Graduation Semester and Year

2014

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Kytai Truong Nguyen

Abstract

Drug delivery via pulmonary route has emerged as an attractive area of study in the past two decades. This method of administration has multiple advantages for both systemic and local drug delivery due to the availability of a large surface area for drug absorption and higher solute permeability in the lung. Most importantly, inhalational drug delivery provides direct accessibility to the lung via a noninvasive route of administration. Recent literature has shown a surge in the use of nano/micro particles for a wide range of pulmonary applications ranging from targeted and controlled drug delivery to drug screening and tissue regeneration. In this research, polymeric nano and micro particles were first screened and characterized for diagnosis and treatment of pulmonary ailments such as restrictive lung diseases and lung cancer. Initially, various natural and synthetic polymer-based nanoparticles (NPs) were screened for delivery of protein and deoxyribonucleic acid (DNA) to the lung. Poly lactic-co-glycolic acid (PLGA) NPs showed the highest stability, burst drug release and cytocompatibility. Although natural polymer-based NPs showed the highest cellular uptake in vitro, results from in vivo studies indicated more sustained and uniform tissue distribution on nebulization of PLGA NPs. Our major contribution to the field of drug delivery is that in vitro NP properties need not necessarily reflect their behavior in vivo. It is therefore necessary to validate in vitro findings of NPs encapsulating biological agents with in vivo results in order to choose the most favorable nanocarrier for the desired application. The PLGA NPs thus chosen were incorporated with superparamagnetic iron oxide (SPIO) and coated with a poly N-isopropylacrylamide - carboxymethyl chitosan (PNIPAAm-CMC) shell to form novel temperature- and pH-sensitive multi-layered NPs to provide better controlled drug delivery options for lung cancer treatment. Additionally, these core-shell particles were conjugated with folic acid for targeted lung cancer therapy. The particles produced good negative contrast using MRI in vivo. The NU7441 (radiosensitizer)- and gemcitabine hydrochloride (chemotherapeutic drug)- loaded NPs also significantly slowed down tumor growth when administered in combination with radiation in vivo. These observations indicate that our novel core-shell nanoparticles could potentially be used as a drug carrier to provide efficient chemo-therapy and/or combined chemo- and radiation-therapy to treat lung cancers. Finally, PLGA was used to synthesize stable, degradable and porous microparticles using porogens such as sodium bicarbonate, gelatin and poly-N-isopropylacrylamide (PNIPAAm) microparticles, to form 3D lung cancer models for screening of chemotherapeutic drugs in vitro. An innovative aspect of this research is the use of PNIPAAm nanoparticles to generate uniform pores on the PLGA microparticles. Comparison between particles prepared using different porogens to form an in vitro tissue model is also novel. Our preliminary in vitro results indicate that the responses of 2D cancer cell monolayer and our 3D lung tumor model vary significantly when exposed to chemotherapeutic drugs of the same concentration. These results suggest the potential of our porous microparticles for high throughput screening of therapeutic agents in an in vitro setting, while mimicking in vivo conditions more closely than a conventional 2D model.

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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