Purification-Free Bortezomib-Drug Conjugates Optimize Drug Economy and Cancer Therapeutic Synergy

As a promising candidate in overcoming resistance, providing synergy, and developing treatments, conjugated combination drugs mostly prevail over drug cocktails in establishing prodrugs and precisely codelivering multiple drugs for combination chemotherapies. However, current drug-drug conjugation methods (e.g., esterification, amidation, etherification, etc.) do not allow quantitative drug conversion and require necessary purification of crude products, resulting in a limited economy of initial drugs. Meanwhile, practical stimulus concentration in vivo usually fails to efficiently activate parent drug release from drug conjugates in target sites, which diminishes their efficacy. Herein, we report a click conjugation strategy based on boronic acid-cis diol complexation, realizing a fast (<30 min), quantitative, and purification-free conjugation of bortezomib (BTZ) and azacytidine (AZA) or capecitabine or doxifluridine. Notably, the BTZ-AZA conjugate spontaneously self-assembles into nanomedicine and exhibits enhanced synergistic efficacy. Furthermore, BTZ and AZA could be conjugated into a polyprodrug with controlled size and composition, and different organelle uptakes augment the synergy of BTZ-AZA conjugate by approximately 1000-fold versus free BTZ toward A549 adenocarcinoma cells (IC₅₀: 0.55 nM versus 536.7 nM). This click strategy would expand the vision for developing smart combination drugs.