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Polymeric Nanogel-based Treatment Regimen for Enhanced Efficacy and Sequential Administration of Synergistic Drug Combination in Pancreatic Cancer.

J Pharmacol Exp Ther; 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683666
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 non-targeted delivery. More than 80% of the PDAC aberrantly expresses Sialyl Tn (STn) antigen due to the loss of function of COSMC, a specific chaperone for the activity of core 1 ß3-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 mAb) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered significantly higher amount of platinum into the cells and tumors that are 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 co-delivery 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 the tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces a highly synergistic therapeutic efficacy against pancreatic cancer. Our results provide the rationale for development of combination drug regimens using targeted nanomedicines to maximize therapeutic efficiency and improve outcomes of therapy of PDAC.