Pancreatic cancer (PC) is the third leading cause of cancer-related death in the United States. It is challenging to treat PC due to the existence of intrinsic and extrinsic chemoresistance mechanisms. We previously reported that honokiol, a phytochemical isolated from Magnolia plant, targets important signaling pathways involved in PC associated with survival, chemoresistance and stromal remodeling, and exhibits significant anti-tumor activity both in vitro and in vivo. However, considering poor bioavailability and tumor uptake as major hurdles in clinical translation, we made efforts to develop an exosomal nanoformulation of honokiol. Mesenchymal cell-derived exosomes are non-immunogenic and express surface markers that could support tumor-targeted delivery. Maximum entrapment of honokiol was achieved when it was used in 1:4 weight ratio with exosomes and subjected to 6 cycles of sonication. Data from dynamic light scattering suggested that key features of exosomes (size, polydispersity and integrity) remained intact post-honokiol encapsulation. The comparative half maximal inhibitory concentration (IC50) data suggested 4 to 5 times greater therapeutic efficacy of exosomal honokiol as compared to that of free honokiol. Similarly, exosomal-honokiol had significantly superior effect on cell cycle progression, apoptosis and expression of cell cycle- and survival-associated proteins than that observed in PC cells treated with equivalent doses of free honokiol. We also found that the cellular uptake of honokiol was significantly greater for exosomal-honokiol as compared to its free form. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved anti-tumor efficacy against pancreatic cancer.

Citation Format: Mohammad Aslam Khan, Rajashekhar Kanchanapally, Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Seema Singh, Ajay P. Singh. Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6259.