCQ; however, this did not translate to better therapeutic effects when used in combination with gefitinib to treat a gefitinib-resistant tumor model.

Anthracycline doxorubicin (DOX) remains the first-line chemotherapeutic drug for the efficient treatment of breast cancer, but its severe cardiotoxicity limits its long-term application in clinical tumor chemotherapy. Until now, the pathogenesis mechanism of DOX-induced cardiotoxicity (DIC) is still not fully understood. According to current studies, the oxidative stress caused by the imbalance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and mitochondrial dysfunction in myocardial cells are closely related to DIC. Presently, the usual technology to solve the DIC problem is to use a multifunctional nanoplatform to load DOX and obtain a new medicinal agent, thereby enhancing the efficacy of chemotherapeutic drugs and reducing toxic side effects.Herein, the present investigation employed the Mannich condensation reaction, initiated by L-cysteine and (-)-epigallocatechin-3-gallocarboxylate (EGCG), to synthesize EGCG&Cys nanoformulation with both anti-tumor and anti-oxidant properties. The EGCG&Cys were then employed as the DOX carrier to construct a novel chemotherapeutic drug, EGCG&Cys(DOX), for high-efficiency breast cancer treatment. The tumor growth inhibition index of EGCG&Cys(DOX) in tumor-bearing mice was 12.56% superior to the DOX group with the same concentration. Meanwhile, the anti-oxidant properties of EGCG can effectively eliminate a large amount of free radicals produced by DOX and significantly alleviate DIC by improving mitochondrial functional pathways. Ultrasound echocardiography (UCG) showed that the mean LVEF and LEFS values in the 5 mg/kg DOX treatment group were significantly reduced by 54.4% and 63.4%, and the EGCG&Cys(DOX) group mice were consistent with those of the non-chemotherapy group. Moreover, electrocardiogram, serum biochemical indicators, and histopathological analysis results also demonstrate that the cardiotoxicity of EGCG&Cys(DOX) novel chemotherapy drugs is significantly reduced. Consequently, this study presents a new technology for preparing highly efficient and safe nano-chemotherapeutic drugs and an in-depth evaluation of the antitumor efficacy and safety of the synthesized novel drugs, which gave fresh life to the development of nanomedicine in the clinical treatment of breast cancer.

Nanomedicine, the most promising approach for regulated and targeted drug delivery, is frequently applied in cancer treatment. Essentially, accumulating evidence indicates that nanomedicine has positive results in the treatment of breast cancer (BC), with many BC patients benefiting from nanomedicine-related treatments. Currently, nanodrug delivery systems based on stimulus responses are gaining popularity because of their additional ability to manage drug release depending on the interior environment of the cancer. This review includes a synopsis of several types of internal (pH, redox, enzyme, reactive oxygen species, and hypoxia) stimuli-responsive nanoparticle drug delivery systems as well as perspectives for forthcoming times. Stimulus-responsive nanoparticles can remain stable under physiological conditions while being rapidly activated to release drugs in response to specific stimuli, prolonging blood circulation and increasing cancer cellular uptake, resulting in excellent therapeutic performance and improved biosafety. In this paper, we discuss tumor microenvironment responsive Nanoformulation for breast cancer treatment.

Self-assembly is a powerful strategy for building nanosystems for biomedical applications. We have recently developed small amphiphilic dendrimers capable of self-assembling into nanomicelles for tumor imaging. In this context, we studied the impact of increased hydrophobicity of the amphiphilic dendrimer on hydrophilic/hydrophobic balance and consequently on the self-assembly and subsequent biodistribution. Remarkably, despite maintaining the exact same surface chemistry, similar zeta potential, and small size, the altered and enlarged hydrophobic component within the amphiphilic dendrimer led to enhanced stability of the self-assembled nanomicelles, with prolonged circulation time and massive accumulation in the liver. This study reveals that even structural alteration within the interior of nanomicelles can dramatically impact biodistribution profiles. This finding highlights the deeper complexity of rational design for nanomedicine and the need to consider factors other than surface charge and chemistry, as well as size, all of which significantly impact the biodistribution of self-assembling nanosystems.

The present study aimed to explore an ideal delivery system for triptolide (TPL) by utilizing the thin-film hydration method to prepare drug-loaded, folate-modified mixed pluronic micelles (FA-F-127/F-68-TPL). Scanning electron microscopy and atomic force microscopy showed that the drug-loaded micelles had a spherical shape with a small particle size, with an average of 30.7 nm. Cell viability experiments showed that FA-F-127/F-68-TPL significantly reduced HepG2 cell viability, exhibiting strong cytotoxicity. Its cytotoxicity was markedly enhanced compared with bare TPL. Nile red (Nr) was used as a model drug to prepare FA-F-127/F-68-Nr to further validate its tumor-targeting and cellular uptake capability. After coincubation with HepG2 cells, a multifunctional microplate reader showed that intracellular fluorescence intensity significantly increased, indicating that FA-F-127/F-68-Nr could more effectively enter the cells. A nude mouse model of subcutaneous hepatocellular carcinoma was constructed. Following tail vein injection of FA-F-127/F-68-Nr, the fluorescence imaging system showed that FA-F127/F-68-Nr could significantly target tumor tissue, and even if entering the small-sized tumor was challenging, it could be excreted through urine. Nude mice with subcutaneous hepatocellular carcinoma were treated with tail vein injections of FA-F-127/F-68-TPL (45 µg/kg) every other day for 21 days. The results showed that the growth of the transplanted tumors was significantly slowed, with no significant difference compared with bare TPL. In summary, the FA-F-127/F-68-TPL exhibits the advantages of low cost, excellent biological properties, active/passive targeting capabilities, notable cytotoxicity against liver cancer cells, and significant inhibition of transplanted hepatocellular carcinoma growth. Significantly, the FA-F-127/F-68-TPL, despite challenges in targeting tumors with an insignificant EPR effect, can be efficiently excreted via the kidneys, thereby preventing the release of the drug during prolonged circulation and potential damage to normal tissues. Therefore, FA-F-127/F-68-TPL represents a promising antitumor drug delivery system.

The past decades have witnessed great strides in phototherapy as an experimental option or regulation-approved treatment in numerous cancer indications. Of particular interest is nanoscale photosensitizer-based phototherapy, which has been established as a prominent candidate for advanced tumor treatment by virtue of its high efficacy and safety. Despite considerable research progress on materials, methods and devices in nanoscale photosensitizing agent-based phototherapy, their mechanisms of action are not always clear, which impedes their practical application in cancer treatment. Hence, from a new perspective, this review elaborates the working mechanisms, involving impairment and moderation effects, of diverse phototherapies on cells, organelles, organs, and tissues. Furthermore, the most current available phototherapy modalities are categorized as photodynamic, photothermal, photo-immune, photo-gas, and radio therapies in this review. A comprehensive understanding of the inferiority and superiority of various phototherapies will facilitate the advent of a new era of cancer phototherapy.

The past 30 years have brought undeniable progress in medicine, biology, physics, and research. Knowledge of the nature of the human body, diseases, and disorders has been constantly improving, and the same is true regarding their treatment and diagnosis. One of the greatest advances in recent years has been the introduction of nanoparticles (NPs) into medicine. NPs refer to a material at a nanometer scale (0.1-100 nm) with features (specific physical, chemical, and biological properties) that are broadly and increasingly used in the medical field. Their applications in cancer treatment and radiotherapy seem particularly attractive. In this field, inorganic/metal NPs with high atomic number Z have been employed mainly due to their ability to enhance ionizing radiation's photoelectric and Compton effects and thereby increase conventional radiation therapy's efficacy. The improvement NPs enable relates to their enhanced permeation ability and longer retention effect in tumor cells, capacity to reduce toxicity of commercially available cancer drugs through advanced NPs drug delivery systems, radiation sensitizers of tumors, or enhancers of radiation doses to tumors. Advanced options according to size, core, and surface modification allow even such multimodal approaches in therapy as nanotheranostics or combined treatments. The current state of knowledge emphasizes the role of gold nanoparticles (AuNPs) in sensitizing tumors to radiation. We have reviewed AuNPs and their radiosensitizing power during radiation treatment. Our results are divided into groups based on AuNPs' surface modification and/or core structure design. This study provides a complete summary of the in vivo sensitizing effect of AuNPs, surface-modified AuNPs, and AuNPs combined with different elements, providing evidence for further successful veterinarian and clinical implementation.

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α-HO-1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

Chemoradiation therapy is on the forefront of pancreatic cancer care, and there is a continued effort to improve its safety and efficacy. Liposomes are widely used to improve chemotherapy safety, and may accurately deliver high-Z element- radiocatalytic nanomaterials to cancer tissues. In this study, the interaction between X-rays and long-circulating nanoliposome formulations loaded with gold nanoclusters is explored in the context of oxaliplatin chemotherapy for desmoplastic pancreatic cancer. Hydrophobic gold nanoclusters stabilized with dodecanethiol (AuDDT) are efficiently incorporated in nanoliposomal bilayers. AuDDT-nanoliposomes significantly augmented radiation-induced •OH production, which is most effective with monochromatic X-rays at energies that exceed the K-shell electron binding energy of Au (81.7 keV). Cargo release assays reveal that AuDDT-nanoliposomes can permeabilize lipid bilayers in an X-ray dose- and formulation-dependent manner. The radiocatalytic effect of AuDDT-nanoliposomes significantly augments radiotherapy and oxaliplatin-chemoradiotherapy outcomes in 3D pancreatic microtumors. The PEGylated AuDDT-nanoliposomes display high tumor accumulation in an orthotopic mouse model of pancreatic cancer, showing promise for nanoliposomes as carriers for radiocatalytic nanomaterials. Altogether, compelling proof for chemo-radiation dose-enhancement using AuDDT-nanoliposomes is presented. Further improving the nanoliposomal loading of high-Z elements will advance the safety, efficacy, and translatability of such chemoradiation dose-enhancement approaches.

Cancer is a leading cause of death worldwide, and imposes a substantial socioeconomic burden with little impact especially on aggressive types of cancer. Conventional therapies have many serious side effects including generalised systemic toxicity which limits their long-term use. Tumour resistance and recurrence is another main problem associated with conventional therapy. Purified or extracted natural products have been investigated as cost-effective cancer chemoprotective agents with the potential to reverse or delaying carcinogenesis. Curcumin (CUR) as a natural polyphenolic component, exhibits many pharmacological activities such as anti-cancer, anti-inflammatory, anti-microbial, activity against neurodegenerative diseases including Alzheimer, antidiabetic activities (type II diabetes), anticoagulant properties, wound healing effects in both preclinical and clinical studies. Despite these effective protective properties, CUR has several limitations, including poor aqueous solubility, low bioavailability, chemical instability, rapid metabolism and a short half-life time. To overcome the pharmaceutical problems associated with free CUR, novel nanomedicine strategies (including polymeric nanoparticles (NPs) such as poly (lactic-co-glycolic acid) (PLGA) NPs have been developed. These formulations have the potential to improve the therapeutic efficacy of curcuminoids. In this review, we comprehensively summarise and discuss recent in vitro and in vivo studies to explore the pharmaceutical significance and clinical benefits of PLGA-NPs delivery system to improve the efficacy of CUR in the treatment of cancer.