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Structure‐Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy
Author(s) -
Wang Hangxiang,
Xie Haiyang,
Wu Jiaping,
Wei Xuyong,
Zhou Lin,
Xu Xiao,
Zheng Shusen
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201406685
Subject(s) - prodrug , rational design , drug delivery , ethylene glycol , lipophilicity , nanoparticle , combinatorial chemistry , nanotechnology , nanomedicine , chemistry , materials science , organic chemistry , biochemistry
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.