Antibody-bottlebrush conjugates (ABCs) offer unique advantages for targeted cancer therapy. An ABC consists of a tumor-targeting antibody conjugated to a bottlebrush polymer. Each “bristle” of the bottlebrush is covalently conjugated to a chemotherapeutic drug molecule via a cleavable linker, followed by a PEG chain to shield the drug molecule from premature release. This design minimizes off-target effects, enabling ABCs to deliver a larger number of drug molecules than is possible using currently approved antibody-drug conjugates (ADCs). However, current ABC research does not address the need for sustained-release versions of ABC therapies. We are systematically optimizing linker chemistry to create sustained-release bottlebrushes. Here, we investigate whether modulating linker release kinetics by fine-tuning aromatic substituents and functional groups can be used to achieve multiple drug release rates within a single ABC. Once developed for clinical application, sustained-release ABC therapies may reduce treatment frequency, boosting accessibility and patient outcomes.

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