Transmucosal drug delivery is a promising alternative to other more invasive delivery routes. Aside from the ease of administration and good patience compliance, transmucosal delivery offers improved drug bioavailability, increased therapeutic effects, and the possibility of targeting particular organs. The obstacle to effective transmucosal delivery starts with the mucosal barrier itself, as mucus is a complex viscoelastic gel that functions as a dynamic barrier to protect tissue from invasion by allergens, bacteria, and viruses. Two parameters only recently explored for mucus transport are particle shape and stiffness. Recent studies indicate synthetic rodlike nanoparticles exhibit coupled translational and rotational motion that increases their net transport within the mesh structure of mucus compared to spherical analogs. Herein, we discuss the use of zwitterionic bottlebrushes as a mucopenetrant delivery strategy. We have examined the mucopenetration of bottlbrushes with variable backbone length, side-chain length, backbone rigidity, and surface chemistry. These copolymers were synthesized through a combination of ring-opening, reversible addition−fragmentation chain-transfer (RAFT), and actovator regenerated by electron transfer atom transfer radical polymerizations (ARGET ATRP), as well as straightforward conjugation techniques. Characterization was done by DLS, SAXS, TEM, and confocal microscopy. The effects of the molecular properties of these bottlebrushes on their transport through mucus was evaluated using MUC5AC samples. Bottlebrushes were functionalized with boronic acids exhibiting different binding constants to evaluate their mucoadhesion. Additonally, we examined the role of pH and Ca<sup>2+</sup> on transport.

Zwitterionic bottlebrush copolymers for effective mucosal transport

ACS Spring 2022

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