RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells.
Bo Lou
Kate Connor
Kieron Sweeney
Ian S. Miller
Alice C. O'Farrell
Eduardo Ruiz-Hernandez
David M. Murray
Garry P. Duffy
Alan Wolfe
Enrico Mastrobattista
Annette Byrne
Wim E. Hennink
10779/rcsi.10790522.v1
https://repository.rcsi.com/articles/journal_contribution/RGD-decorated_cholesterol_stabilized_polyplexes_for_targeted_siRNA_delivery_to_glioblastoma_cells_/10790522
<p>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 (~ 40 nm) 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.</p>
2019-11-22 16:55:41
Cancer targeting; Cholesterol modification; Glioblastoma; cRGD peptide; siRNA delivery
Physiology
Medical Physics