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Polymeric micelles with dual thermal and reactive oxygen species (ROS)-responsiveness for inflammatory cancer cell delivery.

ABSTRACT: The object of this study was to develop a thermally and reactive oxygen species-responsive nanocarrier system for cancer therapy.PPS-PNIPAm block copolymer was designed and synthesised using a combination of living anionic ring-opening polymerization and atom transfer radical polymerization. The synthesized polymer formed micellar aggregates in water and demonstrated dual responsiveness towards temperature and oxidants. Using doxorubicin (DOX) as a model drug, encapsulation and in vitro release of the drug molecules in PPS-PNIPAm nanocarriers confirmed the responsive release properties of such system. Cell uptake of the DOX loaded micelles was investigated with human breast cancer cell line (MCF-7). The results showed Dox-loaded micelles were able to be taken by the cells and mainly reside in the cytoplasma. In the stimulated cells with an elevated level of ROS, more released DOX was observed around the nuclei. In the cytotoxicity experiments, the Dox-loaded micelles demonstrated comparable efficacy to free DOX at higher concentrations, especially on ROS stimulated cells.These results demonstrated that PPS-PNIPAm nanocarriers possess the capability to respond two typical stimuli in inflammatory cells: temperature and oxidants and can be used in anticancer drug delivery.

SUBMITTER: Tang M

PROVIDER: S-EPMC5434630 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Polymeric micelles with dual thermal and reactive oxygen species (ROS)-responsiveness for inflammatory cancer cell delivery.

Tang Meiqiong M Hu Ping P Zheng Qiang Q Tirelli Nicola N Yang Xiaohong X Wang Zhanlong Z Wang Yanfang Y Tang Qing Q He Yun Y

Journal of nanobiotechnology 20170516 1

<h4>Background</h4>The object of this study was to develop a thermally and reactive oxygen species-responsive nanocarrier system for cancer therapy.<h4>Results</h4>PPS-PNIPAm block copolymer was designed and synthesised using a combination of living anionic ring-opening polymerization and atom transfer radical polymerization. The synthesized polymer formed micellar aggregates in water and demonstrated dual responsiveness towards temperature and oxidants. Using doxorubicin (DOX) as a model drug, ...[more]

PMID: 28511687

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Project description:RNA interference (RNAi) drugs have significant therapeutic potential, but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions and a second ampholytic block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization with an overall molecular weight of 22 000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL, respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90% mRNA knockdown and 65% protein knockdown at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility of this carrier design for delivering therapeutic siRNA drugs.

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Polymeric micelles with dual thermal and reactive oxygen species (ROS)-responsiveness for inflammatory cancer cell delivery.

Publications

Polymeric micelles with dual thermal and reactive oxygen species (ROS)-responsiveness for inflammatory cancer cell delivery.

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