Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Andrew . Tsourkas

Abstract

One of the biggest hurdles in clinical therapy is ensuring that drugs have appropriate pharmacokinetic profiles; they must traffic to sites of interest and accumulate there at relevant concentrations, but must also be eliminated from tissues at a desirable rate. This is especially important in oncology because precise tumor locations may be unknown and therapeutics are often toxic to off-target healthy tissues. Nanoscale drug formulations provide a useful way to modulate and improve the behavior of drugs within biological systems. For example, gold nanoparticles (AuNPs) can be designed with physiochemical properties that allow them to traffic from the bloodstream into tumors. Once there, gold can be utilized for a number of clinical applications in imaging (e.g., photoacoustic, CT) and therapy (e.g., photothermal, radiosensitization). Gold nanoformulations can also provide an excellent platform for delivery of other drugs, thereby allowing targeted multifunctional therapy. However, despite their potential utility, gold particles have been slow to translate into the clinic. One area of concern is the slow biodegradation of gold; AuNPs that are too large for renal excretion (> 5-10 nm) are likely to persist in tissues for months, with unknown long-term health consequences. To address this issue, we have developed novel nanomaterials comprising ultrasmall gold particles (~2-3 nm) that are incorporated within a larger micelle structure (~50-200 nm). The large overall size promotes localization into tumors; however, the use of small individual AuNPs improves long-term excretion. In this work, we first present a polymeric micelle containing ultrasmall AuNPs with a pH-sensitive coating. These nanoassemblies are stable at neutral pH but dissociate in acidic environments (pH 5.0); they demonstrate rapid degradation within cellular lysosomes, which contribute to their progressive and substantial in vivo bioelimination. Next, we describe a multifunctional nanocluster combining ultrasmall AuNPs with a near-infrared dye, indocyanine green, without the need for additional complexing reagents. In an aggressive mouse breast cancer model, intravenously-injected clusters accumulate within tumors and enable photoacoustic imaging and photothermal ablation, ultimately resulting in significantly improved animal survival. Together, these novel clusters present exciting and useful tools for cancer imaging and therapy.

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