Application of modified gemcitabine-loaded solid lipid nanoparticle in the treatment of pancreatic cancer patient-derived xenograft model

Abstract

Abstract Purpose: Gemcitabine (Gem) remains a preferred first-line anticancer drug used for the treatment of pancreatic cancer (PCa). However, rapid metabolism and systemic instability (short half-life) have limited its therapeutic efficacy. The purpose of this study was to modify Gem to a more stable form, 4-(N)-stearoyl-gemcitabine (4NSG), and to evaluate its efficacy in patient-derived xenograft (PDX) mouse models harboring African American (AA) and Caucasian (White) patients' tumors. Methods: 4NSG was developed and characterized using high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and elemental analysis. 4NSG-loaded solid lipid nanoparticles (4NSG-SLN) were developed using the cold homogenization technique and characterized. Cytotoxicity, cell migration, and clonogenic studies were performed to determine the effectiveness of 4NSG-SLN against AA primary PCa cells (PPCL-192, PPCL-135) and White PCa primary cells (PPCL-46, PPCL-68). Pharmacokinetics (PK), and tumor efficacy studies were conducted using PDX mouse models bearing tumors from AA and white PCa patients. Results: The effective particle size of 4NSG-SLN was 82 nm and (IC50) values of 4NSG-SLN treated AA cells (PPCL-192, 9 ± 1.1 µM and PPCL-135, 11 ± 1.3 µM) and White cells (PPCL-46, 12 ± 2.1 and PPCL-68, 22 ± 2.6) were found to be significantly lower compared to Gem treated AA cells (PPCL-192, 57 ± 1.5 µM and PPCL-135, 56 ± 1.5 µM) and White cells (PPCL-46, 56 ± 1.8 µM and PPCL-68, 57 ± 2.4 µM). The area under the curve (AUC), half-life, and clearance pharmacokinetic parameters for 4NSG-SLN were 3-4-fold higher compared to that of GemHCl. 4NSG-SLN treated PDX mice exhibited a two-fold decrease in tumor growth inhibition in PDX mice bearing AA and Whites patients' tumors compared to Gem treated PDX mice bearing AA and Whites tumors. Conclusion: 4NSG-SLN significantly improved the pharmacokinetics of Gem, enhanced systemic stability of Gem, and increased its antitumor efficacy in PCa PDX mice bearing AA and White tumors.