Abstract PO-108: Evaluation of antitumor activity of modified-gemcitabine solid-lipid nanoparticle in pancreatic pdx models

Abstract

Abstract Purpose: Pancreatic cancer (PCa) is one of the most aggressive and devastating malignancies in the United States, with a high mortality rate. Despite the remarkable advances in cancer therapy, there are limited treatment options for PCa patients. Gemcitabine (Gem), a nucleoside analog, remains the preferred choice, either alone or in combination with other chemotherapeutic agents, to treat PCa. While Gem has proven to be effective against PCa in the early stages of treatment, PCa cells resistance to Gem and rapid metabolism of Gem has resulted in poor treatment outcomes. The objective of this study was to address the issues associated with Gem via chemical modification of Gem to 4NSG. This significantly reduced the metabolism and highly sensitized PCa cells to Gem. Methods: Gem was modified by linking the 4-amino group of Gem and stearoyl acyl derivative to form 4NSG and characterized using nuclear magnetic resonance (NMR) for) to determine new bond formation, micro-elemental analysis micro-elemental analysis used to ascertain the presence of elemental composition and purity, high liquid chromatography (HPLC) used to determine percent purity of 4NSG. The 4NSG was developed into solid lipid nanoparticles (4NSG-SLN), and the size was determined using a particle size analyzer. Patient-derived primary pancreatic cancer cells (CMZ and G68Ca) and MiaPaCa-2 cells were treated with free Gem and 4NSG-SLN. Percent cell viability was determined using resazurin assay and antitumor efficacy testing of Gem, and 4NSG-SLN was performed in patient-derived xenograft (PDX) mouse models bearing G68Ca PCa. Results: Analysis of the H-NMR spectra displayed an amide bond at 11ppm, confirming the conjugated bond between the 4-amino group of Gem and stearoyl derivative. The half-maximal inhibitory concentration (IC50 =11±1.3µM) of 4NSG-SLN-treated CMZ culture was significantly higher than that of Gem treated CMZ culture (IC50 = 56±2 µM, p<0.001). We found a similar trend of higher growth inhibition of 4NSG-SLN treated G68Ca and MiaPaCa-2 cultures (IC50 (4NSG-SLN-G68Ca) = 12±2.1 µM; IC50(Gem-MiaPaCa-2) = 27±4 µM) respectively. Where p< 0.001 (4NSG-SLN-G68Ca vs. Gem-G68Ca) and p<0.001 (4NSG-SLN-MiaPaCa-2 vs Gem-MiaPaCa-2) compared with Gem treated G68Ca and Mia-PaCa-2 cultures (IC50 (G68Ca) = 68±26 µM; IC50 (Mia-PaCa-2) =54±5 µM) respectively. Put together, the anticancer activity of 4NSG-SLN demonstrated enhanced efficacy in CMZ, G68Ca, and MiaPaCa-2 treated cultures compared with their corresponding Gem treated cultures. For antitumor efficacy testing, 4NSG-SLN demonstrated significant tumor growth inhibition in PDX models harboring G68Ca pancreatic tumors compared with Gem treated with PDX models. Immunohistostaining studies of 4NSG-SLN treated pancreatic tumors significantly reduced vascular endothelial growth factor receptor (VEGFR) expression compared with Gem treated pancreatic tumors. Conclusion: This study demonstrated that 4NSG might be a novel approach to significantly enhance the therapeutic efficacy of Gem in the treatment of PCa. Citation Format: Edward Agyare, Taylor Smith, Andriana Inkoom, Bo Han, Jose Trevino, Nkafu Bechem Ndemazie. Evaluation of antitumor activity of modified-gemcitabine solid-lipid nanoparticle in pancreatic pdx models [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-108.