A Proximity-Driven Neighbor Effect in the Degradation of PLA/PLGA Bottlebrush Copolymers

Abstract Tuning the degradation profile of resorbable polymers is a longstanding goal in materials design. Bottlebrush copolymers (BBCs) offer an additional handle, relative to linear polymers, which is the spatial arrangement of chemically distinct sidechains along a common backbone. We report that backbone sequence modulates the sidechain degradation rate in BBCs bearing poly(lactic acid) (PLA) and/or poly(lactic-co-glycolic acid) (PLGA, 50/50 L:G) sidechains. Using a grafting-through strategy with vinyl-terminated PLA and PLGA macromonomers, we prepared BBCs of matched overall composition but distinct sidechain distributions: random, alternating, gradient, and diblock. Hydrolytic degradation was tracked by 1H NMR spectroscopy, size-exclusion chromatography, and multi-angle light scattering. The architectures exhibit sequence-dependent PLA degradation rates in the order diblock < gradient < (random ≈ alternating), with random and alternating profiles indistinguishable within experimental error. This ordering is consistent with a neighboring effect wherein greater PLGA-PLA proximity accelerates PLA degradation. The finding that the random and alternating BBCs share a degradation profile despite different local adjacencies indicates that the effect is regional, set by the fraction of nearby fast-cleaving PLGA rather than by direct neighbor identity. Sidechain arrangement along the backbone is therefore a distinct handle for tuning hydrolytic degradation, alongside composition, molecular weight, stereochemistry, and microstructure.