Journal
ACTA BIOMATERIALIA
Volume 9, Issue 8, Pages 7746-7757Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2013.04.031
Keywords
Reduction-sensitive; Disulfide; Polycation-detachable; Nanoparticles; siRNA delivery
Funding
- National High Technology Research and Development Program of China (863) [2012AA022501]
- National Natural Science Foundation of China [31271073, 81273422]
- Department of Education of China [20090001110052]
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Long circulation, cell internalization, endosomal escape and small interfering RNA (siRNA) release to the cytoplasm are the prerequisite considerations for siRNA delivery vectors. Herein, a kind of sheddable nanoparticles (NPs) with micelle architecture for siRNA delivery were fabricated by using an intracellular-activated polycation-detachable copolymer (PECssD), which was prepared by introducing highly reducing environment-responsive disulfide linkages between PEGylated polycaprolactone (PCL) and the grafted polycation, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). The architecture of PECssD self-assembled NPs includes a biodegradable hydrophobic PCL core, a PEG shield and a detachable comb-like polycation surface. The stable nanosized complexes of PECssD NPs with siRNA, termed PECssD/siRNA micelleplexes, were formed, which could prolong circulation, improve accumulation and retention in tumor tissue, and be favorable for internalization. In particular, the cleavage of the disulfide linkages in the intracellular microenvironment and the subsequent dissociation of the PDMAEMA/siRNA polyplexes from the PEGylated PCL cores of PECssD/siRNA micelleplexes were also confirmed, which facilitated the endosomal escape and the efficient release of siRNA. As a result, the distribution of siRNA in cytoplasm was enhanced and subsequently promoted the efficiency of siRNA in gene silencing. Furthermore, systemic administration of the NPs carrying siPlk1 (polo-like kinase 1 specific siRNA) induced a tumor-suppressing effect in the HeLa-Luc xenograft murine model. Therefore, the devised strategy of the polycation-detachable copolymer PECssD NPs could address the requirements of the multistep systemic delivery process of siRNA. The hydrophobic core of the PECssD/siRNA micelleplexes is expected to entrap antitumor drugs or other therapeutic agents for combined therapies. (C) 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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