siRNA-Loaded Polyion Complex Micelle Decorated with Charge-Conversional Polymer Tuned to Undergo Stepwise Response to Intra-Tumoral and Intra-Endosomal pHs for Exerting Enhanced RNAi Efficacy
| Autor: | Yoshinori Maeda, Kanjiro Miyata, Nobuhiro Nishiyama, Hyun Jin Kim, Mitsuru Naito, Ryota Azuma, Jooyeon Ahn, Montira Tangsangasaksri, Kazunori Kataoka, Hiroyasu Takemoto, Daiki Sueyoshi, Yutaka Miura |
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| Rok vydání: | 2015 |
| Předmět: |
Small interfering RNA
Lung Neoplasms Polymers and Plastics Polymers Endosome Stereochemistry Bioengineering 02 engineering and technology Transfection 010402 general chemistry 01 natural sciences Micelle Biomaterials chemistry.chemical_compound Cell Line Tumor Materials Chemistry Humans RNA Small Interfering Micelles Chemistry RNA Biological Transport Genetic Therapy Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology Endocytosis 0104 chemical sciences Cancer cell Click chemistry Biophysics Click Chemistry RNA Interference Peptides 0210 nano-technology Ethylene glycol |
| Zdroj: | Biomacromolecules. 17:246-255 |
| ISSN: | 1526-4602 1525-7797 |
| Popis: | Small interfering RNA (siRNA) needs an efficient delivery vehicle to reach the cytoplasm of target cells for successful RNA interference (RNAi) therapy. This study aimed to develop an siRNA-loaded polyion complex (PIC) micelle equipped with a smart polymeric shell featuring tumor targetability and endosome escapability for enhanced RNAi activity in cancer cells. To this end, an acidic pH-responsive polypeptide was designed to exert a stepwise change in its charged state from negative to modestly positive and highly positive in response to slightly acidic environment of tumor (pH ∼6.7) and further lowered-pH condition of late endosomal compartments (pH ∼5.0), respectively, for selective binding to cancer cell surface and subsequent endosome disruption. This polypeptide, termed PAsp(DET-CDM/DBCO), was synthesized by introducing acid-labile carboxydimethyl maleate (CDM) and dibenzylcyclooctyne (DBCO) moieties into a polyaspartamide derivative bearing two-repeated aminoethylene side chains (PAsp(DET)). Then, PAsp(DET-CDM/DBCO) was installed on the surface of disulfide cross-linked PIC micelles prepared from cholesterol-modified siRNA (Chol-siRNA) and azide-poly(ethylene glycol)-b-poly[(3-mercaptopropylamidine)-L-lysine] (N3-PEG-b-PLys(MPA)) through the copper-free click reaction. Successful PAsp(DET-CDM/DBCO) coverage of PIC micelles was confirmed by a significant decrease in ζ-potential as well as a narrowly distributed size of 40 nm. The PAsp(DET-CDM/DBCO)-installed micelles significantly improved the gene-silencing efficiency in cultured lung cancer cells, compared with nonmodified control micelles, especially after incubation at pH 6.7. This improved silencing activity was nicely correlated with the facilitated cellular uptake of siRNA payloads at the acidic pH and the efficient endosomal escape. These results demonstrate that the acidic pH-responsive polypeptide shell is a promising design strategy for tumor-targeted siRNA delivery. |
| Databáze: | OpenAIRE |
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