4.7 Article

Balancing the efficacy vs. the toxicity of promiscuous natural products: Paclitaxel-based acid-labile lipophilic prodrugs as promising chemotherapeutics

期刊

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113891

关键词

Paclitaxel; Prodrugs; Leukopenia; Low-density lipoprotein; Xenograft; Transacetalization

资金

  1. Prompt Praxis Laboratories LLC, Vernon Hills

向作者/读者索取更多资源

TumorSelect (R) is a innovative anticancer technology that combines cytotoxics, nanotechnology, and knowledge of human physiology to deliver anticancer drugs specifically to tumor tissues with minimal side effects. By incorporating designer prodrugs into pseudo-LDL nanoparticles, the system can effectively inhibit cancer cell proliferation. The method shows promising results in both cell line screenings and in vivo tumor reduction efficacy studies.
TumorSelect (R) is an anticancer technology that combines cytotoxics, nanotechnology, and knowledge of human physiology to develop innovative therapeutic interventions with minimal undesirable side effects commonly observed in conventional chemotherapy. Tumors have a voracious appetite for cholesterol which facilitates tumor growth and fuels their proliferation. We have transformed this need into a stealth delivery system to disguise and deliver anticancer drugs with the assistance of both the human body and the tumor cell. Several designer prodrugs are incorporated within pseudo-LDL nanoparticles, which carry them to tumor tissues, are taken up, internalized, transformed into active drugs, and inhibit cancer cell proliferation. Highly lipophilic prodrug conjugates of paclitaxel suitable for incorporation into the pseudo-LDL nanoparticles of the TumorSelect (R) delivery vehicle formulation were designed, synthesized, and evaluated in the panel of 24-h NCI-60 human tumor cell line screening to demonstrate the power of such an innovative approach. Taxane prodrugs, viz., ART-207 was synthesized by tethering paclitaxel to lipid moiety with the aid of a racemic solketal as a linker in cost-effective, simple, and straightforward synthetic transformations. In addition to the typical 24-h NCI screening protocol, these compounds were assessed for growth inhibition or killing of ovarian cell lines for 48 and 72h-time intervals and identified the long-lasting effectiveness of these lipophilic prodrugs. All possible, enantiomerically pure isomers of ART-207 were also synthesized, and cytotoxicities were biosimilar to racemic ART-207, suggesting that enantiopurity of linker has a negligible effect on cell proliferation. To substantiate further, ART-207 was evaluated for its in vivo tumor reduction efficacy by studying the xenograft model of ovarian cancer grown in SCID mice. Reduced weight loss (a measure of toxicity) in the ART-207 group was observed, even though it was dosed at 2.5x the paclitaxel equivalent of Abraxane (R). As a result, our delineated approach is anticipated to improve patient quality of life, patient retention in treatment regimes, post-treatment rapid recovery, and overall patient compliance without compromising the efficacy of the cytotoxic promiscuous natural products. (C) 2021 Elsevier Masson SAS. All rights reserved.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据