Co-Delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-Responsive Star Polymer that Forms Unimolecular Micelles in Water

Abstract

Dual functional unimolecular micelles based on a pH-responsive amphiphilic star polymer β-CD-(PLA-b-PDMAEMA-b-PEtOxMA) 21 have been developed for the co-delivery of imiquimod and plasmid DNA to dendritic cells. The star polymer with well-defined triblock arms was synthesized by combining activator regenerated by electron-transfer atom-transfer radical polymerization with ring-opening polymerization. Dissipative particle dynamics simulation showed that core-mesophere-shell-type unimolecular micelles could be formed. Imiquimod-loaded micelles had a drug loading of 1.6 wt % and a larger average size (28 nm) than blank micelles (19 nm). The release of imiquimod in vitro was accelerated at the mildly acidic endolysosomal pH (5.0) in comparison to physiologic pH (7.4). Compared with blank micelles, a higher N:P ratio was required for imiquimod-loaded micelles to fully condense DNA into micelleplexes averaging 200-400 nm in size. In comparison to blank micelleplexes, imiquimod-loaded micelleplexes of the same N:P ratio displayed similar or slightly higher efficiency of gene transfection in a mouse dendritic cell line (DC2.4) without cytotoxicity. These results suggest that such pH-responsive unimolecular micelles formed by the well-defined amphiphilic star polymer may serve as promising nano-scale carriers for combined delivery of hydrophobic immunostimulatory drugs (such as imiquimod) and plasmid DNA with potential application in gene-based immunotherapy.

Development of novel self-assembled polymeric micelles from partially hydrolysed poly(2-ethyl-2-oxazoline)-co-PEI-b-PCL block copolymer as non-viral vectors for plasmid DNA in vitro transfection

“…These findings indicated that particle size of micelle/DNA complexes decreased gradually when the N/P ratio increased. Our results are compatible that increasing amount of cationic polymer caused more tight condensation with DNA that leads to small particles [1,24]. The largest particle size was observed at N/P ¼ 4 for PPP30 micelle/DNA complexes and at N/P ¼ 2 for PPP60 micelle/DNA complexes.…”

Nano‐Star‐Shaped Polymers for Drug Delivery Applications

“…Some typical signals include changes in temperature, irradiation with light, application of mechanical force, exposure to alternating electric or magnetic fields, and changes in chemical composition or pH of the external environment . In a parallel manner, recent advances in biomedicine have led to an increased interest toward controlled drug release which can be achieved with these star‐shaped polymer systems . Conventional methods of drug administration are nonspecific and they usually involve periodic application to the patients, raising the concentration of drug levels throughout the entire biological system.…”

Complex Polymeric Architectures Self-Assembling in Unimolecular Micelles: Preparation, Characterization and Drug Nanoencapsulation

“…β-cyclodextrin (CD) was also used as multivalent scaffold to build multi-arm block copolymers of poly-lactic acid (PLA), poly-2-(dimethylamino)ethyl methacrylate (PDMAEMA) and poly-oligo(2-ethyl-2-oxazoline)methacrylate (PEtOxMA) [78]. PDMAEMA, containing tertiary amines, made the polymers pH responsive.…”