Journal
JOURNAL OF CONTROLLED RELEASE
Volume 263, Issue -, Pages 102-111Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.01.015
Keywords
Drug conjugate; Capecitabine; Camptothecin; Drug delivery; Chemotherapy
Funding
- National Science Foundation [DMR 1255281]
- National Institutes of Health [NIH/R21CA191740]
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [1255281] Funding Source: National Science Foundation
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The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self-assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short beta-sheet-forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT-Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPTCap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy. (C) 2017 Elsevier B.V. All rights reserved.
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