Date of Award

Winter 2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Pratik Adhikari

Abstract

Personalized medicine, seen as the solution to address the variability among the individuals, is the movement which proposes customization of medical procedures based on the need of the patient during the stages of prevention, diagnosis, treatment, and follow up. As the technology in medicine expands and newer methods of diagnosis and treatment are introduced in the clinic, real time data from the procedures is critical to assess the performance at point of care. Real time feedback, through collection of data at point of care would help make informed clinical decisions, potentially improving the efficacy of the treatment. In this dissertation, the development of instrumentation and data analysis protocols for rapid feedback during clinical application of antimalarial quinine, antifungal amphotericin b, and gold nanoparticles are discussed.

Nanoparticles have emerged as powerful treatment modality in many biomedical sensing and therapeutic applications. The application of intravenously delivered near-infrared absorbing gold nanoparticles for photothermal ablation of solid tumors has been previously reported. A lot of research has been devoted to the development and characterization of gold nanoparticles for clinical applications, and with multiple clinical trials underway, ongoing pre-clinical research continues towards better understanding the in vivo interactions of these particles. The current need for a set of best practices in nanomedicine to increase the in vivo treatment efficacy was the rationale for this investigation.

In an effort to enable informed decisions at point-of-care applications, within a relevant time frame, instrumentation for real-time plasma concentration (multi-wavelength photoplethysmography) and protocols for rapid elemental analysis (energy dispersive X-Ray fluorescence) of tumor tissue samples have been developed in a murine model. This dissertation describes the implementation and characterization of the novel pulse photometer in terms of its sensing application, and outlines the development of a protocol for quantifying the concentration of gold in excised tumors in a clinically relevant time frame (< 24 hours) using energy dispersive X-ray fluorescence protocol developed for this specific purpose. In this dissertation, we evaluate the relationship between circulation pharmacokinetics and tumor accumulation using gold nanorods which passively accumulated in a murine subcutaneous colon cancer model. The plasma concentration of the near-infrared absorbing nanoparticles was monitored in real-time using a novel pulse photometer. The data collected was used to build a bio distribution curve and to calculate circulation half-life as well as the area under the curve (AUC) using an exponential decay model.

New research efforts are described, which focus on adjuvant therapies that are employed to modify circulation parameters, including the AUC, of nanorods and gold nanoshells. Based on the premise that nanoparticles are primarily removed from the blood by the reticuloendothelial system (RES), this dissertation also demonstrates the effects of RES blockade to prolong the circulation of gold nanoparticles tested on a murine model via intravenous administration of X-carrageenan at a concentration of 50 mg/kg. Transient RES blockade techniques have the potential to enhance the circulation time of agents that are cleared by the RES. Preliminary studies demonstrated a greater than 300% increase in average AUC using a reticuloendothelial blockade agent against the control groups.

Further expansion of the application of the novel pulse photometer was achieved by modification of the device for in vivo sensing of other clinically applicable molecular drugs such a quinine and amphotericin b. This dissertation reports the development of a non-invasive optical system capable of reporting the in vivo vascular concentration of these molecular drugs in near real time.

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