All ETDs from UAB

Advisory Committee Chair

Veena Antony

Advisory Committee Members

Shane A Catledge

Selvarangan Ponnazhagan

Vinoy Thomas

Yogesh K Vohra

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Malignant mesothelioma is an aggressive deadly pleural cancer overexpressing Ephrin A2 receptors which are biomarkers for malignant mesothelioma. The Ephrin A1 ligand binding to the Ephrin A2 receptor downregulates overexpression of the Ephrin A2 in malignant mesothelioma cells (MMC). Similarly, the YSA peptide can mimic the Ephrin A1 ligand and both could be suitable as targeting agents and tumor suppressing agents for MMC. In this work, we conjugated the surface of nanoparticles with the YSA peptide and Ephrin A1 ligand to deliver paclitaxel with low solubility by targeting the MMC. We have obtained nanoparticles ranging 188-278 nm with the Ephrin A1 surface conjugated nanoparticles having 57-90 µm smaller size compared to any the other four nanoparticle formulations we studied. Nanoparticles released 32% of the drug encapsu-lated by day 5 and showed slow sustained release afterwards with very minimal variation in drug release amount. This stable and sustained release profile of paclitaxel loaded na-noparticles provides the desired amount of drug supplied to cells. Highest uptake (100%) was achieved by the Ephrin A1 conjugated nanoparticles (EPH NP) at 125 µg/ml concentration in 5 hours. The highest killing (71%) was achieved by the YSA peptide conjugated and paclitaxel loaded nanoparticles (YSA-PTX NP) at 1.5 µg/ml over 48 hours. This is 32% more cytotoxicity with 90% less of the drug used compared to free paclitaxel. Based on combined results of efficient targeting ability and improved cytotoxici-ty, surface conjugated and paclitaxel loaded nanoparticle formulations stands out with YSA-PTX NP as being one step further. This is ideal and promising in that it has signifi-cant potential for in vivo targeted delivery. In this study, we successfully prepared particles in an ideal nano-range with suc-cessful targeting agent conjugation and sufficient anticancer drug encapsulation. They are suitable and ideal for cancer diagnoses and treatments. The targeting ability of the Ephrin A1 ligand and YSA peptide is already proven. This work has introduced successful for-mulation of PLGA nanoparticles with high loading efficiency as a great potential for di-agnosis and treatment of many cancer types overexpressing the Ephrin A2 receptors. This work further will be carried by in vitro/ in vivo studies of the Ephrin A2 overexpressing other cancer cells.

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