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Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Jun 14; Vol. 61 (11), pp. 4904-4917. Date of Electronic Publication: 2018 May 24. - Publication Year :
- 2018
-
Abstract
- To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.
- Subjects :
- Animals
Biological Availability
Cell Line, Tumor
Delayed-Action Preparations
Deoxycytidine chemistry
Deoxycytidine metabolism
Deoxycytidine pharmacokinetics
Deoxycytidine pharmacology
Endocytosis
Female
Humans
Intracellular Space metabolism
Mice
Oxidation-Reduction
Prodrugs pharmacokinetics
Rats
Gemcitabine
Carbamates chemistry
Carbonates chemistry
Deoxycytidine analogs & derivatives
Disulfides chemistry
Prodrugs metabolism
Serum Albumin, Bovine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29768008
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00293