Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) bottlebrush copolymer excipients have recently been shown to have great potential as unimolecular vehicles for the non-covalent sequestration and solubilization of model small-molecule therapeutics. In this talk, we will elucidate the performance of bottlebrush polymer excipients compared to common linear polymer excipients (hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone vinyl acetate, and linear PND) with an orally administered selective estrogen receptor degrader, GDC-0810, with proven efficacy against tamoxifen resistant, estrogen receptor positive breast cancers. The superior performance of bottlebrush copolymers over linear copolymer analogues has previously been attributed to the synthetically-fixed density of bottlebrush polymer side-chains and the ability to modulate the functional groups decorating the exterior of the bottlebrush copolymer using post-polymerization modification. Herein, we further characterize the differences between the solubilization mechanisms of linear and bottlebrush excipients using dynamic light scattering and cryogenic transmission electron microscopy linking drug-loaded solution structures to performance. Beyond solubility enhancement, by synthetically controlling the surface functionality of unimolecular drug-loaded micelle-like nanoparticles, we investigated how mucoadhesive versus non-mucoadhesive end-groups affected the delivery of GDC-0810 with in vivo studies. A thorough understanding of excipient-drug interactions in vitro and in vivo will be key to optimize the sequestration, solubilization, and delivery of future impactful active payloads.

Bottlebrush polymer excipients to improve the solubility and delivery of an orally administered breast cancer therapeutic

ACS Fall 2021

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