Prodrug Nanomedicine Inhibits Chemotherapy-Induced Proliferative Burst by Altering the Deleterious Intercellular Communication.
Yanting YuKeqi XiangMingzhi XuYuqiang LiJiajunzi CuiLanqiong ZhangXiaohu TangXianqi ZhuLili QianMeng ZhangYan YangQingsong YuYou-Qing ShenZhihua GanPublished in: ACS nano (2021)
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.
Keyphrases
- drug resistant
- drug induced
- induced apoptosis
- multidrug resistant
- liver injury
- acinetobacter baumannii
- high frequency
- cell cycle arrest
- cancer therapy
- signaling pathway
- chemotherapy induced
- stem cells
- healthcare
- high glucose
- endoplasmic reticulum stress
- gene expression
- radiation therapy
- genome wide
- oxidative stress
- cell therapy
- pseudomonas aeruginosa
- emergency department
- pi k akt
- bone marrow
- mesenchymal stem cells
- endothelial cells
- adverse drug
- combination therapy
- replacement therapy
- rectal cancer