Revival of a Potent Therapeutic Maytansinoid Agent using a Strategy that Combines Covalent Drug Conjugation with Sequential Nanoparticle Assembly

Publication date: Available online 13 December 2018Source: International Journal of PharmaceuticsAuthor(s): Ke Xie, Shanshan Song, Liqian Zhou, Jianqin Wan, Yiting Qiao, Min Wang, Haiyang Xie, Lin Zhou, Shusen Zheng, Hangxiang WangAbstractMaytansine and its related analogues are a class of highly potent anti-proliferation agents that have failed to be exploited as clinical drugs for human therapy due to unacceptable systemic toxicity. Here, we delineate a novel strategy that combines rational drug conjugation with subsequent nanoparticle assembly to systemically deliver this highly potent and toxic drug. To demonstrate this concept, we covalently coupled the thiolated maytansine derivative, the DM1 agent, to amphiphilic block co-polymers, polyethylene glycol (PEG)-block-polylactide (PLA), in varying molecular weights to generate two prodrug constructs (i.e., PEG2K-PLA2K-DM1 and PEG2K-PLA4K-DM1) via the maleimide-thiol reaction. The resulting two constructs are amenable to self-assembly in aqueous solutions and are systemically injectable for preclinical studies. In vivo evaluations indicate that PEG-PLA-DM1 conjugate-assembled nanoparticles (NPs) display substantially reduced drug toxicity compared to the free drug forms and NPs that physically encapsulate DM1. Furthermore, following systemic administration, these nanodrugs produced superior therapeutic efficacy over free DM1 in a colon tumor xenograft-bearing mouse model. Therefore, this study provides evidence that the conj...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research