Prodrug Nanomedicine Inhibits Chemotherapy-Induced Proliferative Burst by Altering the Deleterious Intercellular Communication

Chemotherapy is one of the most commonly used clinical antitumor strategies. However, the therapy-induced proliferative burst, which always accompanies drug resistance and metastasis, has become a major obstacle during treatment. Except for some endogenous cellular or genetic mechanisms and some microenvironmental selection pressures, the intercellular connections in the tumor microenvironment (TME) are also thought to be the driving force for the acquired drug resistance and proliferative burst. Even though some pathway inhibitors or cell exempting strategies could be applied to partially avoid these unwanted communications, the complexity of the TME and the limited knowledge about those unknown detrimental connections might greatly compromise the efforts. Therefore, a more broad-spectrum strategy is urgently needed to relieve the drug-induced burst proliferation during various treatments. In this article, based on the possible discrepancies in metabolic activity between cells with different growth rates, several ester-bond-based prodrugs were synthesized. After screening, 7-ethyl-10-hyodroxycamptothecin-based prodrug nanoparticles were found to efficiently overcome the paclitaxel resistance, to selectively act on the malignantly proliferated drug-resistant cells and, furthermore, to greatly diminish the proliferative effect of common cytotoxic agents by blocking the detrimental intercellular connections. With the discriminating ability against malignant proliferating cells, the as-prepared prodrug nanomedicine exhibited significant anticancer efficacy against both drug-sensitive and drug-resistant tumor models, either by itself or by combining with highly potent nonselective chemotherapeutics. This work provides a different perspective and a possible solution for the treatment of therapy-induced burst proliferation.