Molecular Bottlebrush Prodrugs as Next-Generation Mono and Triplex Combination Therapies for Multiple Myeloma

Current anticancer agents suffer from narrow therapeutic indexes and suboptimal therapeutic combinations stemming from mixtures of drugs with dissimilar physical properties. Nanomedicine platforms for drug delivery could address these challenges but it remains unclear whether synergistic free drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here, we report a bottlebrush prodrug (BPD) platform to answer these questions in the context of multiple myeloma (MM) therapy. We show that a bortezomib-based BPD monotherapy slows tumor progression in vivo and that mixtures of bortezomib, pomalidomide, and dexamethasone BPDs exhibit in vitro synergistic, additive, or antagonistic patterns distinct from the free drug counterparts. BPDs carrying a statistical mixture of 3 drugs in a synergistic ratio outperform the free drug combination at the same ratio and a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line mono- and combination therapies for MM.