A cationic supramolecular system based on host–guest pseudoblock copolymers was developed for nonviral DNA delivery. In this system, the macromolecular host was a cationic star-shaped polymer composed of a β-cyclodextrin (β-CD) core and multiple poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chains grafted on the core, while the macromolecular guest was a linear adamantyl-ended poly(ethylene glycol) (mPEG-Ad). Pseudoblock copolymers were self-assembled from the polymeric host–guest pairs (typically, 1:1 molar ratio) in aqueous media through the inclusion of an adamantyl group at the end of guest polymer into the β-CD cavity of host polymers. Through such an approach, the resultant supramolecular system was integrated with not only a superior DNA condensing ability due to the host polymer but also an outstanding polyplex-stabilizing ability as well as biocompatibility due to the guest polymer. The cationic star-shaped host polymers alone were capable of condensing plasmid DNA efficiently into nanoparticles (70–100 nm) with positive surface charge. They showed obviously lower cytotoxicity than PEI 25K (commercial branched polyethylenimine with a molecular weight around 25 kDa) in cell lines of L929, MB231, and Hela under high dose. In serum-free or serum-containing culture conditions, these host polymers exhibited either higher or lower in vitro DNA transfection efficiency as compared with PEI 25K in the three cell lines under study, which was dependent on the N/P ratios and PDMAEMA arm length. Upon incorporation of the PEG block through host–guest complexation with mPEG-Ad (i.e., supramolecular PEGylation), the resulting host–guest supramolecular systems exhibited even lower cytotoxicity than the host polymers alone. The polyplexes between plasmid DNA (pDNA) and the host–guest systems showed significantly improved stability in BSA-PBS buffer solution (pH 7.4) and enhanced in vitro DNA transfection efficiency in the cases of higher N/P ratios or longer PDMAEMA arms in all tested cell lines under both serum-free and serum-containing culture conditions, as compared with the corresponding polyplexes without supramolecular PEGylation. Further, through forming pseudoblock copolymer, the DNA transfection ability of the supramolecular system can be easily modulated and optimized either by changing the ratio between the guest and host or by using different hosts with varied PDMAEMA arm lengths.
Zhongxing Zhang, Yuting Wen, Xia Song, Jingling Zhu, and Jun Li* (2021) Nonviral DNA Delivery System with Supramolecular PEGylation Formed by Host–Guest Pseudo-Block Copolymers. ACS Appl. Bio Mater.
Publication Date:June 1, 2021