Journal
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
Volume 9, Issue 3, Pages 679-693Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s13346-019-00637-y
Keywords
Cancer targeting; siRNA delivery; Glioblastoma; cRGD peptide; Cholesterol modification
Funding
- China Scholarship Council (CSC)
- Science Foundation Ireland Technology Innovation Award [15/TIDA/2963]
- GLIOTRAIN award, a Horizon 2020 Research and Innovation program under the Marie Sklodowska-Curie ETN initiative [766069]
- Science Foundation Ireland (SFI) [15/TIDA/2963] Funding Source: Science Foundation Ireland (SFI)
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The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (similar to 40nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.
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