Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Chemical Engineering


Chemical Engineering

First Advisor

Samantha A. Meenach


With the rapidly growing popularity and sophistication of inhalable therapeutics, there is an increased demand for tailor made inhalable drug-loaded particles capable of efficient delivery to the lungs with optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel technologies have emerged. Preparation of particle formulations suitable for inhalation and loaded with biomolecules is also of interest for gene therapy and vaccination applications. Dry powder inhalers (DPI) capable of delivering high dosages of therapeutics have rapidly evolved over the last decade, and nanoparticles have proven to be highly beneficial for controlled and sustained release of therapeutics both locally and systemically. Unlike conventional delivery systems, particle-based drug delivery systems offer increased surface area, colloidal stability, and tunability, all of which can be used to target the disease state of interest and specific patient population. In addition to the above drug delivery advantages, an advanced particle technology can further improve the pharmaceutical manufacturing process by affording better quality control over the particulate and solid-state properties as well as ensuring better product consistency and process economics for inhalable products.

Pulmonary drug delivery has demonstrated advantages over other delivery routes due to the ability to use lower the dosage requirement of therapeutics, reduction in systemic toxicity, access to high blood flow, and offering better targeting to the disease site. Effective application of dry powder therapeutics requires optimum particle deposition in the lungs and avoidance of physiological defense mechanisms such as mucosal entrapment, mucociliary clearance, and alveolar macrophage clearance. In addition to this, there is a need for the development of nanoparticle-based therapeutics capable of delivering therapeutics agents due to their poor water solubility and high concentration requirements for efficacy.

This thesis was aimed to (1) develop and characterize cell membrane-coated nanoparticles to overcome pulmonary epithelial barriers and evaluate the nanoparticle internalization pathways into and across the cell, (2) develop and characterize inhalable cell membrane-coated nanocomposite microparticles capable of enhanced transcytosis across epithelial cells grown in air interface culture, and (3) optimize aerosol nanocomposite microparticle spray drying properties to allow for deep lung delivery of therapeutics following aerosolization.

Curcumin-encapsulated biodegradable nanoparticles were formulated using a pH-sensitive, tunable, biocompatible polymer acetalated dextran. Curcumin was used as a model drug due to its hydrophobic nature and fluorescent properties that aids in easy detection of that nanoparticles. The nanoparticles were coated with cancer cell membranes, lipids, or polymers to provide different surface properties such as composition and charge. The interaction between different nanoparticle surface properties were evaluated in terms of internalization into and transport across an in vitro pulmonary cell monolayer. Different pharmacological inhibitors were used to block the internalization pathways to elucidate the endocytosis mechanisms of the particle formulations. The resulting nanoparticles were used to formulate nanocomposite microparticles using mannitol as excipient via spray drying. Spray-dried nanocomposite microparticles demonstrated excellent aerosol performance when evaluated with an in vitro Next Generation Impactor, with a tunable targeted deposition depending on the formulation and spray drying conditions. Additionally, the disassociated nanoparticles from the dry powder nanocomposite microparticle retained the desirable properties of the nanoparticles and crossed the air-blood barriers effectively for pulmonary drug delivery applications. Finally, the spray drying parameters were manipulated to optimize the aerosol performance of the resulting nanocomposite microparticles and to maintain the desirable properties of the parent nanoparticles.

Acetalated dextran-based dry powder aerosol formulations demonstrated significant promise as a versatile, cost-effective, and promising drug carrier for a wide range of applications and disease states. The main goal of particle engineering is to incorporate into the particles desirable attributes such as narrow particle size distribution, improved dispersibility, enhanced drug stability, optimized bioavailability, sustained release, and/or specific targeting, considering the specifics of inhaler design and drug delivery requirements. A practical particle engineering process must be significantly advantageous for the final drug product, consistent and economically feasible at the industrial scale.



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