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Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance.

ABSTRACT: As an alternative to cell specific cancer targeting strategies (which are often afflicted with the heterogeneity of cancer cells as with most biological systems), a novel polymeric micelle constitute of two block copolymers of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine)-TAT (transactivator of transcription) and poly(L-histidine)-b-poly(ethylene glycol) was developed. The micelle formed via the dialysis method was approximately 95 nm in diameter and contained 15 wt.% of doxorubicin (DOX) by weight. The micelle surface hides TAT during circulation, which has the strong capability to translocate the micelle into cells, and exposes TAT at a slightly acidic tumor extracellular pH to facilitate the internalization process. The micelle core was engineered for disintegration in early endosomal pH of tumor cells, quickly releasing DOX. The ionization process of the block copolymers and ionized polymers assisted in disrupting the endosomal membrane. This processes permitted high DOX concentrations in the cytosol and its target site of the nucleus, thus increasing DOX potency in various wild and multidrug resistant (MDR) cell lines (3.8-8.8 times lower IC50 than free DOX, depending on cell line). When tested with the xenografted tumors of human ovarian tumor drug-resistant A2780/AD, human breast tumor drug-sensitive MCF-7, human lung tumor A549 and human epidermoid tumor KB in a nude mice model, all tumors significantly regressed in size by three bolus injections at a dose of DOX 10 mg equivalent/kg body per injection of DOX-loaded micelle at three day interval, while minimum weight loss was observed. This approach may replace the need for cell-specific antibodies or targeting ligands, thereby providing a general strategy for solid tumor targeting.

SUBMITTER: Lee ES

PROVIDER: S-EPMC2603624 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance.

Lee Eun Seong ES Gao Zhonggao Z Kim Dongin D Park Kyeongsoon K Kwon Ick Chan IC Bae You Han YH

Journal of controlled release : official journal of the Controlled Release Society 20080509 3

As an alternative to cell specific cancer targeting strategies (which are often afflicted with the heterogeneity of cancer cells as with most biological systems), a novel polymeric micelle constitute of two block copolymers of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine)-TAT (transactivator of transcription) and poly(L-histidine)-b-poly(ethylene glycol) was developed. The micelle formed via the dialysis method was approximately 95 nm in diameter and contained 15 wt.% of doxoru ...[more]

PMID: 18539355

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Project description:The ability of small interfering RNA (siRNA) to efficiently silence the expression of specific genes provides the basis for exciting new therapies based on RNA interference (RNAi). The efficient intracellular delivery of siRNA from cell uptake through the endosomal trafficking pathways into the cytoplasm remains a significant challenge. Previously we described the synthesis of a new family of diblock copolymer siRNA carriers using controlled reversible addition-fragmentation chain transfer (RAFT) polymerization. The carriers were composed of a positively charged block of dimethylaminoethyl methacrylate (DMAEMA) to mediate siRNA binding and a second pH-responsive endosome releasing block composed of DMAEMA and propylacrylic acid (PAA) in roughly equimolar ratios and butyl methacylate (BMA). Here we describe the development of a new generation of siRNA delivery polymers based on this design that exhibit enhanced transfection efficiency and low cytotoxicity. This design incorporates a longer endosomolytic block with increased hydrophobic content to induce micelle formation. These polymers spontaneously form spherical micelles in the size range of 40 nm with CMC (critical micelle concentration) values of approximately 2 μg/mL based on dynamic light scattering (DLS), (1)H NMR, electron microscopy, and selective partitioning of the small molecule pyrene into the hydrophobic micelle core. The siRNA binding to the cationic shell block did not perturb micelle stability or significantly increase particle size. The self-assembly of the diblock copolymers into particles was shown to provide a significant enhancement in mRNA knockdown at siRNA concentrations as low as 12.5 nM. Under these conditions, the micelle-based systems showed an 89% reduction in GAPDH mRNA levels as compared to only 23% (10 nM siRNA) for the nonmicelle system. The reduction in mRNA levels becomes nearly quantitative as the siRNA concentration is increased to 25 nM and higher. Flow cytometry analysis of fluorescent-labeled siRNA showed uptake in 90% of cells and a 3-fold increase in siRNA per cell compared to a standard lipid transfection agent. These results demonstrate the potential utility of this carrier design for siRNA drug delivery.

Dataset Information

Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance.

Publications

Super pH-sensitive multifunctional polymeric micelle for tumor pH(e) specific TAT exposure and multidrug resistance.

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