Self‐Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy. (6th July 2015) - Wang, Hangxiang
Abstract : The availability of precisely modulated chemical modifications dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self‐assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site‐specific attachment of a variety of lipophilic moieties to the antitumor agent SN‐38 (7‐ethyl‐10‐hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self‐assembly in aqueous environments, allowing for the identification of five prodrugs capable of self‐assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long‐term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor‐specific targeting ligands) to the particle surface, which is further exploited to improve antitumor efficacy in mouse xenograft models. Thus, this structure‐based reconstruction of SN‐38 molecules significantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs. Abstract : A novel carrier‐free drug delivery platform relying on amphiphilic self‐assembly of pure prodrugs is successfully constructed by rational engineering of antitumor agent 7‐ethyl‐10‐hydroxycamptothecin (SN‐38). Specifically, the prodrugs modified with polyunsaturated fatty acids exhibit enhanced stability, which contributes to their superior antitumor activity in vivo. Besides, additional valuable functionalities such as tumor‐specific ligands can be readily incorporated to improve antitumor efficacy.