Abstract 305: Novel nanoformulation of piperlongumine for pancreatic cancer therapy

Abstract

Abstract Background: Pancreatic cancer (PanCa) is expected to be the second leading cause of cancer-related death by 2030. The treatment of PanCa is highly challenging due to the extremely poor response to existing therapeutic options. Highly desmoplastic tumor microenvironment in pancreatic tumor causes suboptimal delivery of therapeutic agents in tumors that eventually resulted to chemo-resistance. Piperlongumine (PL) is a natural alkaloid isolated from the long pepper, Piper longum L., and has shown substantial cancer-preventive and therapeutic efficacy against variety of cancers. However, delivering its effective concentration in pancreatic tumors has been challenging. In this study, we have synthesized and characterized a novel nano-formulation of PL composed of a PLGA core (PLGA-PL), stabilized with polyvinyl alcohol (PVA) and coated with poly-L-lysine (PLL), and evaluated its therapeutic effects against PanCa. Methods: The various physicochemical approaches (FT-IR, DSC, TEM, TGA, and HPLC) was used to characterize the PLGA-PL formulation for particle size, chemical composition, and drug loading efficiency. Cellular uptake of PLGA-PL was achieved in incubation with PLGA-PL in PanCa cells. Further, the therapeutic efficacy of PLGA-PL was determined by using various in vitro assays (MTS, wound healing, boyden chamber, cell cycle and apoptosis assays) using PanCa cells. The effects of PLGA-PL on various key oncogenic signaling pathways were evaluated by qRT-PCR, Western blot, confocal microscopy, immunohistochemistry (IHC) analyses. Results: Our novel PLGA-PL formulation has an average size of 110 nm in dynamic light scattering and a zeta potential range of -6.52 to -7.68 mV with excellent PL loading efficiency. Cellular uptake and internalization studies show that PLGA-PL escapes lysosomal degradation, allowing for effective endosomal release into the cytosol. PLGA-PL showed superior anti-cancer activity in various PanCa cells (BxPC-3, HPAF-II, AsPC-1, Panc-1, and MIA PaCa-2) compared to free PL. Moreover, PLGA-PL showed a remarkable inhibition of the migration and invasion potential of PanCa cells. Furthermore, PLGA-PL more effectively inhibited the components of the Shh pathway and Gli targets as determined by qPCR and Western blot analysis. Additionally, PLGA-PL treatment targets cancer stem cells by regulating pluripotency, maintaining stemness factors (Oct-4, Sox2, Nanog and c-Myc), and limiting tumor sphere formation. Conclusions: Taken together, our results demonstrate that PLGA-PL nanoformulation exhibits superior anti-cancer potential than free PL against and could be used as a novel therapeutic modality for the management of PanCa. Citation Format: Vivek Kumar Kashyap, Godwin P. Darkwah, Swati Dhasmana, Neeraj Chauhan, Anupam Dhasmana, Sudhir Kotnala, Partha Laskar, Mohammed Sikander, Bilal B. Hafeez, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel nanoformulation of piperlongumine for pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 305.