Text

theses

Early detection and effective drug delivery remain unresolved challenges that limit the effectiveness of therapeutic regimens against a variety of cancers. Particularly acute are the challenges associated with penetration into the dense matrix of solid tumors and the targeting of metastatic lesions before they become unmanageable. Current clinical imaging techniques employed to detect these lesions are only able to provide anatomical macroscopic information on a tumor state. Additionally, many of these modalities lack the resolution to detect microlesions at a stage ideal for therapeutic intervention, and are unable to resolve lesions in specific tissues such as bone. The early detection and sensitive tracking of disease states is critical to successful management and treatment. While imaging modalities such as MRI and ultrasound provide only anatomical details, optical imaging techniques can provide high content, high resolution images detailing the location and molecular phenotype of a tumor. This is critical in the management of many malignancies including breast cancer, as cell receptor expression dictates therapeutic regimen and is often not conserved through disease progression. Despite the potential for optical imaging to fill this critical role in breast cancer management, there are still numerous challenges that limit its clinical translation. Rare earth nanoprobes (ReNPs) are bright, stable, optically efficient contrast agents that provide many unique advantages over traditional optical imaging fluorophores. When excited with near infrared (NIR, 700-1000 nm) photons, ReNPs emit fluorescence in both the visible (400-700 nm) and short wave infrared (SWIR, 1000-3000 nm) ranges. While the “upconverted” visible photons are quickly absorbed or scattered by biological tissue, SWIR photons can more easily penetrate tissue and be detected via specialized cameras and sensors. In order to impart solubility and cytocompatability, we have encapsulated ReNPs in human serum albumin to generate rare earth albumin nanocomposites (ReANCs). The tunable albumin coating of ReANCs allows for a wide range of ligands, therapeutic payloads, and permeation enhancers to be conjugated to the surface of the particle’s shell. These characteristics yield multifunctional nanoprobes that can be adapted for many purposes including targeted imaging. This dissertation is focused on engineering biocompatible ReANCs as a multifunctional contrast agent capable of improved payload delivery, in vivo SWIR based optical imaging, and targeted imaging and molecular mapping of solid tumors. This study describes the development of drug loaded, tumor penetrating albumin nanoshells designed to overcome physiological barriers to solid tumor drug delivery. These nanoparticles are then further engineered to encapsulate SWIR emitting contrast agents, which form the basis of a novel optical imaging platform capable of the sensitive and specific detection of metastatic breast cancer. The resulting ReANCs were targeted to markers of breast cancer metastasis to enable early detection of small–scale lesions in the animal’s lungs. Strikingly, these targeted particles were capable of identifying receptor positive lesions, allowing for a non-invasive ‘optical biopsy’ that could be used to determine therapeutic intervention. These nanoparticles were then used to detect distant site metastasis in animal’s long bones and adrenal glands. Notably, ReANCs were capable of accumulating in and identifying metastatic lesions in animal’s bones prior to their detection with MRI. The cumulative findings of this work describe a multifunctional probe capable of surveillance of metastatic disease and of its therapeutic responsiveness.

ETD_7586

Ph.D.

Includes bibliographical references

by Margot Alexandra Nash Zevon

doi:10.7282/T3FN18JJ

ETD doctoral

The author owns the copyright to this work.