Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering

Department

Chemical Engineering

First Advisor

Samantha A. Meenach

Abstract

Chronic pulmonary diseases such as lung cancer and cystic fibrosis represent significant global health concerns because of their resulting high mortality and low life expectancy. Pulmonary drug delivery has demonstrated advantages over other delivery routes due to the ability to use lower concentrations of drug, reduction in systemic toxicity, and offering better targeting to the area of disease. Effective application of dry powder therapeutics requires the optimization of particle deposition in the lungs and avoidance of physiologic defense mechanisms such as mucosal entrapment, mucociliary clearance, and macrophage engulfment. Evaluation of aerosol pulmonary therapeutic parameters demands accurate in vitro models that can appropriately simulate the pulmonary environment, such that the results can accurately translate to in vivo testing. In addition, there is a need in the development of nanoparticle-based therapeutics capable of delivering chemopreventive agents owing to their poor water solubility and large concentration requirements for efficacy.

This dissertation was aimed at: (i) developing and evaluating resveratrol-loaded nanoparticles capable of preventing in vitro tumors spheroid growth, (ii) developing and characterizing dry powder paclitaxel-loaded nanocomposite microparticles, and evaluating their efficacy in the growth inhibition of lung cancer tumor spheroids using an in vitro three-dimensional air interface culture model, and (iii) developing and characterizing PEGylated nanocomposite microparticles, and evaluating their ability to penetrate mucus via an artificial mucus transport model.

Biodegradable nanoparticles were formulated with appropriate size for cellular uptake (~200 nm). The nanoparticles demonstrated tunable, pH-dependent sustained release for up to 4 days using 3-hour acetalated dextran. The nanoparticles showed increased colloidal stability with hydrophobic therapeutic agents and improved mucuspenetrating capabilities when coated with vitamin E poly(ethylene glycol) (VP5k). Nanoparticles loaded with resveratrol, a natural chemopreventive agent, showed superior inhibition of tumor growth when dosed in comparison to free resveratrol. Finally, nanocomposite nanoparticles loaded with paclitaxel (PTX), a toxic chemotherapeutic agent, showed comparable efficacy in comparison to free PTX.

Spray-dried nanocomposite microparticles demonstrated excellent aerosol performance when evaluated with an in vitro Next Generation Impactor for dry powder inhaler formulations, with a tunable targeted deposition depending on the formulation and spray drying conditions. These results highlight multiple beneficial characteristics of inhaled drug delivery with nanocomposite microparticles for lung cancer treatment, including sustained release over a long period of time, tunable deposition to the desired area within the bronchopulmonary tract, and improved mucus penetration. Additionally, the results observed in our 3D cell culture models differed from those observed in a 2D monolayer of cells, demonstrating the importance of accurate in vitro models to allow for appropriate translational expectations.

Available for download on Monday, April 19, 2021

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