Bottlebrush macromolecules have emerged as a versatile tool in a wide range of applications such as drug delivery, imaging and self-assembly. Herein, we demonstrate a facile strategy to synthesize a phosphodiester-backboned bottlebrush polymer as a carrier for oligonucleotides drugs. The backbone of the polymer is synthesized via stepwise solid-phase synthesis, which also constructs the therapeutic oligonucleotide portion of the conjugate. Bottlebrush-type structures are formed via a graft-onto methodology using a two-step process with near quantitative efficiency (~95%). The resulting bottlebrushes exhibited very long blood circulation times and high bioavailability. A thrombin-binding aptamer (TBA) was selected to demonstrate the ex vivo and in vivo efficacy of the bottlebrush-oligonucleotide conjugate. Our results show that the bottlebrush structure does not affect the binding affinity of TBA. Furthermore, due to the improved retention in blood, bottlebrush-TBA conjugates exhibit a stronger anticoagulating effect and for longer duration compared with unmodified TBA. We envision that this novel bottlebrush polymer will provide safer and translatable routes for a range of oligonucleotide drug modalities.

Novel phosphodiester-backboned bottlebrush polymers for improved aptamer activity in vivo

ACS Spring 2022

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