(420x) Magnetic Nanoparticles for Non-Invasive Quantification of Prostate Cancer Aggressiveness
Prostate Cancer (PCa) is the most diagnosed non-skin malignancy and the second leading cause of death from cancer among men in the United States. Therapies for PCa, unfortunately, remain ineffective. In order to achieve more effective therapy, early and accurate detection of prostate cancer is necessary. Current Screening technologies for PCa, including the prostate-specific antigen (PSA) test, are limited by false-negatives and false-positives. Additionally, even when PCa is successfully detected, these screens provide no indication of the aggressiveness of the disease. Improved molecular imaging techniques, that are both quantitative and sensitive, and that can non-invasively detect processes deep within the human body are required to monitor changes which may be predictors of treatment outcomes. We have developed multimodal and bioprocess-sensitive “smart” magnetic nanoparticles (MNP) which respond to overexpressed protease activity in the tumor microenvironment – and thus to tumor aggressiveness – and which can be monitored and quantified non-invasively over the entire tumor volume. Cancer cells overexpressing legumain protease have been shown to have an invasive and metastatic phenotype in vivo. Legumain specifically degrades peptides containing an AANL-peptide sequence. We conjugated a fluorescence marker via the legumain cleavable AANL-peptide linker (LCP). This fluorescent-MNP displayed sensitivity to legumain activity; slowly releasing the fluorescent marker in low activity microenvironments and more rapidly in the presence of high legumain activity. Release of Dy747 resulted in a decrease in the fluorescence signal in tumors, due to wash-out into the blood flow, at a rate proportional to the local proteolytic activity. Quantitative MRI analysis indicated the amount of agent delivered to a particular location, providing the baseline to correct for tumor heterogeneity. Taken together, the fluorescent/MRI signal ratio is a function of the local proteolytic activity.