Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Krishnaswami Raja

Committee Members

Richard Magliozzo

Jin Montclare

Fred Naider

Sebastien Poget

Subject Categories

Biochemistry | Biomedical and Dental Materials | Biotechnology | Complex Mixtures | Macromolecular Substances | Materials Chemistry | Pharmaceutical Preparations | Polymer Chemistry

Keywords

polymer, nanofibers, therapeutic proteins, drug delivery, phytochemical, biomaterials

Abstract

Poly-lactic-co-glycolic acid (PLGA) polymers are rapidly gaining momentum as a platform for next-generation drug delivery systems due to their ease and low cost of synthesis, favorable biocompatibility and biodegradability, and lack of toxicity. In particular, the application of drug-loaded PLGA nanofibers directly to a target tissue may represent a promising alternative to traditional routes of drug administration (e.g., oral, injectable) as they offer the potential to greatly improve bioavailability, increase efficacy, and reduce off-target toxicity. Furthermore, the use of such a system may potentially allow for greater flexibility in clinical drug development, by enabling the use of compounds which have potent therapeutic efficacy in vitro, but are limited by poor bioavailability, short half-lives, and/or high off-target effects in vivo. To this end, we aimed in these studies to investigate the potential of PLGA-loaded nanofibers to enable the clinical delivery of two such classes of therapeutics: small-molecule phenolic phytochemicals and proteins.

Phenolic phytochemicals such as curcumin and rosmarinic acid have impressive therapeutic activity (including but not limited to anticancer and wound-healing activity) in vitro, but are of limited use in vivo due to poor absorption and exceedingly rapid metabolism and/or rapid systemic clearance when administered orally or parenterally. In a bid to overcome thislimitation, we hypothesized that a PLGA nanofiber-based slow-release system could facilitate the clinical use of these agents, by permitting controlled release directly onto a target tissue. Here, we characterize and demonstrate the feasibility of this approach in producing wound-healing, and antitumor responses in vitro, with our results indicating that such a system is capable of augmenting conventional modalities in vivo.

In a similar vein, protein-based therapeutics are attractive candidates for drug development due to their large array of bioactivities and high degree of specificity but are significantly hampered by low epithelial/membrane permeability and short in vivo half-lives. Moreover, protein-based therapeutics are largely incompatible with PLGA-based delivery systems, as the preparation of these systems generally requires the use of organic solvents (which cause protein denaturation and loss of activity). To this end, we hypothesized that the loading of bioactive proteins into PLGA nanofibers may be accomplished by complexing protein with polyelectrolytes, which could potentially stabilize protein molecules during the loading process. Using this approach for two different proteins (fibrinogen and lysozyme), we demonstrate preservation of 100% of protein activity, which to the best of our knowledge represents the first report of a protein macromolecule retaining meaningful bioactivity upon loading onto PLGA-based nanofibers. These findings may have clinical implications as this novel strategy may potentially expand the use of protein therapeutics for a wide variety of disease states.

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