化学
体内
化疗
癌症研究
肿瘤微环境
体外
生物标志物
毒性
下调和上调
内科学
肿瘤细胞
医学
生物化学
生物
生物技术
有机化学
基因
作者
Jenniffer Linares,Monica Varese,Anna Sallent-Aragay,Ana Méndez,Sergio Palomo-Ponce,Mar Iglesias,Eduard Batlle,Jorge Pisonero,Clara Montagut,Ernest Giralt,Daniele Lo Re,Alexandre Calon
标识
DOI:10.1021/acs.jmedchem.2c01717
摘要
The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantly lowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, a biomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-based therapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normal cells to improve drug development and patient care.
科研通智能强力驱动
Strongly Powered by AbleSci AI