Protein MRI Contrast Agents(ProCAs)

Based on our proprietary protein design and computational technology for metalloproteins, we have developed a novel class of protein contrast agents (ProCAs) with significantly increased both r1 and r2 relaxivities and a ~100-fold improvement in vivo contrast capabilities and doubled accuracy. This platform technology enables us to develop both blood pool (non-targeted) contrast agents for soft tissues and biomarker targeted molecular imaging contrast agents that address major unmet medical needs in non-invasive precision diagnostics. Due to optimized in vivo and relaxation properties, a single injection of the blood pool non-targeted ProCA contrast agents enables the acquisition of both bright contrast (T1-weighted) and dark contrast (T2-weighted) that has never been achieved before. For example, our contrast agents enable the early detection of small early stage tumors such as primary liver and micrometastatic lesions from breast, ovarian and uveal melanoma cancer down to 0.1-2 mm from the current threshold of 1-2 cm, at relatively late cancer stage. We have created a set of molecular imaging MRI contrast agents (tProCAs) that specifically target major biomarkers including EGFR, HER2/Neu, GRPR, chemokine receptor (CXCR4), PSMA, integrin, and collagen. These targeted MRI contrast agents have further improved sensitivity and specificity with the capability to detect infiltrative small lesions and distinguish benign and subtypes of cancers and their heterogeneity. These molecular imaging contrast agents have unique quantification capability for biomarker expression and occupancy with high spatial resolution due to their strong penetration capability in tumor tissue and the endothelial boundary. We have successfully applied these targeted MRI contrast agents to non-invasively access the expression levels and patterns of biomarkers for cancer staging and to monitor disease progression or regression upon treatment in cluster 2-3 D tumor cell clusters, infiltrative tumor patterns, and xenograft murine models for prostate cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, liver cancer and metastasis. For example, collagen targeted ProCAs are able to detect early stage liver fibrosis that is possible to be reversed with adequate treatment. Thus our molecular imaging contrast agents are expect to avoid limitations of the gold standard biopsy, including large sampling errors by non-invasive and quantitative MRI without use of radiation. Importantly, we recently demonstrated that protein contrast agents exhibit unprecedented metal selectivity over endogenous metal ions. The injected dose in mice application is also about 25-100 fold lower due to their optimized relaxivity, organ, tissue, and tumor distribution. We have not detected any acute toxicity and immunogenicity. These results clearly support the potential of ProCAs to mitigate metal toxicity associated with nephrogenic systematic fibrosis. Our protein-based MRI-CAs are expected to enable non-invasive disease early detection, staging, monitoring therapeutic effects, and image-guided treatment/ intervention with enhanced safety, sensitivity and accuracy in both clinical and preclinical applications.

Publications

  • (1) Fan Pu, Mani Salarian, Shenghui Xue, Jingjuan Qiao, Jie Feng, Shanshan Tan, Anvi Patel Xin Li, Kenza Mamouni, Khan Hekmatyar, Juan Zou, Daqing Wu and Jenny J. Yang. Nanoscale, 2016, DOI: 10.1039/C5NR09071G. (2) Fan Pu, Jingjuan Qiao, Shenghui Xue, Hua Yang, Anvi Patel, Lixia Wei, Khan Heckmataryar, Hans E. Grossniklaus, Zhi-Ren Liu, and Jenny Yang. Scientific Reports, Nature (2015), PMID:26577829.
  • (2) Shenghui Xue, Hua Yang, Jingjuan Qiao, Fan Pu, Jie Jiang, Kendra Harburd, Khan Hekmatarya, Jason Langley, Mani Salarian, Robert Long, Robert R Bryant, Xiaoping Hu, Hans E. Grossniklaus, Zhi-Ren Liu, and Jenny J. Yang. PNAS (2015) PMID: 25971726.
  • (3) Shenghui Xue, Jingjuan Qiao, Jie Jiang, Lixia Wei, Shunyi Li, Kendra Hubbard, Natalie White, Zhiren Liu, Jenny J. Yang, Medical Research Review, (2014), PMID:24615853
  • (4) Shenghui Xue, Jingjuan Qiao, Fan Pu, Mathew Cameron, and Jenny J. Yang. WIREs (2013) Mar;5(2):163-79.
  • (5) Jingjuan Qiao, Shunyi Li, Wei Lixia, Jie Jiang, Robert Long, Hui Mao, Wei Ling, HuaYang, Hans Grossniklauss and Zhi-Ren Liu, Jenny J. Yang PLOS ONE ( 2011) Mar 24;6(3):e18103.PMID: 21455310
  • (6) Shunyi Li, Jie Jiang, Jin Zou,Jinjuan Qiao, Lixia Wei, Yubin Zhou, Shenghui Xue, Yanyi Chen, Robert Long, Liya Wang, Adriana Castiblanco, Natalie White, Jen Ngo, Wanda Zhou, Wei Ling, Hui Mao, Zhi-Ren Liu, and Jenny J. Yang. Journal of Inorganic Biochemistry (2011). PMID:22178673
  • (7) Lixia Wei, Shunyi Li, Jianhua Yang, Yiming Ye, Jin Zou, Omar Zurkiya, Robert Long,Julian Johnson, Jingjuan Qiao, Adriana Castiblanco, Natalie Maor, Yangyi Chen, Wangda Zhou, Hui Mao, Xiaoping Hu, Jenny J. Yang, and Zhi-Ren Liu, Molecular Imaging and Biology (2010). 32(5):521-5, PMID: 20574851
  • (8) Jenny J. Yang, Jianhua Yang, Lixia Wei, Wei Yang, Omar Zurkiya, Hui Mao, Fuqian Zhao, Russell Malchow, Shunyi Li, Anna L. Wilkins Mannicia, Shumin Zhao, Jin Zou, Julian Johnson, Xiaoping Hu, Eirk Krogstad, and Zhi-Ren Liu, Journal of the American Chemical Society (2008) 130(29):9260-7. PMID:18576649.

Patents

  • Patent No.: CN101222878 B; Dec 26, 2012; Issued
  • Patent No.: US8367040 B2; Feb 5, 2013, Issued
  • Patent No.: EP1928507 B1; Nov 11, 2015, Issued
  • Patent No.: US8173105 B2 ; May 8, 2012, Issued
  • Patent No.: CA2614486 A1; Jan 18, 2007, Application
  • Patent No.: CA2614486 C; Sep 16, 2014, Application
  • Patent No.: EP1901659 A2; Mar 26, 2008, Application
  • Patent No.: EP1901659 A4; Jan 29, 2014, Application
  • Patent No.: WO2007009058 A2; Jan 18, 2007, Application
  • Patent No.: WO2007009058 A3; Apr 19, 2007, Application
  • Patent No.: US20110097742 A1; Apr 28, 2011, Application
  • Patent No.: EP2257316 A2; Dec 8, 2010, Application
  • Patent No.: EP2257316 A4; Oct 22, 2014, Application
  • Patent No.: WO2009146099 A2; Dec 3, 2009, Application
  • Patent No.: WO2009146099 A3; Feb 18, 2010, Application
  • Patent No.: PCT/US2009/039276; Feb 18, 2010, Application
  • Patent No.: US20090087382 A1; Apr 2, 2009, Application
  • Patent No.: US20120269735 A1; Oct 25, 2012, Application
  • Patent No.: WO 2007/030802 A2; Mar 15, 2007, Application
  • Patent No.: CA2621763 A1; Mar 15, 2007, Application
  • Patent No.: EP1928507 A2; Jun 11, 2008, Application
  • Patent No.: EP1928507 A4; May 11, 2011, Application
  • Patent No.: WO2007030802 A3; Jan 31, 2008, Application
  • Patent No.: WO2013184786 A3; Jan 30, 2014, Application
  • Patent No.: US20150202330 A1; Jul 23, 2015, Application
  • Patent No.: WO2013184786 A2; Dec 12, 2013, Application