Abstract 4392: Generation of a novel ormeloxifene nanoparticle formulation for pancreatic cancer treatment
Authors: Khan Sheema , Chauhan Neeraj , Yallapu Murali M. , Ebeling Mara C. , Balakrishna Swathi , Ellis Robert T. , Thompson Paul A. , Behrman Stephen W. , Zafar Nadeem , Singh Man M. , Halaweish Fathi T. , Jaggi Meena , Chauhan Subhash C. 
Published: August 2015

Pancreatic cancer (PanCa) is the fourth leading cancer with 85% mortality rate in the United States. Therefore, there is an utmost need to discover new modalities that can result in enhanced therapeutic efficacy with low to minimal side effects. Ormeloxifene (ORM) is a synthetic molecule which is widely used as an oral contraceptive in humans. Numerous studies indicate that ORM exhibits potent anti-cancer effects through inhibition of important oncogenic signaling events in several cancers. Our studies also demonstrate the anticancer effects of ORM in various cancer cells. However, the ORM effects can be improved by encapsulating in a nanoformulation which provides targeted delivery of ORM to the tumors. Therefore, in order to increase the therapeutic efficacy of ORM, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) formulation (PLGA-ORM NPs). This formulation has been characterized for particle size, zeta potential, chemical composition, drug loading efficiency using various physico-chemical methods such as DLS, TEM, FT-IR, DSC, and TGA. Because of its facile composition (PLGA core, PVA, PLL and PEG-linker) this novel formulation is compatible for antibody/aptamer conjugation to achieve tumor specific targeting. The PLGA-ORM formulations indicate efficient encapsulation of ORM. The particle size of PLGA-ORM formulation (∼ 100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeation and Retention (EPR) effect. The uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation providing its efficient endosomal release to cytosol in PanCa cells. PLGA-ORM NPs showed superior anti-cancer potential in various pancreatic cancer cells (HPAF-II, BXPC-3, Panc-1, MiaPaca) and in BXPC-3 xenograft mice. PLGA-ORM NPs suppressed pancreatic xenograft tumor growth and improved the mice survival. In addition, PLGA-ORM NPs also reduce the metastasis potential. PLGA-ORM NPs inhibit tumorigenic and metastatic phenotypes via suppression of AKT phosphorylation and inhibition of key oncogenes involved in pancreatic progression such as MUC1, HER2 and CD31. Additionally, PLGA-ORM NPs treated xenograft tumors showed reduced staining of the proliferating cell nuclear antigen (PCNA), cytokeratin-19 (CK19), MUC1, HER2 and CD31 in immunohistochemical analysis. In conclusion, this study suggests that PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and can be valuable for the treatment of pancreatic cancer in future.

Citation Format: Sheema Khan, Neeraj Chauhan, Murali M. Yallapu, Mara C. Ebeling, Swathi Balakrishna, Robert T. Ellis, Paul A. Thompson, Stephen W. Behrman, Nadeem Zafar, Man M. Singh, Fathi T. Halaweish, Meena Jaggi, Subhash C. Chauhan. Generation of a novel ormeloxifene nanoparticle formulation for pancreatic cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4392. doi:10.1158/1538-7445.AM2015-4392