Bottlebrush polymers with flexible enantiomeric side chains display differential biological properties

Abstract

Chirality and molecular conformation are central components of life: from the genetic code and its inheritance mechanisms to cell surface receptors and trafficking pathways, biological systems rely on stereospecific interactions between discrete (macro)molecular conformers. As a result, drug discovery efforts shifted long ago from the use of racemates to the design of stereoselective syntheses, resolutions, etc. that provided molecules with improved target specificity and reduced off-site toxicity. Nevertheless, the impacts of chirality and conformation on the biological properties of synthetic macromolecules (i.e., polymers) has received comparably little attention, likely due to the significant synthetic challenges posed by such systems. Herein, we introduce a strategy that leverages iterative exponential growth (IEG) and ring-opening metathesis polymerization (ROMP) to produce water-soluble, chiral bottlebrush copolymers (CBPs) from discrete macromonomers (MMs) of varying absolute configurations and conformational rigidities. Molecular dynamics (MD) simulations, circular dichroism (CD) spectroscopy, and small-angle neutron scattering (SANS) show that the spacing between hydroxyl groups on IEG-synthesized MMs inversely correlates with conformational rigidity; moreover, the conformational preferences of MMs are translated to CBPs upon ROMP. Stereochemistry and rigidity are shown to significantly impact the properties of CBPs in an array of biological assays, including cell uptake, membrane rupture potential, blood pharmacokinetics, and biodistribution. This work provides a route to the synthesis of chiral nanostructure polymers and suggests key roles for chirality and conformational rigidity in the design of future biomaterials