Rational Design of a New Class of Cyclodextrin-Containing Polymers for Gene Delivery
TL;DRAbstract
The transfer of gene therapy from an academic exercise to a clinical setting demands the development of an efficient, biocompatible gene delivery vector. Current non-viral systems suffer from toxicity, low transfection efficiency, and in vivo instability. In this work, a new class of polymers was designed to address these issues. Linear, polyamidine, β-cyclodextrin (βCD)-containing polymers (βCDPs) are synthesized by polymerizing difunctionalized cyclodextrins with other difunctionalized comonomers. The inclusion of βCD in the backbone of the polyamidine polymers decreases the IC₅₀s by three orders of magnitude, resulting in a polymer with very low in vitro and in vivo toxicity. The cationic βCDPs are able to self-assemble with and condense DNA into small particles (100-150 nm in diameter). When formulated at a positive charge, the complexes are readily internalized by nearly all exposed cultured cells. The transgene expression from the delivered complexes was increased by fine-tuning
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The transfer of gene therapy from an academic exercise to a clinical setting demands the development of an efficient, biocompatible gene delivery vector. Current non-viral systems suffer from toxicity, low transfection efficiency, and in vivo instability. In this work, a new class of polymers was designed to address these issues. Linear, polyamidine, β-cyclodextrin (βCD)-containing polymers (βCDPs) are synthesized by polymerizing difunctionalized cyclodextrins with other difunctionalized comonomers. The inclusion of βCD in the backbone of the polyamidine polymers decreases the IC₅₀s by three orders of magnitude, resulting in a polymer with very low in vitro and in vivo toxicity. The cationic βCDPs are able to self-assemble with and condense DNA into small particles (100-150 nm in diameter). When formulated at a positive charge, the complexes are readily internalized by nearly all exposed cultured cells. The transgene expression from the delivered complexes was increased by fine-tuning
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