Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Subhash C. Chauhan, Ph.D.

Committee

Stephen W. Behrman, MD. Vivian S. Loveless, Pharm.D. Yi Lu, Ph.D. Murali M. Yallapu, Ph.D.

Keywords

Cervical Cancer, Ormeloxifene, PI3K-Akt, PLGA-ORM

Abstract

Cervical cancer (CxCa) remains the fourth leading cause of cancer related deaths among women worldwide. Cervical cancer is mainly (~ 99.7%) derived from high risk Human papillomavirus (HR HPV). HPV E6/E7 are the two main oncoproteins that interfere with p53 and pRb (retinoblastoma) cell cycle regulatory proteins and hinder their efficacy of controlling cell growth. Additionally, PI3K-Akt is a cell survival pathway that is aberrantly expressed in cervical cancer cells. This pathway has a profound role in inhibiting mitochondrial intrinsic apoptotic signaling pathway. Advanced stage cervical cancer is difficult to treat and patients diagnosed with metastatic disease have a poor survival rate. Therefore, there is an urgent need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-hormonal, anti-estrogen, oral contraceptive for human use. Growing evidences also suggest that ormeloxifene has anti-cancerous properties in a variety of cancers. Developing nanoformulation of drugs has received much attention lately as nanoparticles have site specific targeted drug delivery. Nanoparticles have a specific size range that makes them capable of being entrapped and accumulated at the tumor site due to its leaky vasculature. As a result of it, drug is released from the particle core at a sustained rate; therefore, nanoparticulates offer enhanced bioavailability and better therapeutic efficacy. Considering these benefits, we engineered ormeloxifene loaded PLGA based novel nanoformulation (PLGA-ORM). In this work we validated anti-cancer properties of free ORM and its PLGA based nanoformulation. Our set of data showed that ormeloxifene significantly decreased the cellular proliferation and clonogenic potential of cervical cancer cells. Ormeloxifene also reduced the cellular motility and induced the apoptosis via targeting PI3K-Akt signaling in these cells. Furthermore, ormeloxifene modulated the HPV induced oncogenesis in Caski cells. Ormeloxifene also showed additive inhibitory effects on cellular proliferation and growth when used with radiation. Moreover, our novel PLGA-ORM had a particle size range of 100 – 280 nm and also exhibited excellent encapsulation of ormeloxifene in to PLGA core. PLGA-ORM was labeled with Coumarin 6 (green fluorescent) dye for its uptake studies, where PLGA-ORM internalized in cervical cancer cells in dose, time and energy dependent manner via endocytosis pathway. PLGA-ORM showed improved anti-proliferative/growth properties than free ormeloxifene in cervical cancer cells. When utilized in animals (an orthotopic mouse model) both ormeloxifene and PLGA-ORM showed great anti-tumorous properties, however PLGA-ORM had improved inhibitory effects on tumor growth than free ormeloxifene. To conclude, ormeloxifene and its nanoformulation have the potential to be a novel treatment modality for cervical cancer which can reduce the overall disease burden and improve patients’ life expectancy.

ORCID

http://orcid.org/0000-0002-9252-9897

DOI

10.21007/etd.cghs.2017.0439

Comments

Embargo expires May 2020.

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