1. A Polymeric Nanogel-Based Treatment Regimen for Enhanced Efficacy and Sequential Administration of Synergistic Drug Combination in Pancreatic Cancer.
- Author
-
Soni KS, Thomas D, Caffrey T, Mehla K, Lei F, O'Connell KA, Sagar S, Lele SM, Hollingsworth MA, Radhakrishnan P, and Bronich TK
- Subjects
- Animals, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Cell Line, Tumor, Cisplatin administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Drug Synergism, Gels, Humans, Mice, Mice, Nude, Nanostructures, Platinum metabolism, Polymers chemistry, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Pancreatic Ductal drug therapy, Pancreatic Neoplasms drug therapy
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1 β 3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 β 3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2019
- Full Text
- View/download PDF