Date Approved

6-27-2022

Embargo Period

6-28-2022

Document Type

Dissertation

Degree Name

Ph.D. Doctor of Philosophy

Department

Biomedical Engineering

College

Henry M. Rowan College of Engineering

Advisor

Mark E. Byrne, Ph.D.

Committee Member 1

Jacek Wower, Ph.D.

Committee Member 2

Vince Beachley, Ph.D.

Committee Member 3

Sebastian Vega, Ph.D.

Committee Member 4

Mary Alpaugh, Ph.D.

Committee Member 5

Chun Wu, Ph.D.

Keywords

nanoparticles, biomimetic, controlled release, therapeutic drugs, nucleic acid, nanocarriers

Subject(s)

Nanomedicine; Pharmaceutical biotechnology

Disciplines

Biomedical Engineering and Bioengineering | Medicinal Chemistry and Pharmaceutics | Nanoscience and Nanotechnology

Abstract

The inherent chemical, mechanical, and structural properties of nucleic acids make them ideal candidates for the formulation of tunable, personalized drug nanocarriers. However, none so far have exploited these properties for the controlled release of therapeutic drugs. In this dissertation, a biomimetic approach to controlling drug release is exhibited by specifically manipulating the architecture of novel, DNA nanoparticles to take advantage of drug binding mechanisms of action. Rationally designed DNA strands were immobilized on gold surfaces via a terminal thiol modification. Immobilized monomers can be manipulated to form distinct monolayer architectures including flat, folded, coiled, or stretched structures. Increasing the rate of folding is shown to restrict the diffusion of a surface-bound drug while upright architectures released drug at a 2 - 10 fold rate, depending on sequence length - using this strategy an over four-week release of dexamethasone was achieved. Furthermore, the release of an intercalating drug is controlled by exploiting sequence-specific affinities of the drug toward DNA. Here, using a high-affinity sequence and increasing the strand length a near zero-order release of daunomycin was achieved for up to 12 days. With this work, it is shown for the first time that the mechanisms of drug binding to nucleic acids can be utilized to produce highly controlled drug release from gold-core nucleic acid nanoparticles. These results will have a profound impact on the future design of novel, therapeutic nanocarriers.

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