Abstract
1053
Objectives: The major barrier to our unmet medical needs in early detection of cancer and effective treatment is our limitations in develop novel MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, tumor targeting, high intra-tumoral distribution and no toxicity. To address the critical need, we have pioneered in development of a novel class of protein MRI contrast agents (ProCAs) with significant improvement of both r1 and r2relaxivities and in vivo dose efficiency in mouse models.
Methods: We have developed a sensitive and high-resolution MRI technique called precision and progressive molecular MR Imaging portray (pMRI) to interrogate the changes in molecular signatures of primary tumor and associated early-stage liver fibrosis and metastasis. In this study, we report the successful design of an array of ProCAs comprised of altered human protein scaffolds with engineered metal-chelating sites. ProCAs and pMRI exhibit ~100-fold improvement in tumor detection size and doubled accuracy. We have further developed 9 types of targeted ProCAs to major molecular biomarkers including HER2, EGFR, GRPR, VEGFR, CXCR4, and collagen that expressed on various type of cancers and stroma.
Results: We demonstrate that targeted ProCA32s are capable of non-invasively determination of the identity, quantity, and spatial location of the several major cancer types including breast, lung, ovarian, prostate cancer and liver metastases from uveal melanoma, breast and ovarian cancer in various animal models with significantly improved sensitivity and specificity. In addition, targeted ProCA32s is able to detect early stage of fibrosis, NASH and monitoring liver fibrosis progression as well as monitoring of drug treatment.
Conclusions: ProCAs exhibit super metal safety compared with all approved “safe” agents. Rapid development of pMRI platform technology and regulatory studies of ProCAs are expected to enable us to non-invasively determine the identity, quantity, and spatial location of the several major cancer cell types and their contribution to the heterogeneity of a tumor and its microenvironment. This will fill in the major gap with high translational capability which will have broad applications in medical diagnostics for early detection, monitoring progression, image-guided intervention, and drug development.