Effects of Structure of β-Cyclodextrin-Containing Polymers on Gene Delivery
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Abstract
Linear cationic beta-cyclodextrin-based polymers (betaCDPs) are capable of forming polyplexes with nucleic acids and transfecting cultured cells. The betaCDPs are synthesized by the condensation of a diamino-cyclodextrin monomer A with a diimidate comonomer B. In this paper, the effects of polymer structure on polyplex formation, in vitro transfection efficiency and toxicity are elucidated. By comparison of the betaCDPs to polyamidines lacking cyclodextrins, the inclusion of a cyclodextrin moiety in the comonomer A units reduces the IC50s of the polymer by up to 3 orders of magnitude. The spacing between the cationic amidine groups is also important. Different polymers with 4, 5, 6, 7, 8, and 10 methylene units (betaCDP4, 5, 6, 7, 8, and 10) in the comonomer B molecule are synthesized. Transfection efficiency is dependent on comonomer B length with up to 20-fold difference between polymers. Optimum transfection is achieved with the betaCDP6 polymer. In vitro toxicity varied by 1 order of magnitude and the lowest toxicity is observed with betaCDP8. The LD40 of the betaCDP6 to mice is 200 mg/kg, making this polymer a promising agent for in vivo gene delivery applications.
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