Abstract D050: Enhancing efficacy of modified-gemcitabine nanoparticles in pancreatic PDX model

Abstract

Abstract Gemcitabine (Gem) is preferred anticancer drug for the treatment of pancreatic cancer (PCa) either alone in debilitated patients or in combination with other drugs in healthy patients, however; the therapeutic concentration of Gem is severally reduced due to rapid metabolism. Due to its short stay in the blood, the maintenance of therapeutic concentrations of Gem requires a continuous parenteral administration leading to severe side effects such as renal and hematological toxicities. This inherent drawback has necessitated novel approach of delivering Gem to improve stability. The objective of this study was to chemically modify Gem and evaluate its anticancer activity against pancreatic cancer cells. Gem was modified by linking 4-amino group of Gem and stearoyl linear acyl derivative to form 4-(N)-stearoyl-gemcitabine (Gem-stearate). Gem-stearate nanoparticle (GSN) was further prepared by mixing lecithin and labrasol solutions until homogenous mixture was formed. Gem-stearate was then added to the mixture and vortexed intermittently until homogenous solution was achieved. The bond between 4-amino group of Gem and stearoyl derivative was confirmed by Nuclear Magnetic Resonance (NMR) and micro-elemental analysis. The particle size of GSN was determined by using a Particle Size Analyze. Patient-derived primary pancreatic cancer cells (CMZ and G46Ca) and MiaPaCa-2 cells were treated with blank nanoparticles and different concentrations of free Gem and GSN for 48 hours and determined the viability by using Resazurin assay. Mice with pre-established tumors (patient-derived xenografts (PDX)) of pancreatic model (G46Ca) were treated with Gem and GSN. Results: Analysis of the H-NMR spectra displayed amide bond single peak of interest was at 11ppm suggesting a bond formation between 4-amino group of Gem and stearoyl derivative. The mass fractions of elements of GSN were found to be (Theory (T) and Found (F)): i) Carbon: 61.23% (T) and 60.97±0.07% (F), ii) Hydrogen: 8.56% (T) and 8.59±0.08% (F), iii) Nitrogen: 7.93 % (T) and 7.52±0.01% (F) and iv) Fluorine:7.17% (T) and 6.94±0.02% (F)). Growth inhibition of GSN-treated CMZ culture (IC50 =21±5μM) was remarkably higher than free Gem treated CMZ culture (IC50 = 62±3 μM). Similar trend of higher GSN inhibitions in G46Ca and MiaPaCa-2 cultures were found (IC50 =46±16 μM; IC50 =27±4 μM) respectively compared with free Gem treated G46Ca and Mia-PaCa-2 culture (IC50 =68±26 μM; IC50 =54±52 μM) respectively. Put together, the anticancer activity of GSN nanoparticle was significantly more effective than free Gem in CMZ, G46Ca and MiaPaCa-2 cultures compared with their corresponding free Gem treated cultures. For the tumor efficacy studies, GSN exhibited significant tumor growth inhibition compared with molar equivalent dose of free Gem. Immunohistostaining showed that GSNs have significant antiproliferative activity in G46Ca tumors. Conclusion: This study reveals that GSN may be a novel approach in delivering an effective and stable Gem to treat pancreatic cancer. Citation Format: Tiara King, Taylor Smith, Kevin Affram, Jose Trevino, Bo Han, Edward Agyare, Andriana Inkoom. Enhancing efficacy of modified-gemcitabine nanoparticles in pancreatic PDX model [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D050.