Abstract 2165: Self-microemulsifying drug delivery systems (SMEDDS) containing novel compounds in combination with gemcitabine: Bioavailability enhancement and synergistic anticancer efficacy studies for pancreatic cancer management

Abstract

Abstract Pancreatic cancer (PC) is the third leading cause of deaths in the United States claiming approximately 45,000 lives every year and is predicted to be the second cause of cancer related deaths by 2020. Late diagnosis, poor prognosis, limited success and significant side effects with existing anticancer drugs has resulted in such high mortality rates (5 year survival rate is less than 8%). These limitations have encouraged scientists to develop chemopreventive strategies and combination drug alternatives that can serve as better therapeutics. In our previous studies, we have reported the synergistic chemoprevention potential (formulation patent pending) of lipid nanocarriers (SMEDDS) of Loratadine (LOR), H1-receptor antagonist drug; with free Sulforaphane (SFN), a neutraceutical compound from broccoli when administered at low doses in human PC cell lines (MIA PaCa-2 and Panc-1). To confirm the hypothesis that enhanced efficacy using the SMEDDS formulation results from bioavailability enhancement, preclinical in vivo pharmacokinetic studies were performed in Sprague Dawley rats. The results confirmed that the bioavailability and Cmax of LOR increased 5-fold (2203.2 ± 293.7 ng.h/mL for plain LOR and 10266.1 ± 250.0 ng.h/mL for LOR SMEDDS) and 4-fold (120.9 ± 10.5ng/mL for plain LOR and 503.2 ± 5.8ng/mL for LOR SMEDDS) when administered as SMEDDS compared to plain drug. This corroborated the significant enhancement in bioavailbility with SMEDDS formulation. This promising results in bioenhancement and chemoprevention activity led to an hypothesis to assess the potential of LOR SMEDDS-SFN combination as an adjuvant therapy with classical anticancer drugs like Gemcitabine (GEM) to give synergistic efficacy enhancement in PC treatment. For this, IC50 concentrations were calculated for various treatment groups [GEM alone or in addition to the LOR free drug or as SMEDDS with or without SFN] using MTS viability assay on human PC cell lines in accordance with published protocol over an incubation time of 72 h. The LOR SMEDDS-SFN-GEM combination revealed 2-fold and 2.5-fold enhancement in anticancer activity compared to free drug combination and GEM alone respectively. This confirmed the synergistic anticancer potential of the free drug combination followed by further activity potentiation using SMEDDS formulation. In conclusion, a novel SMEDDS of LOR and free SFN was invented (provisional patent applied) to successfully elicit PC chemoprevention and adjuvant treatment in combination with GEM. We anticipate that, this adjuvant therapy will lead to relatively low doses of anticancer drugs and thereby can reduce the side effects with enhanced efficacy. Citation Format: Sunil Prabhu, Preshita Desai, Naga Jyothi Thumma, Jeffrey Wang. Self-microemulsifying drug delivery systems (SMEDDS) containing novel compounds in combination with gemcitabine: Bioavailability enhancement and synergistic anticancer efficacy studies for pancreatic cancer management [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2165.