Nanomaterials for the detection of cancer-associated biomarkers

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 131-147).Prostate cancer persists as a major public health issue in the United States and remains the second leading cause of cancer death in men. Early detection and disease monitoring in prostate cancer can significantly improve a patient's prognosis. The advent of prostate-specific antigen (PSA) screening has allowed physicians to monitor the levels of a specific protein, or biomarker, as a correlate of disease progression. This thesis focuses on optical detection of prostate tumors through the development of biomarker-targeted molecular imaging probes. In the first part of this work, engineered human prostate cancer cell lines were developed and characterized to determine the dynamics of post-translational processing for PSA proteolytic activity and to establish potential small animal models for validating protease-activatable imaging probes. Target-activatable gold nanoparticle imaging probes that can be self-assembled in a one-step reaction were then developed to detect biomarker proteases in vivo. The activated probes demonstrated a 5 to 8-fold fluorescence signal amplification, extended circulation time, and high image contrast in a mouse tumor model. Lastly, differential phage display selection was performed on human prostate cancer cells with low and high metastatic potentials to (1) identify cell-surface biomarkers specific to highly aggressive tumors, and (2) develop molecular imaging probes for detecting prostate cancer metastases.(cont.) One peptide, LN4P-1, demonstrated preferential binding to highly metastatic PC3M-LN4 cells and identified a highly expressed protein on their cell surface. Fluorescently labeled LN4P-1 was able to detect PC3MLN4 tumors in vivo. In summary, this thesis outlines the development of molecular imaging probes for targeting tumors both at the primary site, through evaluation of biomarker protease activity, and at the metastatic site, through affinity-based analysis of biomarker expression.by Chunyao Jenny Mu.Ph.D