Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Samantha A. Meenach

Abstract

Particle-based delivery systems have been investigated for their potential to increase the efficacy of patient diagnoses and treatments. In many cases, these systems increase the bioavailability and/or decrease the toxicity of clinically relevant drugs. These developments have led to improvements in patient compliance, morbidity, mortality, and quality of life. To date, particle-based delivery systems have been evaluated in hundreds of clinical trials around the world. Unlike conventional delivery systems, particle-based delivery systems offer increased surface area, colloidal stability, and system tunability, all of which can be tailored to target the disease state of interest and specific patient population.

Although there are examples of successful particle-based drug products, there are numerous obstacles that consistently shunt the ability for these systems to be translated from benchside to bedside. Two consistent obstacles are drug toxicity and scale-up manufacturing. Drug toxicity is largely caused by inefficient targeting, inopportune routes of administration (i.e. oral delivery for a pulmonary disease), and unfavorable release mechanisms. Scale-up manufacturing is a continual industrial interest, given that particle-based drug products are increasing in popularity, however scale-up procedures are still in development and face their own challenges. A potential method to overcome the obstacles faced in drug delivery is the development of new polymers, either by synthesis of novel entities or derivatization of current ones. To ensure biocompatibility, the latter is a common practice. Biopolymers such as chitosan, hyaluronic acid, poly(lactic-co-glycolic acid) (PLGA), and naturally occurring polysaccharides undergo modifications to achieve desirable characteristics for drug delivery. Acetalated dextran (Ac-Dex) is a synthetic biopolymer derived from dextran, a naturally produced hydrophilic polysaccharide. Following a one-step reaction, the hydroxyl moieties of dextran are converted to acetal groups, transitioning the biopolymer from hydrophilic to lipophilic solubility. Hydroxyl moieties still present on the backbone can provide a handle for ligand attachment to actively target specific sites of the body. Additionally, controlling the reaction time and altering the molecular weight of the dextran backbone can alter the degradation kinetics, providing flexibility to achieve desirable release kinetics for a therapeutic of interest. Overall, Ac-Dex demonstrates cost-effective and efficient synthesis, easy tunability for targeting, and flexibility in controlling release kinetics, all of which propitiate its promise as a drug carrier.

The purpose of this dissertation was to utilize the advantages of Ac-Dex to investigate its potential as a drug carrier to overcome challenges that exist in the field of drug delivery. Manuscript 1 focuses on decreasing drug toxicity using active targeting. Here, Ac-Dex nanoparticles (NP) were synthesized and coated with phosphatidylserine to instigate macrophage uptake for the potential to treat diseases that use these cells as reservoirs, such as tuberculosis and HIV. Manuscript 2 focuses on the synthesis of Ac-Dex microparticles (MP), followed by an exploration of their ability to modulate the release of water-soluble cargo. Ac-Dex MP were synthesized via spray drying and were loaded with a water-soluble dye. Following the synthesis, MP were evaluated for their characteristics and drug release behaviors in multiple pH environments. Manuscript 3 uses Ac-Dex as an economical model drug carrier and focused on studying the effects of tangential flow filtration (TFF) parameters (factors) on the characteristics of NP (responses) to explore its promise as a scale-up purification technique. The final manuscript focuses on the physical characterization and development of nanocomposite microparticle system for localized delivery of the small molecule Eact, a potential therapeutic for pulmonary arterial hypertension.

Previously published reports show that Ac-Dex demonstrates significant promise as a versatile, cost-and time-effective, and promising drug carrier for a range of applications and disease states. The manuscripts in this dissertation all explore uncharted territories of Ac-Dex’s potential, further demonstrating its versatility and promise to overcome current drug delivery obstacles.

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