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Self-Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy.
- Source :
-
Advanced Functional Materials . Aug2015, Vol. 25 Issue 31, p4956-4965. 10p. - Publication Year :
- 2015
-
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 FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1616301X
- Volume :
- 25
- Issue :
- 31
- Database :
- Academic Search Index
- Journal :
- Advanced Functional Materials
- Publication Type :
- Academic Journal
- Accession number :
- 108938925
- Full Text :
- https://doi.org/10.1002/adfm.201501953