Improvements in early detection and screening for prostate cancer have benefited patients by reducing cancer- specific mortality and decreasing the number of those that suffer from the complications of advanced disease. Nevertheless, the balancing of early diagnosis with the potential for overtreatment of prostate cancer remains a clinical dilemma. To distinguish between aggressive and indolent disease, we propose a minimally invasive molecular imaging approach to detect integrin-free tetraspanin CD151free. CD151free is a pool of CD151 that arises as a result of a cell migration switch in prostate epithelium. Increased CD151free levels are predictive of early biochemical recurrence and metastasis in prostate cancer patients post-prostatectomy. Histology analysis indicates that CD151free is selectively detected in prostate cancer, and not in healthy prostate glands. Our studies indicate CD151free to be an independent prognostic factor, significantly improving predictive value compared to Gleason grading and PSA level alone. We propose a non-invasive magnetic resonance (MR) imaging approach to detect and monitor CD151free expression to aid prostate cancer prognosis. To achieve sufficient payload delivery and MR contrast enhancement, we propose a molecularly-targeted macromolecular MR probe that we recently developed. The contrast agent carries a large payload of chelated gadolinium Gd (DOTA) and exhibits a T1 of ~35,000 mM-1s-1, which is four orders of magnitude higher than the T1 of current clinical agents. The contrast agent is self-assembled using protein-based, hollow nanotubes formed by tobacco mosaic virus (TMV). The elongated shape of the nanotube enables evasion from the mononuclear phagocyte system and enhances molecular target recognition. Specific targeting to CD151free in cancerous lesions and metastatic sites will be achieved through immunoconjugates and peptide ligands that bind to CD151free with high specificity and affinity. We hypothesize that the CD151free-targeted, shape-optimized contrast agent with high MR signal enhancement will provide sensitive delineation of CD151free expression in primary lesions and occult metastases. Through Aim 1, we will develop a CD151free-specific dual optical-MR probe. Targeted, Gd (DOTA)-loaded contrast agents will be assembled, and target-specificity will be evaluated in dependence of surface coating (stealth coating vs. camouflage) and nanoparticle shape.
Aim 2 will focus to determine the in vivo MR imaging parameters in xenograft and metastatic mouse models; targeted MRI enhancement and CD151free-specificity will be validated with optical imaging and histology.
Aim 3 sets out to evaluate the utility of our imaging agent in monitoring disease progression and response to treatment longitudinally. Safety of the contrast agents will be evaluated by studying potential immune response, Gd-release and clearance, as well as tissue toxicity. Success in this approach would enable prostate cancer stratification and prognosis as well as follow-up; data indicate correlation of CD151free with aggressiveness of other human malignancies, and therefore this approach may find broad applicability in cancer prognosis.

Public Health Relevance

Improvements in early detection and screening for prostate cancer have benefited patients by reducing cancer- specific mortality. Nevertheless, the balancing of early diagnosis with the potential for overtreatment of prostate cancer remains a clinical dilemma. We will develop a macromolecular magnetic resonance contrast agent targeted to CD151free, a biomarker and prognostic factor of prostate cancer, to aid risk stratification. Non- invasive detection and monitoring of prognostic factors will aid therapeutic intervention and improve patient survival rates.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Zhang, Huiming
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University of California, San Diego
Engineering (All Types)
Schools of Arts and Sciences
La Jolla
United States
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