Background: Cervical cancer (CxCa) is one of the most common death related cancers among women around the world and associated with poor 5-year survival rate. Therefore, there is an urgent need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, Selective Estrogen Receptor Modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer treatment. Therefore, nanotherapy approach outstands over traditional chemotherapy which is not site specific and often associated with various side effects. Thus, pursuing this novel nanotherapy approach, we have developed ORM nanoformulation using PLGA (poly [lactic-co-glycolic acid]); an FDA approved biodegradable polymer.

Methods: We generated ORM loaded PLGA nanoformulation (PLGA-ORM) employing nanoprecipitation method. PLGA-ORM was characterized for its physicochemical properties such as particle size, FT-IR, DSC and drug loading. We next performed cellular uptake studies in Caski and SiHa cell lines at different concentrations (5, 10, 20 and 25 µM) and temperatures (4° and 37° C) utilizing fluorescent microscope, flow cytometer and TEM. To evaluate the cellular uptake mechanism of PLGA-ORM, we did another flow cytometer experiment using various endocytosis pathways’ inhibitors. Next, we determined anti-proliferative activities of PLGA-ORM by performing MTS and colony formation assays. Furthermore, we investigated anti-tumoral functions of PLGA-ORM in an orthotopic mice model of cervical cancer.

Results: Our optimized PLGA-ORM showed particle size around 250 nm measured by DLS. ORM was completely miscible in this formulation as indicated by FT-IR and DSC spectra, which resulted in excellent drug loading of about 80% done by HPLC. PLGA-ORM nanoformulation exhibited improved internalization in dose, time and energy dependent manner through endocytosis mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells, results showed that this formulation had an improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, PLGA-ORM nanoformulation exhibited superior anti-tumorous activities in an orthotropic cervical cancer mouse model compared to free ORM.

Conclusion: Our findings suggest that, this PLGA-ORM nanoformulation has great potential for repurposing the drug and becoming a novel modality for cervical cancer management which needs to be developed as a lead therapy approach with appropriate clinical investigations.

Citation Format: Neeraj Chauhan, Murali M. Yallapu, Diane M. Maher, Bilal B. Hafeez, Mohammed Sikander, Meena Jaggi, Subhash Chauhan. Generation of polymeric nanoformulation of ormeloxifene for cervical cancer treatment [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 3636.