title: Influence of nano-carrier architecture on in vitro siRNA delivery performance and in vivo biodistribution: polyplexes vs micelleplexes.
abstract: Micelle-based siRNA carriers ("micelleplexes") were prepared from the A-B-C triblock copolymer poly(ethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA), and their in vitro performance and in vivo biodistribution properties were compared with the benchmark PEGylated and basic polycation systems PEG-PDMAEMA and PDMAEMA, respectively. The micelle architecture, incorporating increased PEG shielding and a larger particle size (∼50 nm) than polycation-based complexes (polyplexes; ∼10 nm), enhances siRNA delivery performance in two important aspects: in vitro gene silencing efficiency and in vivo tumor accumulation. The in vitro gene silencing efficiency of the micelleplexes (24% in HeLa cells) was significantly better than the statistically insignificant levels observed for PDMAEMA and PEG-PDMAEMA polyplexes under identical conditions. This enhancement is linked to the different mechanisms by which micelleplexes are internalized (i.e., caveolar, etc.) compared to PDMAEMA and PEG-PDMAEMA polyplexes. Folate-functionalization significantly improved micelleplex uptake but had negligible influence on gene-silencing efficiency, suggesting that this parameter is not limited by cellular internalization. In vivo biodistribution analysis revealed that siRNA delivered by micelleplexes was more effectively accumulated and retained in tumor tissues than that delivered by PEGylated polyplexes. Overall, the micelle particle size and architecture appear to improve in vitro and in vivo delivery characteristics without significantly changing other properties, such as cytotoxicity and resistance to enzymes and dissociation. The self-assembled nature of micelleplexes is expected to enable incorporation of imaging modalities inside the hydrophobic micelle core, thus combining therapeutic and diagnostic capabilities. The findings from the present study suggest that the micelleplex-type carrier architecture is a useful platform for potential theranostic and tumor-targeting applications.
authors: School of Chemical Engineering, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Dana J
authors: DJ
authors: Gary
authors: Hoyoung
authors: H
authors: Lee
authors: Rahul
authors: R
authors: Sharma
authors: Jae-Sung
authors: JS
authors: Lee
authors: Youngwook
authors: Y
authors: Kim
authors: Zheng Yun
authors: ZY
authors: Cui
authors: Di
authors: D
authors: Jia
authors: Valorie D
authors: VD
authors: Bowman
authors: Paul R
authors: PR
authors: Chipman
authors: Lei
authors: L
authors: Wan
authors: Yi
authors: Y
authors: Zou
authors: Guangzhao
authors: G
authors: Mao
authors: Keunchil
authors: K
authors: Park
authors: Brittney-Shea
authors: BS
authors: Herbert
authors: Stephen F
authors: SF
authors: Konieczny
authors: You-Yeon
authors: YY
authors: Won
mesh_terms: D000818:Animals; D020868:Gene Silencing / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008422:Materials Testing; D051379:Mice; D008823:Micelles; D053769:Nanocapsules / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D014018:Tissue Distribution
chemical_list: D008823:Micelles; D053769:Nanocapsules; D034741:RNA, Small Interfering