title: Structure-based rational design of prodrugs to enable their combination with polymeric nanoparticle delivery platforms for enhanced antitumor efficacy.
abstract: Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.
authors.affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003 (PR China).
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Wang
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.forename: Jiaping
authors.initials: J
authors.lastname: Wu
authors.forename: Xuyong
authors.initials: X
authors.lastname: Wei
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004337:Drug Carriers; D000077146:Irinotecan; D046529:Microscopy, Electron, Transmission; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin
keywords: SN-38; antitumor activity; drug delivery; nanoparticles; prodrugs