Date of Award

2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering

Specialization

Pharmaceutical Engineering

Department

Chemical Engineering

First Advisor

Samantha Meenach

Abstract

The success of the development of drug delivery formulations hinges upon their ability to maintain therapeutic efficacy, while simultaneously aiming to minimize off-site side effects and reduce the dosing burden often faced by patients. Localized formulations deliver therapeutics directly to the disease site and can help circumvent physiological obstacles such as the first pass effect, which remains one of the primary barriers for oral drug delivery. Barriers such as the first pass effect can drastically reduce the overall bioavailability of a formulation, potentially requiring a higher initial dose to remain therapeutically effective. However, many compounds demonstrate dose dependent side effects, which can be undesirable for patients and can lead to decreased patient compliance.

In general, localized delivery platforms are more capable of achieving therapeutically relevant drug concentrations at a target site, while reducing off-site side effects. The pulmonary delivery route is advantageous for many reasons, including high surface area of tissue available in the lungs due to the vast number of alveoli present, allowing for efficient gas exchange and drug transport to occur, while remaining a non-invasive route of administration.

Dry powder aerosolized formulations can help overcome traditional barriers to pulmonary delivery, including demonstrating more favorable pulmonary deposition and improved formulation stability. Recent advancements in dry powder formulation development have resulted in the fabrication of nanocomposite microparticles (nCmP), which combine the advantages of both nano- and micro-particle platforms. Nanoparticles are advantageous in that they can extend the residence time of the formulation in the lungs, providing for a long lasting, sustained release capability, which may reduce the dosing burden faced by patients, where microparticles have the ability to effectively aerosolize to pulmonary tissue. Combining nanoparticle and microparticles in the same drug delivery platform can allow patients to take advantage of favorable nanoparticle-related properties, in addition to maintaining efficient pulmonary deposition. The ability to fabricate drug delivery formulations with a wide variety of release profiles can also be advantageous in wound healing applications. The wound healing process is complex in nature and needs to proceed in a specific manner to be successful. Thus, drug delivery platforms capable of releasing therapeutics in a finely controlled manner have the potential to accelerate the wound healing process.

This dissertation aimed to (1) develop and characterize dry powder aerosol doxorubicin- and paclitaxel-l loaded microparticles for the potential treatment of lung cancer, (2) fabricate and characterize tacrolimus-loaded nanocomposite microparticles for the attenuation of pulmonary arterial hypertension, and (3) investigate the feasibility of developing a theranostic wound healing platform capable of providing infection sensing through the use of DNA-wrapped carbon nanotubes and drug release of a relevant wound healing agent, using curcumin used as a model compound.

Doxorubicin and paclitaxel-based microparticles were produced by spray drying each therapeutics with acetalated dextran. Acetalated dextran is a biocompatible, biodegradable, and pH-responsive polymer capable of providing sustained release of drugs. The microparticle formulations demonstrated advantageous aerosol dispersion properties, with particle diameters of 1.9 μm and 2.1 μm for doxorubicin-loaded and paclitaxel-loaded microparticles, respectively. Solid-state characterization analysis demonstrated that the therapeutics remained in a more dissolution favoring amorphous state and remained thermally stable throughout the spray drying process. In addition, in vitro release data demonstrated the formulations achieved drug release up to at least 48 hours, which can help reduce dosing burden and potentially improve patient compliance.

Tacrolimus, which has been used to treat pulmonary arterial hypertension, was combined with acetalated dextran to produce tacrolimus-loaded acetalated dextran based nanoparticles. These nanoparticles were then spray dried in the presence of the inert excipient, mannitol, to produce tacrolimus loaded-nanocomposite microparticles. Solid-state characterization demonstrated that tacrolimus transitioned from its crystalline to a more dissolution favoring amorphous state throughout the spray drying process. In addition, in vitro pulmonary deposition studies showed that the nanocomposite microparticles can deposit in the alveolar regions of the lungs. In vitro tacrolimus release studies from the tacrolimus-loaded nanoparticles and associated nanocomposite microparticles demonstrated a pH dependent release profile, as tacrolimus was shown to be released over the course of several days. In addition, in vivo biodistribution studies demonstrated that tacrolimus was primarily delivered to the lungs, as there was minimal tacrolimus detected in other organs.

Lastly, a wound healing bandage capable of infection sensing and drug delivery was produced containing curcumin, a wound healing agent that plays key roles in many states of the wound healing process, via electrospinning. Fibers exhibiting distinct core and shell compartments were produced using a coaxial needle using biocompatible and well-studied polymers including polycaprolactone (shell) and polyethylene oxide (core). Drug-loaded fibers were fabricated by incorporating curcumin in the shell phase prior to electrospinning. Single stranded DNA-wrapped single walled carbon nanotubes were loaded into the solution for the core prior to electrospinning, allowing for the detection of hydrogen peroxide, a biomarker indicating increased inflammation and chronicity in the wound healing process. Solid-state characterization is revealed that curcumin transitioned from crystalline to amorphous during the electrospinning process. In vitro curcumin release studies demonstrated the sustained release capability of curcumin from the formulation, as curcumin was released over the course of at least one week. Near infrared microscopy demonstrated that the embedded carbon nanotube sensors remained well dispersed throughout the blank and curcumin-loaded fibers, with minimal signs of aggregation. Polyvinyl alcohol-coated acetalated dextran nanoparticles containing curcumin were also fabricated to be loaded in the core, to achieve curcumin-loaded fibers with more complex release profiles that may lead to accelerated wound healing.

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