Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab' antibody fragments was developed using click chemistry. The heterodimer was dual-labeled with a radionuclide (⁶⁴Cu) and fluorescent dye. PET/NIRF imaging and biodistribution studies were performed in four-to-five week old nude athymic mice bearing BxPC-3 (CD105/TF^+/+) or PANC-1 (CD105/TF^-/-) tumor xenografts. A blocking study was conducted to investigate the specificity of the tracer. Ex vivo tissue staining was performed to compare TF/CD105 expression in tissues with PET tracer uptake to validate in vivo results. PET imaging of Cu-NOTA-heterodimer-ZW800 in BxPC-3 tumor xenografts revealed enhanced tumor uptake (21.0 ± 3.4%ID/g; n = 4) compared to the homodimer of TRC-105 (9.6 ± 2.0%ID/g; n = 4; p < 0.01) and ALT-836 (7.6 ± 3.7%ID/g; n = 4; p < 0.01) at 24 h postinjection. Blocking studies revealed that tracer uptake in BxPC-3 tumors could be decreased by 4-fold with TF blocking and 2-fold with CD105 blocking. In the negative model (PANC-1), heterodimer uptake was significantly lower than that found in the BxPC-3 model (3.5 ± 1.1%ID/g; n = 4; p < 0.01). The specificity was confirmed by the successful blocking of CD105 or TF, which demonstrated that the dual targeting with ⁶⁴Cu-NOTA-heterodimer-ZW800 provided an improvement in overall tumor accumulation. Also, fluorescence imaging validated the PET imaging, allowing for clear delineation of the xenograft tumors. Dual-labeled heterodimeric imaging agents, like ⁶⁴Cu-NOTA-heterodimer-ZW800, may increase the overall tumor accumulation in comparison to single-targeted homodimers, leading to improved imaging of cancer and other related diseases.

Professor, Wuhan National Laboratory for Optoelectronics

Education  
2007-2013  Ph.D. College of Life Science and Technolog, HuaZhong University of Science and Technology, Wuhan, China  
2003 -2007  B.S. Department of Plant Science and Technolog, Huazhong Agricultural University, Wuhan, China

  
Research Experience  
2013-2015  Postdoctoral Associate, University of Wisconsin–Madison, Wisconsin, USA 
           Mentor: Associate Professor Weibo Cai 
2015-2018  Research Fellow, Harvard Medical School-Massachusetts General Hospital, Boston, USA 
           Mentor: Associate Professor Annie Chan 
2016- 2018  Research Affiliate, McGovern Institute for Brain Research at MIT, Boston, USA  
           Mentor: Professor Guoping Feng 
2018-now   Professor, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China

Selected Publications 
[1] Haiming Luo*, Reinier Hernandez*, Hao Hong, Stephen A. Graves, Yunan Yang, Christopher G. England, Charles P. Theuer, Robert J. Nickles, and Weibo Cai. Dual-targeting of CD105 and EGFR in vivo using a heterodimer generated via Click Chemistry. Proc Natl Acad Sci U S A, 112(41):12806-11, 2015. (PMID: 26417085; IF 9.504) 
[2] Haiming Luo, Christopher G. England, Sixiang Shi, Stephen A. Graves, Reinier Hernandez, Bai Liu, Charles P. Theuer, Hing C. Wong, Robert J. Nickles, and Weibo Cai. Dual-targeted PET imaging of pancreatic cancer. Clin Cancer Res, 22(15):3821-30, 2016. (PMID: 27026197; IF 10.199) 
[3] Haiming Luo, Lisen Lu, Fei Yang, Liang Wang, Xiaoquan Yang, Qingming Luo, and Zhihong Zhang. Nasopharyngeal Cancer-Specific Therapy Based on Fusion Peptide-Functionalized Lipid Nanoparticles. ACS Nano, 8(5):4334-47, 2014 (PMID: 24766601; IF 13.709) 
[4] Haiming Luo, Christopher G. England, Shreya Goel, Stephen A. Graves, Fanrong Ai, Bai Liu, Charles P. Theuer, Hing C. Wong, Robert J. Nickles, and Weibo Cai. ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment. Mol Pharm, 14(5):1646-1655, 2017. (PMID 28292180; IF 3.987) 
[5] Haiming Luo*, Christopher G. England*, Stephen A. Graves, Haiyan Sun, Glenn Liu, Robert J. Nickles, and Weibo Cai. PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab. J Nucl Med, 57(2):285-90, 2016. (PMID: 26541778; IF 7.439) 
[6] Haiming Luo, Hao Hong, Michael R. Slater, Stephen A. Graves, Sixiang Shi, Yunan Yang, Robert J. Nickles, Frank Fan, and Weibo Cai. PET of c-Met in cancer with 64Cu-labeled Hepatocyte Growth Factor. J Nucl Med, 56(5):758-63, 2015. (PMID: 25840981; IF 7.439)