Maytansine (DM1), a powerful tubulin polymerization inhibitor, has superior anti-tumor activity toward multiple malignant tumors compared with most anti-tumor drugs including doxorubicin, camptothecin, and cabazitaxel in current clinical studies. Nevertheless, DM1 is hard to be accepted as a clinical drug, due to its systemic toxicity to the human body, no targeting and insolubility in aqueous solutions. In this work, a strategy, called PUFAylation with a polyunsaturated fatty acid (PUFA), is developed to modify DM1 to solve above problems by covalently coupling of DM1 and docosahexaenoic acid (DHA). Two types of PUFAylated prodrugs (i.e., dSS-DM1 and dMT-DM1) prepared through different linking strategies via thiol-disulfide exchange reaction and maleimide-thiol reaction, respectively, can self-assemble in aqueous solution to form nanoassemblies (NAs) for intravenous injection. In an xenograft model of cervical cancer, there were no significant weight loss in mouse groups treated with dSS-DM1 NAs and dMT-DM1 NAs. On the contrary, the mice with intravenous injection of free DM1 suffered a significant weight loss during the treatment, and the maximum reached ~21% on the fourth day of treatment. Furthermore, dMT-DM1 NAs exhibits similar anti-tumor effects to free DM1 (p&gt;0.05). Overall, the data show that by modifying chemotherapeutic drugs, the systemic toxicity and side effects can be effectively decreased without reducing their anti-tumor effect. This DM1-formulated platform may be further applied to other anticancer agents due to its simplicity.

Transforming a highly toxic agent into injectable safe nanomedicines via prodrug self-assembly for the treatment of taxane-resistant cancer

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.