Targeted Molecular Imaging Agents

Tuesday 23 April 2013

Jing Huang¹, Hyunseok Kang², Liya Wang¹, Run Lin¹, Xianghong Peng², Lily Yang³, Dong Moon Shin², and Hui Mao^4
1Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United States, ²Department of Haematology and Oncology, Emory University, Atlanta, GA, United States, ³Department of Surgery, Emory University, Atlanta, GA, United States, ⁴1. Department of Radiology and Imaging Sciences, 2. Center for Systems Imaging, Emory University, Atlanta, GA, United States

Magnetic iron oxide nanoparticles have shown not only superb MRI contrast enhancement for improving diagnostic sensitivity but also unique capability of imaging guided drug delivery to facilitate the treatment. Here we report the development of a novel theranostic nanoplatform that is composed of milk protein casein coated magnetic iron oxide nanoparticles (CNIOs), near infrared dye Cy5.5, chemotherapy agent cisplatin (cis) and targeting ligand folic acid (FA). We demonstrated that Cy5.5-FAIO-cis are highly efficient in drug delivery and inhibiting tumor growth. Furthermore, the drug delivery process could be monitored by in vivo NIR/MR imaging in cancer animal models.

Rajesh Dash¹, Paul Kim¹, Yuka Matsuura¹, Fumiaki Ikeno¹, Jennifer Lyons¹, Xiaohu Ge¹, Scott Metzler², Ngan Huang¹, Patricia Nguyen³, Joseph Wu^1,4, John Cooke¹, Pilar Ruiz-Lozano², Robert C. Robbins⁵, Michael V. McConnell¹, Alan C. Yeung¹, Phillip Harnish⁶, and Phillip C. Yang^1
1Medicine / Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, United States, ²Pediatrics, Lucille Packard Childrens Hospital, Stanford, CA, United States, ³Medicine / Cardiovascular Medicine, Palo Alto VA Medical Center, Stanford, CA, United States, ⁴Radiology, Stanford University Medical Center, Stanford, California, United States, ⁵Cardiac Surgery, Stanford University Medical Center, Stanford, CA, United States, ⁶Eagle Vision Pharmaceutical Corporation, Downington, PA, United States

We delivered human amnion-derived mesenchymal stem cells (hAMSCs) intramyocardially and tracked in vivo survival using manganese-enhanced MRI (MEMRI). hAMSC therapy led to durable improvements cardiac function due to prolonged survival in vivo, which was confirmed by both MEMRI and co-localized signal from a HSV-tk PET reporter gene. Significant, persistent increases in ejection fraction, as well as reduced LV dilatation and scar volume were observed for up to 6 weeks after hAMSC therapy. Notably, MEMRI CNR increased over time in hAMSC-treated hearts, and immunohistochemistry confirmed the presence of hAMSCs with both human anti-mitochondrial and anti-nuclear antigen antibody staining.

Yoshinori Kato^1,2, Wenlian Zhu¹, Marina V. Backer³, Ronnie C. Mease^1,4, Susanta K. Sarkar⁵, Joseph M. Backer³, and Dmitri Artemov^1,2
1JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, ²Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, ³SibTech, Inc., Brookfield, Connecticut, United States, ⁴Division of Neuroradiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, ⁵Translational/Clinical Imaging, Sanofi Oncology, Cambridge, Massachusetts, United States

Molecular imaging of cancer vasculature via vascular endothelial growth factor receptors (VEGFR) can be important for image-guided drug delivery and for evaluation of the efficacy of anti-angiogenic therapy. Single-chain VEGF (scVEGF)-decorated liposomes loaded with GdDTPA and superparamagnetic iron oxide (SPIO) can serve as a theranostic (therapeutic and imaging) platform that provides targeted delivery of therapeutic agents and MRI probes to tumor vasculature, and simultaneous monitoring of the stability of the carrier. Unique MR contrast enhancement patterns can reliably report the delivery of intact carriers to the target site and the release of the therapeutic cargo.

Brigit den Adel¹, Ernst Suidgeest², Carmen Burtea³, Marieke Stammes², Kim van der Heiden⁴, Sophie Laurent³, Robert E. Poelmann⁵, Robert N. Muller^3,6, and Louise van der Weerd^2
1Pathology, Amsterdam Medical Center, Amsterdam, Netherlands, ²Radiology, Leiden University Medical Center, Leiden, Netherlands, ³General, Organic and Biomedical Chemistry, University of Mons-Hainault, Mons, Belgium, ⁴Biomedical Engineering, Erasmus Medical Center, Rotterdam, Netherlands, ⁵Anatomy, Leiden University Medical Center, Leiden, Netherlands, ⁶Center for Microscopy and Molecular Imaging, University of Mons, Mons, Belgium

The aim of this study was to test whether E-selectin targeted USPIOs could visualize the treatment-specific effects of statin or fibrate treatment on atherosclerotic plaques in ApoE-/- mice. Imaging at two timepoints after USPIO injection allowed us to visualize both endothelial activation and the macrophage pool. E-selectin targeted molecular imaging showed different contrast enhanvement patterns after treatment with the two drugs, consistent with their mechanisms of action. With the fibrate treatment, we shown that plaque size alone is not necessarily a good marker for treatment response.

Sudath Hapuarachchige¹, Wenlian Zhu¹, Yoshinori Kato^1,2, and Dmitri Artemov^1,2
1Division of Cancer Imaging Research, Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, ²Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

Here, we have demonstrated MR/optical image-guided delivery of a two-component system based on modified azido-trastuzumab and drug containing albumin functionalized with strained promoted alkynes. These two components undergo multiple click reactions and assemble on cell surface enhancing the cellular internalization. This strategy was used for the efficient and synergistic delivery of biotherapeutic (trastuzumab) and chemotherapeutic (paclitaxel) as potential new strategy for treatment of trastuzumab resistant HER2/neu overexpressing tumors. Specific delivery of the components to BT-474 xenografts and increased cytotoxicity in vitro in HER2/neu expressing cancer cells is reported.

Zhihang Chen¹, Marie-France Penet¹, Balaji Krishnamachary¹, Sangeeta Ray¹, Cong Li², Paul T. Winnard¹, Martin G. Pomper¹, and Zaver M. Bhujwalla^3
1The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States, ²School of Pharmacy, Fudan University, Shanghai, Shanghai, China, ³Johns Hopkins University, Baltimore, Maryland, United States

Prostate cancer (PCa) is the second leading cause of death from cancer in men in the U.S, and there is a compelling need to find effective treatments for refractory metastatic disease. Theranostic approaches combining detection with treatment hold promise for cancer-cell-specific treatments especially with molecular reagents such as cDNA or siRNA that can increase or decrease the expression of genes of interest. Here we have developed a prostate-specific membrane antigen (PSMA) targeted nanoplex carrying tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cDNA and a prodrug enzyme for theranostic imaging of metastatic PCa.

Ketao Mu¹, Yuanyuan Qin¹, Yan Zhang¹, He Wang², and Wenzhen Zhu^1
1Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, ²MR Rresearch China,GE Healthcare, Shang hai, Shang hai, China

Magnetic targeting is a promising strategy for developing the diagnosis of brain glioma. The purpose of this study was to elucidate strategies for further improvement of this promising approach. Here we present a biocompatible nanocarrier composed of an epidermal growth factor receptor monoclonal antibody (EGFRmAb) coated superparamagnetic iron oxide nanoparticles (SPIONPs) that is capable of specifically targeting glioma tumors via the cellular transmembrane-bound targeting receptor, EGFR. The preferential accumulation of the EGFRmAb-SPIONPs within gliomas and subsequent MRI contrast enhancement were demonstrated in vitro in C6 cells and in vivo in tumors of rat model. The results from cytotoxicity, histopathology and blood toxicity assays suggested that the EGFRmAb-SPIONPs had good biocompatibility and exhibited no toxicity, which was very important for the clinical application. Therefore, these results suggest that EGFRmAb-SPIONPs could be a potential targeting MRI detection platform to aid in the diagnosis of brain gliomas.

Karsten Beiderwellen¹, Thorsten D. Poeppel², Verena Hartung-Knemeyer², Christian Buchbender³, Hilmar Kuehl¹, Andreas Bockisch², and Thomas C. Lauenstein^1
1Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany, ²Clinic for Nuclear Medicine, University Hospital Essen, Essen, Germany, ³Department of Diagnostic and Interventional Radiology, University Hospital Dusseldorf, Dusseldorf, Germany

The current goldstandard in diagnostic imaging consists of PET/CT with somatostatin-analogues such as 68Ga-DOTATOC. Due to the superb soft tissue contrast of MRI and the tendency towards early liver metastases, promising results on retrospective PET-MRI-fusion have been suggested for NETs. Since this method is time consuming and often defective, it is rarely performed in clinical routine. This is the first study on integrated PET/MRI with 68Ga-DOTATOC demonstrating its potential in whole-body staging of NETs, especially in the detection of NET liver metastases.

Patrick Winter¹, John Pearce¹, Zhengtao Chu², Jing-Huei Lee³, and Xiaoyang Qi^2
1Radiology, Cincinnati Children's Hospital, Cincinnati, OH, United States, ²Hematology and Oncology, University of Cincinnati, Cincinnati, OH, United States, ³Center for Imaging Research, University of Cincinnati, Cincinnati, OH, United States

Saposin C (SapC) preferentially binds to phosphatidylserine, which is expressed on tumor cells, but not normal tissues. A novel targeted MRI contrast agent was produced by incorporating paramagnetic gadolinium chelates onto SapC vesicles. The targeting ability of paramagnetic SapC vesicles was studied in vitro with cultured cancer cells and in vivo with a tumor bearing mouse model. These experiments demonstrate that paramagnetic SapC vesicles can target tumors in vivo, providing noninvasive mapping of the cancer biomarker phosphatidylserine.

Jia Zhong^1,2, Penelope Morel³, Hongyan Xu^1,2, Lisa Pusateri^1,2, and Eric T. Ahrens^1,2
1Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States, ²The Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States, ³Department of Immunology, University of Pittsburgh School of Medicine, pittsburgh, Pennsylvania, United States

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system affecting millions of people worldwide. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of MS. EAE is a T cell-mediated inflammatory and demyelinating disease that displays perivascular and parenchymal infiltrates in the central nervous system (CNS). In this study, we applied in vivo 19F MRI methods to quantify the macrophage burden in EAE rats; we show that large number of infiltrates are present in both the CNS and proximal vertebral bone marrow Also, we demonstrate that 19F MRI is very effective in monitoring the therapeutic effects of cyclophosphamide, an apparent EAE treatment. .