4 research outputs found

    Reduction-Cleavable Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release Behavior for Reversing Drug Resistance

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    In the treatment of cancer, multidrug resistance (MDR) has been the major obstacle to the success of chemotherapy. The underlying mechanism relies on the overexpression of drug-efflux transporters that prevent the intracellular transport of the drug. In this study, reduction-cleavable vesicles were designed and developed with efficient glutathione-mediated drug-release behavior for reversing drug resistance. Polymeric vesicles were self-assembled from triblock copolymers with disulfide-bond-linked poly­(ethylene glycol) (PEG) and poly­(ε-benzyloxycarbonyl-l-lysine) (PzLL). Observations from transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) outline an obvious hollow structure surrounded by a thin outer layer, indicating the successful formation of the vesicles. Using fluorescently detectable doxorubicin hydrochloride (DOX·HCl) as the model drug, a significant acceleration of drug release regulated by glutathione (GSH) was found (>3-fold difference). Upon incubation of the DOX·HCl-loaded polymeric vesicles with the HeLa cervical cancer cell line exposed to glutathione, an enhanced nuclear accumulation of DOX·HCl was observed, elicited by the preferred disassembly of the vesicle structure under reducing conditions. Importantly, by using the gemcitabine hydrochloride (GC·HCl)-resistant breast cancer cell line MDA-MB-231, it was found that cell viability was significantly reduced after treatment with GC·HCl-loaded polymeric vesicles, indicating that these vesicles can help to reverse the drug resistance

    Cleavable PEGylation and Hydrophobic Histidylation of Polylysine for siRNA Delivery and Tumor Gene Therapy

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    Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub>) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine­(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis

    “Minimalist” Nanovaccine Constituted from Near Whole Antigen for Cancer Immunotherapy

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    One of the major challenges in vaccine design has been the over dependence on incorporation of abundant adjuvants, which in fact is in violation of the “minimalist” principle. In the present study, a compact nanovaccine derived from a near whole antigen (up to 97 wt %) was developed. The nanovaccine structure was stabilized by free cysteines within each antigen (ovalbumin, OVA), which were tempospatially exposed and heat-driven to form an extensive intermolecular disulfide network. This process enables the engineering of a nanovaccine upon integration of the danger signal (CpG-SH) into the network during the synthetic process. The 50 nm-sized nanovaccine was developed comprising approximately 500 antigen molecules per nanoparticle. The nanovaccine prophylactically protected 70% of mice from tumorigenesis (0% for the control group) in murine B16-OVA melanoma. Significant tumor inhibition was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes. This strategy can be adapted for the future design of vaccine for a minimalist composition in clinical settings
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