RRC ID 33958
Author Dirisala A, Osada K, Chen Q, Tockary TA, Machitani K, Osawa S, Liu X, Ishii T, Miyata K, Oba M, Uchida S, Itaka K, Kataoka K.
Title Optimized rod length of polyplex micelles for maximizing transfection efficiency and their performance in systemic gene therapy against stroma-rich pancreatic tumors.
Journal Biomaterials
Abstract Poly(ethylene glycol) (PEG) modification onto a gene delivery carrier for systemic application results in a trade-off between prolonged blood circulation and promoted transfection because high PEG shielding is advantageous in prolonging blood retention, while it is disadvantageous with regard to obtaining efficient transfection owing to hampered cellular uptake. To tackle this challenging issue, the present investigation focused on the structure of polyplex micelles (PMs) obtained from PEG-poly(l-lysine) (PEG-PLys) block copolymers characterized as rod-shaped structures to seek the most appreciable formulation. Comprehensive investigations conducted with particular focus on stability, PEG crowdedness, and rod length, controlled by varying PLys segment length, clarified the effect of these structural features, with particular emphasis on rod length as a critical parameter in promoting cellular uptake. PMs with rod length regulated below the critical threshold length of 200 nm fully exploited the benefits of cross-linking and the cyclic RGD ligand, consequently, exhibiting remarkable transfection efficiency comparable with that of ExGen 500 and Lipofectamine(®) LTX with PLUS™ even though PMs were PEG shielded. The identified PMs exhibited significant antitumor efficacy in systemic treatment of pancreatic adenocarcinoma, whereas PMs with rod length above 200 nm exhibited negligible antitumor efficacy despite a superior blood circulation property, thereby highlighting the significance of controlling the rod length of PMs to promote gene transduction.
Volume 35(20)
Pages 5359-5368
Published 2014-7-1
DOI 10.1016/j.biomaterials.2014.03.037
PII S0142-9612(14)00284-1
PMID 24720877
MeSH Animals Cell Line, Tumor Female Flow Cytometry Gene Transfer Techniques Genetic Therapy / methods* HeLa Cells Humans Mice Mice, Inbred BALB C Micelles* Microscopy, Electron, Transmission Pancreatic Neoplasms / therapy* Peptides, Cyclic / metabolism Polyethylene Glycols / chemistry Polymers / chemistry Transfection / methods*
IF 10.273
Times Cited 28
DNA material pCAcc-Luc+ (RDB02443)