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.