Publications by authors named "Monica Shokeen"

26 Publications

  • Page 1 of 1

Novel Agents and Future Perspectives on Theranostics.

Semin Radiat Oncol 2021 Jan;31(1):83-92

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Radiology, Weill Cornell Medical College, New York, NY.. Electronic address:

In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed therapy and norepinephrine transporter targeted I-MIBG therapies by the FDA and the rapid progress of highly promising beta and alpha emitter tagged PSMA directed therapy of prostate cancer have stimulated clinically impactful changes in practice. Many novel strategies are being explored and novel radiopharmaceutical therapeutic agents including peptide based ligands as well as antibodies or antibody fragments are being developed preclinically or are in early phase clinical trials. While beta particle emitters have most commonly been used for targeted radiotherapy and radioimmunotargeting, there is an emerging interest in alpha emitters that cause greater density of ionization events leading to increased double-strand DNA damage and cluster breaks because of the high-energy particles within a shorter tissue range of penetration and thereby lower toxicity to adjacent normal tissues.
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http://dx.doi.org/10.1016/j.semradonc.2020.07.010DOI Listing
January 2021

Development of [Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma.

Eur J Nucl Med Mol Imaging 2020 Nov 11. Epub 2020 Nov 11.

Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models.

Methods: Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [Zr]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [Zr]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [F]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [Zr]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography.

Results: [Zr]DFO-elotuzumab was produced with high specific activity (56 ± 0.75 MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1S-CG cells. Compared to [Zr]DFO-IgG, [Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [Zr]DFO-elotuzumab in the bones. Importantly, while [F]FDG demonstrated similar uptake in the bone and muscle, [Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones.

Conclusion: These data demonstrate the feasibility of [Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
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http://dx.doi.org/10.1007/s00259-020-05097-yDOI Listing
November 2020

Preclinical Development of Near-Infrared-Labeled CD38-Targeted Daratumumab for Optical Imaging of CD38 in Multiple Myeloma.

Mol Imaging Biol 2021 Apr 22;23(2):186-195. Epub 2020 Sep 22.

Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Purpose: Cluster of differentiation 38 (CD38) is a promising therapeutic target in multiple myeloma (MM) patients and has resulted in the development of several CD38 immunotherapies. Current methods to evaluate CD38 expression in the preclinical setting include ex vivo flow cytometry and immunohistochemistry, which can be cumbersome and do not give whole-body information. In vivo imaging technologies such as positron emission tomography rely on decay of radioisotopes, limiting the number of molecular interactions observed at any given time point. Here, we demonstrate the use of near-infrared (NIR) fluorescence imaging for spatiotemporal monitoring of CD38 expression in preclinical MM using the anti-CD38 daratumumab (DARA) conjugated to the NIR fluorophore IRDye800CW (DARA-IRDye800).

Procedures: Stability studies with human serum and binding assays with human myeloma cells were performed with DARA-IRDye800. Immunocompromised mice with intra- and extramedullary tumors (n = 5/group) were administered with DARA-IRDye800 for in vivo imaging up to 7 days after injection. Ex vivo biodistribution and flow cytometry studies were performed to validate in vivo imaging results. A separate therapy study was performed in mice with intramedullary tumors that were treated and not treated with DARA at a therapeutic dose (n = 7/group). DARA-IRDye800 was administered for subsequent in vivo and ex vivo imaging in both cohorts of mice.

Results: DARA-IRDye800 maintained stability and had high affinity for CD38 (K = 3.5 ± 0.05 nM). DARA-IRDye800 demonstrated a 5- and 18-fold increase in contrast in tumor-bearing regions of mice with extra- and intramedullary MM. Finally, mice treated with therapeutic doses of DARA and imaged with DARA-IRDye800 showed an 11-fold decrease in fluorescence intensities in vivo compared with untreated controls.

Conclusions: Our studies establish DARA-IRDye800 as a promising contrast agent for preclinical evaluation of CD38 expression and for further investigating myeloma engraftment and kinetics in relation to anti-CD38 therapies.
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http://dx.doi.org/10.1007/s11307-020-01542-4DOI Listing
April 2021

Osteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma.

ACS Nano 2020 04 6;14(4):4255-4264. Epub 2020 Apr 6.

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Rapid liver and spleen opsonization of systemically administered nanoparticles (NPs) for applications remains the Achilles' heel of nanomedicine, allowing only a small fraction of the materials to reach the intended target tissue. Although focusing on diseases that reside in the natural disposal organs for nanoparticles is a viable option, it limits the plurality of lesions that could benefit from nanomedical interventions. Here we designed a theranostic nanoplatform consisting of reactive oxygen (ROS)-generating titanium dioxide (TiO) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide (Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO NPs with Zr afforded thermodynamically and kinetically stable chelate-free Zr-TiO-Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with Zr-TiO-Tf generated cytotoxic ROS to induce cancer cell killing the apoptosis pathway. Positron emission tomography/X-ray computed tomography (PET/CT) imaging and tissue biodistribution studies revealed that administration of Zr-TiO-Tf in mice leveraged the osteotropic effect of Zr to selectively localize about 70% of the injected radioactivity in mouse bone tissue. A combination of small-animal PET/CT imaging of NP distribution and bioluminescence imaging of cancer progression showed that a single-dose Zr-TiO-Tf treatment in a disseminated MM mouse model completely inhibited cancer growth at euthanasia of untreated mice and at least doubled the survival of treated mice. Treatment of the mice with cold Zr-TiO-Tf, Zr-oxalate, or Zr-Tf had no therapeutic benefit compared to untreated controls. This study reveals an effective radionuclide sensitizing nanophototherapy paradigm for the treatment of MM and possibly other bone-associated malignancies.
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http://dx.doi.org/10.1021/acsnano.9b09618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295119PMC
April 2020

Changing landscape of optical imaging in skeletal metastases.

J Bone Oncol 2019 Aug 27;17:100249. Epub 2019 Jun 27.

Department of Radiology, Washington University School of Medicine, 4515 McKinley Ave, St. Louis, MO 63110, United States.

Optical imaging is an emerging strategy for and visualization of the molecular mechanisms of cancer over time. An increasing number of optical imaging contrast agents and techniques have been developed in recent years specifically for bone research and skeletal metastases. Visualizing molecular processes in relation to bone remodeling in metastasized cancers provides valuable information for understanding disease mechanisms and monitoring expression of primary molecular targets and therapeutic efficacy. This review is intended to provide an overview of tumor-specific and non-specific contrast agents in the first near-infrared window (NIR-I) window from 650 nm to 950 nm that can be used to study functional and structural aspects of skeletal remodeling of cancer in preclinical animal models. Near-infrared (NIR) optical imaging techniques, specifically NIR spectroscopy and photoacoustic imaging, and their use in skeletal metastases will also be discussed. Perspectives on the promises and challenges facing this exciting field are then given.
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http://dx.doi.org/10.1016/j.jbo.2019.100249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611980PMC
August 2019

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy.

NMR Biomed 2019 09 17;32(9):e4122. Epub 2019 Jun 17.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.

Multiple myeloma (MM) is a largely incurable, debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Identification of therapeutic response is critical for improving outcomes and minimizing costs and off-target toxicities. To assess changes in BM environmental factors and therapy efficacy, there is a need for noninvasive, nonionizing, longitudinal, preclinical methods. Here, we demonstrate the feasibility of preclinical magnetic resonance imaging (MRI) for longitudinal imaging of diffuse tumor burden in a syngeneic, immunocompetent model of intramedullary MM. C57Bl/KaLwRij mice were implanted intravenously with 5TGM1-GFP tumors and treated with a proteasome inhibitor, bortezomib, or vehicle control. MRI was performed weekly with a Helmholtz radiofrequency coil placed on the hind leg. Mean normalized T1-weighted signal intensities and T2 relaxation times were quantified for each animal following manual delineation of BM regions in the femur and tibia. Finally, tumor burden was quantified for each tissue using hematoxylin and eosin staining. Changes in T2 relaxation times correlated strongly to cell density and overall tumor burden in the BM. Median T2 relaxation times and regional T1-weighted contrast uptake were shown to be most relevant in identifying posttherapy disease stage in this model of intramedullary MM. In summary, our results highlighted potential preclinical MRI markers for assessing tumor burden and BM heterogeneity following bortezomib therapy, and demonstrated the application of longitudinal imaging with preclinical MRI in an immunocompetent, intramedullary setting.
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http://dx.doi.org/10.1002/nbm.4122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692195PMC
September 2019

Assessment of Targeted Nanoparticle Assemblies for Atherosclerosis Imaging with Positron Emission Tomography and Potential for Clinical Translation.

ACS Appl Mater Interfaces 2019 May 19;11(17):15316-15321. Epub 2019 Apr 19.

Materials Department , University of California , Santa Barbara , California 93106 , United States.

Nanoparticles have been assessed in preclinical models of atherosclerosis for detection of plaque complexity and treatment. However, their successful clinical translation has been hampered by less than satisfactory plaque detection and lack of a general strategy for assessing the translational potential of nanoparticles. Herein, nanoparticles based on comb-co-polymer assemblies were synthesized through a modular construction approach with precise control over the conjugation of multiple functional building blocks for in vivo evaluation. This high level of design control also allows physicochemical properties to be varied in a controllable fashion. Through conjugation of c-atrial natriuretic factor (CANF) peptide and radiolabeling with Cu, the Cu-CANF-comb nanoparticle was assessed for plaque imaging by targeting natriuretic peptide clearance receptor (NPRC) in a double-injury atherosclerosis model in rabbits. The prolonged blood circulation and enhanced binding capacity of Cu-CANF-comb nanoparticles provided sensitive and specific imaging of NPRC overexpressed in atherosclerotic lesions by positron emission tomography at intervals during the progression of the disease. Ex vivo tissue validation using autoradiography and immunostaining on human carotid endarterectomy specimens demonstrated specific binding of Cu-CANF-comb to human NPRC receptors. Taken together, this study not only shows the potential of NPRC-targeted Cu-CANF-comb nanoparticles for increased sensitivity to an epitope that increases during atherosclerosis plaque development but also provides a useful strategy for the general design and assessment of the translational potential of nanoparticles in cardiovascular imaging.
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http://dx.doi.org/10.1021/acsami.9b02750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918720PMC
May 2019

Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice.

Am J Physiol Regul Integr Comp Physiol 2019 05 20;316(5):R678-R686. Epub 2019 Mar 20.

Department of Internal Medicine, Hematology and Oncology Division, University of Iowa , Iowa City, Iowa.

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival ( = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.
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http://dx.doi.org/10.1152/ajpregu.00388.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589607PMC
May 2019

Nanotherapeutics for multiple myeloma.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2018 11 26;10(6):e1526. Epub 2018 Apr 26.

Department of Radiology, Washington University, St. Louis, Missouri.

Multiple myeloma (MM) is an age-related hematological malignancy with an estimated 30,000 new cases and 13,000 deaths per year. A disease of antibody-secreting malignant plasma B-cells that grow primarily in the bone marrow (BM), MM causes debilitating fractures, anemia, renal failure, and hypercalcemia. In addition to the abnormal genetic profile of MM cells, the permissive BM microenvironment (BMM) supports MM pathogenesis. Although advances in treatment options have significantly enhanced survival in MM patients, transient perfusion of small-molecule drugs in the BM does not provide sufficient residence to enhance MM cell-drug interaction, thus allowing some myeloma cells to escape the first line of treatment. As such, there remains a crucial need to develop advanced drug delivery systems that can navigate the complex BMM and effectively reach the myeloma cells. The high vascular density and spongy nature of bone structure suggest that nanoparticles (NPs) can serve as smart drug-delivery systems capable of extravasation and retention in various BM compartments to exert a durable therapeutic effect. In this focus article, we first summarize the pathophysiology of MM, emphasizing how the BM niche presents serious challenges for effective treatment of MM with small-molecule drugs. We then pivot to current efforts to develop NP-based drug carriers and intrinsically therapeutic nanotherapeutics. The article concludes with a brief perspective on the opportunities and challenges in developing and translating nanotherapeutics to improve the treatment outcomes of MM patients. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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http://dx.doi.org/10.1002/wnan.1526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185771PMC
November 2018

Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with F-FDOPA and F-FDG PET.

J Nucl Med 2018 10 26;59(10):1551-1557. Epub 2018 Apr 26.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-F-fluoro-l-phenylalanine (F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic F-FDG and F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUV, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both F-FDG and F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in F-FDG and F-FDOPA uptake, with an increase in F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. F-FDOPA PET/CT complemented F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.
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http://dx.doi.org/10.2967/jnumed.118.208744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167538PMC
October 2018

Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer.

Nat Commun 2018 01 18;9(1):275. Epub 2018 Jan 18.

Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease.
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http://dx.doi.org/10.1038/s41467-017-02758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773683PMC
January 2018

Preclinical Development of CD38-Targeted [Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma.

J Nucl Med 2018 02 12;59(2):216-222. Epub 2017 Oct 12.

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri

Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein overexpressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is a U.S. Food and Drug Administration-approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [Zr]Zr-desferrioxamine (DFO)-daratumumab PET/CT imaging in MM tumor models. Daratumumab was conjugated to DFO--benzyl-isothiocyanate (DFO-Bz-NCS) for radiolabeling with Zr. Chelator conjugation was confirmed by electrospray ionization-mass spectrometry, and radiolabeling was monitored by instant thin-layer chromatography. Daratumumab was conjugated to Cyanine5 (Cy5) dye for cell microscopy. In vitro and in vivo evaluation of [Zr]Zr-DFO-daratumumab was performed using CD38 human myeloma MM1.S- (MM1.S) cells. Cellular studies determined the affinity, immunoreactivity, and specificity of [Zr]Zr-DFO-daratumumab. A 5TGM1- (5TGM1)/KaLwRij MM mouse model served as control for imaging background noise. [Zr]Zr-DFO-daratumumab PET/CT small-animal imaging was performed in severe combined immunodeficient mice bearing solid and disseminated MM tumors. Tissue biodistribution (7 d after tracer administration, 1.11 MBq/animal, = 4-6/group) was performed in wild-type and MM1.S tumor-bearing mice. A specific activity of 55.5 MBq/nmol (0.37 MBq/μg) was reproducibly obtained with [Zr]Zr-daratumumab-DFO. Flow cytometry confirmed CD38 expression (>99%) on the surface of MM1.S cells. Confocal microscopy with daratumumab-Cy5 demonstrated specific cell binding. Dissociation constant, 3.3 nM (±0.58), and receptor density, 10.1 fmol/mg (±0.64), was obtained with a saturation binding assay. [Zr]Zr-DFO-daratumumab/PET demonstrated specificity and sensitivity for detecting CD38 myeloma tumors of variable sizes (8.5-128 mm) with standardized uptake values ranging from 2.1 to 9.3. Discrete medullar lesions, confirmed by bioluminescence images, were efficiently imaged with [Zr]Zr-DFO-daratumumab/PET. Biodistribution at 7 d after administration of [Zr]Zr-DFO-daratumumab showed prominent tumor uptake (27.7 ± 7.6 percentage injected dose per gram). In vivo blocking was achieved with a 200-fold excess of unlabeled daratumumab. [Zr]Zr-DFO- and Cy5-daratumumab demonstrated superb binding to CD38 human MM cells and significantly low binding to CD38 cells. Daratumumab bioconjugates are being evaluated for image-guided delivery of therapeutic radionuclides.
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http://dx.doi.org/10.2967/jnumed.117.196063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807532PMC
February 2018

Enhancing in vivo tumor boundary delineation with structured illumination fluorescence molecular imaging and spatial gradient mapping.

J Biomed Opt 2016 08;21(8):80502

Washington University School of Medicine, Department of Radiology, 4515 McKinley Avenue, St. Louis, Missouri 63110, United States.

Fluorescence imaging, in combination with tumor-avid near-infrared (NIR) fluorescent molecular probes, provides high specificity and sensitivity for cancer detection in preclinical animal models, and more recently, assistance during oncologic surgery. However, conventional camera-based fluorescence imaging techniques are heavily surface-weighted such that surface reflection from skin or other nontumor tissue and nonspecific fluorescence signals dominate, obscuring true cancer-specific signals and blurring tumor boundaries. To address this challenge, we applied structured illumination fluorescence molecular imaging (SIFMI) in live animals for automated subtraction of nonspecific surface signals to better delineate accumulation of an NIR fluorescent probe targeting α4β1 integrin in mice bearing subcutaneous plasma cell xenografts. SIFMI demonstrated a fivefold improvement in tumor-to-background contrast when compared with other full-field fluorescence imaging methods and required significantly reduced scanning time compared with diffuse optical spectroscopy imaging. Furthermore, the spatial gradient mapping enhanced highlighting of tumor boundaries. Through the relatively simple hardware and software modifications described, SIFMI can be integrated with clinical fluorescence imaging systems, enhancing intraoperative tumor boundary delineation from the uninvolved tissue.
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http://dx.doi.org/10.1117/1.JBO.21.8.080502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005463PMC
August 2016

Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma.

Clin Cancer Res 2017 Jan 2;23(2):416-429. Epub 2016 Aug 2.

Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.

Purpose: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo EXPERIMENTAL DESIGN: Acetate fate tracking using C-edited-H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using C-acetate-PET/CT imaging and tissue biodistribution.

Results: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, C-acetate uptake was significantly reduced in MM tumors after treatment.

Conclusions: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. C-Acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. C-Acetate-PET also detected response to therapy in vivo Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that C-acetate-PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416-29. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241171PMC
January 2017

Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents.

J Nucl Med 2016 Apr 7;57(4):640-5. Epub 2016 Jan 7.

Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, Missouri

Unlabelled: Very-late-antigen-4 (VLA-4, α4β1 integrin, CD49d/CD29) is a transmembrane adhesion receptor that plays an important role in cancer and immune responses. Enhanced VLA-4 expression has been observed in multiple myeloma (MM) cells and surrounding stroma. VLA-4 conformational activation has been associated with MM pathogenesis. VLA-4 is a promising MM imaging and therapeutic biomarker.

Methods: Specificity of (64)Cu-LLP2A ((64)Cu-CB-TE1A1P-PEG4-LLP2A), a high-affinity VLA-4 peptidomimetic-based radiopharmaceutical, was evaluated in α4 knock-out mice and by competitive blocking in wild-type tumor-bearing mice. (64)Cu-LLP2A PET/CT (static and dynamic) imaging was conducted in C57BL6/KaLwRij mice bearing murine 5TGM1-GFP syngeneic tumors generated after intravenous injection via the tail. Blood samples were collected for serum protein electrophoresis. Bone marrow and splenic cells extracted from tumor-bearing and control mice (n= 3/group) were coincubated with the optical analog LLP2A-Cy5 and mouse B220, CD4, Gr1, and Mac1 antibodies and analyzed by fluorescence-activated cell sorting. Human radiation dose estimates for (64)Cu-LLP2A were extrapolated from mouse biodistribution data (6 time points, 0.78 MBq/animal, n= 4/group). Ten formalin-fixed paraffin-embedded bone marrow samples from deceased MM patients were stained with LLP2A-Cy5.

Results: (64)Cu-LLP2A and LLP2A-Cy5 demonstrated high specificity for VLA-4-positive mouse 5TGM1-GFP myeloma and nonmalignant inflammatory host cells such as T cells and myeloid/monocytic cells. Ex vivo flow cytometric analysis supported a direct effect of myeloma on increased VLA-4 expression in host hematopoietic microenvironmental elements. SUVs and the number of medullar lesions detected by (64)Cu-LLP2A PET corresponded with increased monoclonal (M) protein (g/dL) in tumor-bearing mice over time (3.29 ± 0.58 at week 0 and 9.97 ± 1.52 at week 3). Dynamic PET with (64)Cu-LLP2A and (18)F-FDG demonstrated comparable SUV in the prominent lesions in the femur. Human radiation dose estimates indicated urinary bladder wall as the dose-limiting organ (0.200 mGy/MBq), whereas the dose to the red marrow was 0.006 mGy/MBq. The effective dose was estimated to be 0.017 mSv/MBq. Seven of the ten human samples displayed a high proportion of cells intensely labeled with LLP2A-Cy5 probe.

Conclusion: (64)Cu-LLP2A and LLP2A-Cy5 demonstrated binding specificity for VLA-4 in an immune-competent murine MM model. (64)Cu-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for overexpressed VLA-4.
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http://dx.doi.org/10.2967/jnumed.115.164624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887080PMC
April 2016

New Approaches to Molecular Imaging of Multiple Myeloma.

J Nucl Med 2016 Jan 5;57(1):1-4. Epub 2015 Nov 5.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri

Molecular imaging plays an important role in detection and staging of hematologic malignancies. Multiple myeloma (MM) is an age-related hematologic malignancy of clonal bone marrow plasma cells characterized by destructive bone lesions and is fatal in most patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolytic lesions manifested in MM. Progressive biomedical imaging technologies such as low-dose CT, molecularly targeted PET, MRI, and the functional-anatomic hybrid versions (PET/CT and PET/MRI) provide incremental advancements in imaging MM. Imaging with PET and MRI using molecularly targeted probes is a promising precision medicine platform that might successfully address the clinical ambiguities of myeloma spectrum diseases. The intent of this focus article is to provide a concise review of the present status and promising developments on the horizon, such as the new molecular imaging biomarkers under investigation that can either complement or potentially supersede existing standards.
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http://dx.doi.org/10.2967/jnumed.115.163808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673073PMC
January 2016

Utilizing the Multiradionuclide Resolving Power of SPECT and Dual Radiolabeled Single Molecules to Assess Treatment Response of Tumors.

Mol Imaging Biol 2015 Oct;17(5):671-9

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO, 63110, USA.

Purpose: Single photon emission computed tomography (SPECT) radionuclide pairs having distinct decay rates and different energy maxima enable simultaneous detection of dual gamma signals and real-time assessment of dynamic functional and molecular processes in vivo. Here, we report image acquisition and quantification protocols for a single molecule labeled with two different radionuclides for functional SPECT imaging.

Procedures: LS370 and LS734 were prepared using modular solid phase peptide synthesis. Each agent has a caspase-3 cleavable reporting motif, flanked by a tyrosine residue and a chelator at the opposite end of molecule. Cell uptake and efflux were assessed in human MDA-MB-231 breast cancer cells. Biodistribution studies were conducted in tumor naive and orthotopic 4T1 metastatic breast cancer tumor mice. NanoSPECT dual-imaging validation and attenuation correction parameters were developed using phantom vials containing varying radionuclide concentrations. Proof-of-principle SPECT imaging was performed in MMTV-PyMT transgenic mice.

Results: LS370 and LS734 were singly or dually radiolabeled with (125)I and (111)In or (99m)Tc. Cell assays demonstrated 11-fold higher percent uptake (P < 0.001) of [(125)I]LS734 (3.6 ± 0.5) compared to [(125)I]LS370 (0.3 ± 0.3) at 2 h. Following chemotherapy, cellular retention of [(125)I]LS734 was 3-fold higher (P < 0.05) than untreated cells. Pharmacokinetics at 1 h postinjection demonstrated longer blood retention (%ID/g) for [(125)I]LS734 (3.2 ± 0.9) compared to [(125)I]LS370 (1.6 ± 0.1). In mice bearing bilateral orthotopic 4T1 tumors, the uptake (%ID/g) was 2.4 ± 0.3 for [(125)I]LS734 and 1.2 ± 0.03 for [(125)I]LS370. The iodinated tyrosine peptide residue label was stable under in vitro conditions for up to 24 h; rapid systemic deiodination (high thyroid uptake) was observed in vivo. Phantom studies using standards demonstrated deconvolution of radionuclide signals based on different gamma ray energies. In MMTV-PyMT mice imaged with dual-labeled [(111)In]-[(125)I]LS734, the gamma signals were separable and quantifiable.

Conclusions: Image processing protocols were developed for quantitative signal separation resulting from a caspase-3 responsive dual-radiolabeled SPECT probe. Crosstalk unmixing was obtained for multiradionuclide NanoSPECT imaging. In vitro and in vivo data demonstrated structure-activity relationships for developing functional agents for ratiometric SPECT imaging.
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http://dx.doi.org/10.1007/s11307-015-0842-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853202PMC
October 2015

Noninvasive imaging of focal atherosclerotic lesions using fluorescence molecular tomography.

J Biomed Opt 2014 ;19(11):110501

Washington University School of Medicine, Department of Radiology, 4525 Scott Avenue, St. Louis, Missouri 63110, United States.

Insights into the etiology of stroke and myocardial infarction suggest that rupture of unstable atherosclerotic plaque is the precipitating event. Clinicians lack tools to detect lesion instability early enough to intervene, and are often left to manage patients empirically, or worse, after plaque rupture. Noninvasive imaging of the molecular events signaling prerupture plaque progression has the potential to reduce the morbidity and mortality associated with myocardial infarction and stroke by allowing early intervention. Here, we demonstrate proof-of-principle in vivo molecular imaging of C-type natriuretic peptide receptor in focal atherosclerotic lesions in the femoral arteries of New Zealand white rabbits using a custom built fiber-based, fluorescence molecular tomography (FMT) system. Longitudinal imaging showed changes in the fluorescence signal intensity as the plaque progressed in the air-desiccated vessel compared to the uninjured vessel, which was validated by ex vivo tissue studies. In summary, we demonstrate the potential of FMT for noninvasive detection of molecular events leading to unstable lesions heralding plaque rupture.
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http://dx.doi.org/10.1117/1.JBO.19.11.110501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229053PMC
January 2015

Very late antigen-4 (α(4)β(1) Integrin) targeted PET imaging of multiple myeloma.

PLoS One 2013 8;8(2):e55841. Epub 2013 Feb 8.

Department of Medicine, Washington University, St. Louis, Missouri, United States of America.

Biomedical imaging techniques such as skeletal survey and (18)F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET) are frequently used to diagnose and stage multiple myeloma (MM) patients. However, skeletal survey has limited sensitivity as it can detect osteolytic lesions only after 30-50% cortical bone destruction, and FDG is a marker of cell metabolism that has limited sensitivity for intramedullary lesions in MM. Targeted, and non-invasive novel probes are needed to sensitively and selectively image the unique molecular signatures and cellular processes associated with MM. Very late antigen-4 (VLA-4; also called α(4)β(1) integrin) is over-expressed on MM cells, and is one of the key mediators of myeloma cell adhesion to the bone marrow (BM) that promotes MM cell trafficking and drug resistance. Here we describe a proof-of-principle, novel molecular imaging strategy for MM tumors using a VLA-4 targeted PET radiopharmaceutical, (64)Cu-CB-TE1A1P-LLP2A. Cell uptake studies in a VLA-4-positive murine MM cell line, 5TGM1, demonstrated receptor specific uptake (P<0.0001, block vs. non-block). Tissue biodistribution at 2 h of (64)Cu-CB-TE1A1P-LLP2A in 5TGM1 tumor bearing syngeneic KaLwRij mice demonstrated high radiotracer uptake in the tumor (12±4.5%ID/g), and in the VLA-4 rich organs, spleen (8.8±1.0%ID/g) and marrow (11.6±2.0%ID/g). Small animal PET/CT imaging with (64)Cu-CB-TE1A1P-LLP2A demonstrated high uptake in the 5TGM1 tumors (SUV 6.6±1.1). There was a 3-fold reduction in the in vivo tumor uptake in the presence of blocking agent (2.3±0.4). Additionally, (64)Cu-CB-TE1A1P-LLP2A demonstrated high binding to the human MM cell line RPMI-8226 that was significantly reduced in the presence of the cold targeting agent. These results provide pre-clinical evidence that VLA-4-targeted imaging using (64)Cu-CB-TE1A1P-LLP2A is a novel approach to imaging MM tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055841PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568146PMC
August 2013

Comparison of two cross-bridged macrocyclic chelators for the evaluation of 64Cu-labeled-LLP2A, a peptidomimetic ligand targeting VLA-4-positive tumors.

Nucl Med Biol 2013 Feb 23;40(2):245-51. Epub 2012 Dec 23.

Department of Chemistry, Washington University, St. Louis, Missouri, USA.

Integrin α(4)β(1) (also called very late antigen-4 or VLA-4) plays an important role in tumor growth, angiogenesis and metastasis, and there has been increasing interest in targeting this receptor for cancer imaging and therapy. In this study, we conjugated a peptidomimetic ligand known to have good binding affinity for α(4)β(1) integrin to a cross-bridged macrocyclic chelator with a methane phosphonic acid pendant arm, CB-TE1A1P. CB-TE1A1P-LLP2A was labeled with (64)Cu under mild conditions in high specific activity, in contrast to conjugates based on the "gold standard" di-acid cross-bridged chelator, CB-TE2A, which require high temperatures for efficient radiolabeling. Saturation binding assays demonstrated that (64)Cu-CB-TE1A1P-LLP2A had comparable binding affinity (1.2 nM vs 1.6 nM) but more binding sites (B(max)=471 fmol/mg) in B16F10 melanoma tumor cells than (64)Cu-CB-TE2A-LLP2A (B(max)=304 fmol/mg, p<0.03). In biodistribution studies, (64)Cu-CB-TE1A1P-LLP2A had less renal retention but higher uptake in tumor (11.4±2.3 %ID/g versus 3.1±0.6 %ID/g, p<0.001) and other receptor-rich tissues compared to(64)Cu-CB-TE2A-LLP2A. At 2h post-injection, (64)Cu-CB-TE1A1P-LLP2A also had significantly higher tumor:blood and tumor:muscle ratios than (64)Cu-CB-TE2A-LLP2A (CB-TE1A1P=19.5±3.0 and 13.0±1.4, respectively, CB-TE2A=4.2±1.4 and 5.5±0.9, respectively, p<0.001). These data demonstrate that (64)Cu-CB-TE1A1P-LLP2A is an excellent PET radiopharmaceutical for the imaging of α(4)β(1) positive tumors and also has potential for imaging other α(4)β(1) positive cells such as those of the pre-metastatic niche.
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http://dx.doi.org/10.1016/j.nucmedbio.2012.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563241PMC
February 2013

Molecular imaging of very late antigen-4 (α4β1 integrin) in the premetastatic niche.

J Nucl Med 2012 May 10;53(5):779-86. Epub 2012 Apr 10.

Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, USA.

Unlabelled: Despite advances in cancer treatment over the past few decades, metastatic disease remains the primary cause of morbidity and mortality. Recent reports suggest the formation of a "premetastatic niche" before the metastatic cascade, where niche is defined as the microenvironment for tumor cells to be able to engraft and proliferate at secondary sites. Bone marrow-derived (BMD) cells that express vascular endothelial growth factor receptor-1 and very late antigen-4 (VLA-4) have been shown to arrive at sites of metastasis to form a receptive environment for tumor cells. Here we describe experiments toward imaging of VLA-4-positive BMD cells using a high-affinity PET probe, (64)Cu-labeled 11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane (CB-TE2A)-LLP2A.

Methods: VLA-4-negative MDA-MB-231/firefly luciferase (fluc) human breast tumor cells were injected intraarterially in the left ventricle in nude mice. Tumor metastasis in mice was monitored for 30 d by bioluminescence imaging and small-animal PET/CT. Small-animal PET images were collected 2 h after mice were injected in the tail vein with (64)Cu-CB-TE2A-LLP2A (5.6-11.1 MBq [150-300 μCi; specific activity, 400 μCi/μg]). Cellular uptake of (64)Cu-CB-TE2A-LLP2A was determined in VLA-4-positive B16F10 mouse melanoma cells and VLA-4-negative MDA-MB-231/fluc human breast cancer tumor cells. Biodistribution experiments in nude mice bearing VLA-4-positive B16F10 subcutaneous tumors in the flank were conducted to validate targeting of VLA-4-positive cells in vivo.

Results: Uptake of (64)Cu-CB-TE2A-LLP2A was higher in VLA-4-positive human melanoma B16F10 cells than in VLA-4-negative MDA-MB-231 cells (P < 0.05). In B16F10 tumor-bearing mice, (64)Cu-CB-TE2A-LLP2A had high uptake in the VLA-4-rich organs marrow, spleen, and tumor (11.26% ± 2.59%, 8.36% ± 2.15%, and 3.09% ± 0.58% injected dose/g, respectively). Cumulative standardized uptake value data from 2 independent studies (n = 7 and 8 mice) on nude mice implanted with VLA-4-negative MDA-MB-231/fluc human breast tumor cells suggested an influx of VLA-4-positive BMD cells that corresponded to metastasis (P < 0.05). Immunohistochemical analysis and flow cytometry also showed upregulation of VLA-4-positive cell clusters and BMD cells at the metastatic sites, providing evidence for noninvasive imaging of BMD cells in the premetastatic niche.

Conclusion: The results of the study demonstrated the potential of PET with VLA-4-targeted (64)Cu-CB-TE2A-LLP2A to visualize BMD cell reorganization and expansion noninvasively in vivo.
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http://dx.doi.org/10.2967/jnumed.111.100073DOI Listing
May 2012

The development of copper radiopharmaceuticals for imaging and therapy.

Med Chem 2011 Sep;7(5):413-29

Division of Radiological Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA.

The increasing use of positron emission tomography in preclinical and clinical settings has widened the demand for radiopharmaceuticals with high specificity that can image biological phenomena in vivo. While many PET tracers have been developed from small organic molecules labeled with carbon-11 or fluorine-18, the short half-lives of these radionuclides preclude their incorporation into radiotracers, which can be used to image biological processes that are not induced immediately after system perturbation. Additionally, the continuing development of targeted agents, such as antibodies and nanoparticles, which undergo extended circulation, require that radionuclides with half-lives that are complimentary to the biological half-lives of these molecules be developed. Copper radionuclides have received considerable attention since they offer a variety of half-lives and decay energies and because the coordination chemistry of cooper and its role in biology is well understood. However, in addition to the radiometal chelate, a successful copper based radiopharmaceutical depends upon the chemical structure of the entire radiotracer, which may include a biologically important molecule and a chemical linker that can be used to deliver the copper radionuclide to a specific target and modulate its in vivo properties, respectively. This review discusses the development of copper radiopharmaceuticals and the importance of factors such as chemical structure on their pharmacokinetics in vivo.
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http://dx.doi.org/10.2174/157340611796799177DOI Listing
September 2011

Evaluation of multivalent, functional polymeric nanoparticles for imaging applications.

ACS Nano 2011 Feb 28;5(2):738-47. Epub 2011 Jan 28.

Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri 63110, USA.

A series of multivalent, functional polymer nanoparticles with diagnostic/imaging units and targeting ligands for molecular targeting were synthesized with the loading of the chain-end-functionalized GRGDS peptide targeting sequence (model system based on integrin α(v)β(3)) ranging from 0 to 50%. Accurate structural and functional group control in these systems was achieved through a modular approach involving the use of multiple functionalized macromonomer/monomer units combined with living free radical polymerization. In cellulo results show an increase in uptake in α(v)β(3) integrin-positive U87MG glioblastoma cells with increasing RGD loading and a possible upper limit on the effectiveness of the number of RGD peptides for targeting α(v)β(3) integrin. Significantly, this increased targeting efficiency is coupled with in vivo biodistribution results, which show decreased blood circulation and increased liver uptake with increasing RGD loading. The results demonstrate the importance of controlling ligand loading in order to achieve optimal performance for therapeutic and imaging applications for multivalent nanoparticle-based systems.
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http://dx.doi.org/10.1021/nn102278wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043165PMC
February 2011

Design of targeted cardiovascular molecular imaging probes.

J Nucl Med 2010 May 15;51 Suppl 1:3S-17S. Epub 2010 Apr 15.

Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, Missouri, USA.

Molecular imaging relies on the development of sensitive and specific probes coupled with imaging hardware and software to provide information about the molecular status of a disease and its response to therapy, which are important aspects of disease management. As genomic and proteomic information from a variety of cardiovascular diseases becomes available, new cellular and molecular targets will provide an imaging readout of fundamental disease processes. A review of the development and application of several cardiovascular probes is presented here. Strategies for labeling cells with superparamagnetic iron oxide nanoparticles enable monitoring of the delivery of stem cell therapies. Small molecules and biologics (e.g., proteins and antibodies) with high affinity and specificity for cell surface receptors or cellular proteins as well as enzyme substrates or inhibitors may be labeled with single-photon-emitting or positron-emitting isotopes for nuclear molecular imaging applications. Labeling of bispecific antibodies with single-photon-emitting isotopes coupled with a pretargeting strategy may be used to enhance signal accumulation in small lesions. Emerging nanomaterials will provide platforms that have various sizes and structures and that may be used to develop multimeric, multimodal molecular imaging agents to probe one or more targets simultaneously. These platforms may be chemically manipulated to afford molecules with specific targeting and clearance properties. These examples of molecular imaging probes are characteristic of the multidisciplinary nature of the extraction of advanced biochemical information that will enhance diagnostic evaluation and drug development and predict clinical outcomes, fulfilling the promise of personalized medicine and improved patient care.
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http://dx.doi.org/10.2967/jnumed.109.068130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629978PMC
May 2010

Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET).

Acc Chem Res 2009 Jul;42(7):832-41

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Molecular imaging has evolved over the past several years into an important tool for diagnosing, understanding, and monitoring disease. Molecular imaging has distinguished itself as an interdisciplinary field, with contributions from chemistry, biology, physics, and medicine. The cross-disciplinary impetus has led to significant achievements, such as the development of more sensitive imaging instruments and robust, safer radiopharmaceuticals, thereby providing more choices to fit personalized medical needs. Molecular imaging is making steadfast progress in the field of cancer research among others. Cancer is a challenging disease, characterized by heterogeneity, uncontrolled cell division, and the ability of cancer cells to invade other tissues. Researchers are addressing these challenges by aggressively identifying and studying key cancer-specific biomarkers such as growth factor receptors, protein kinases, cell adhesion molecules, and proteases, as well as cancer-related biological processes such as hypoxia, apoptosis, and angiogenesis. Positron emission tomography (PET) is widely used by clinicians in the United States as a diagnostic molecular imaging tool. Small-animal PET systems that can image rodents and generate reconstructed images in a noninvasive manner (with a resolution as low as 1 mm) have been developed and are used frequently, facilitating radiopharmaceutical development and drug discovery. Currently, [(18)F]-labeled 2-fluorodeoxyglucose (FDG) is the only PET radiotracer used for routine clinical evaluation (primarily for oncological imaging). There is now increasing interest in nontraditional positron-emitting radionuclides, particularly those of the transition metals, for imaging with PET because of increased production and availability. Copper-based radionuclides are currently being extensively evaluated because they offer a varying range of half-lives and positron energies. For example, the half-life (12.7 h) and decay properties (beta(+), 0.653 MeV, 17.8%; beta(-), 0.579 MeV, 38.4 %; the remainder is electron capture) of (64)Cu make it an ideal radioisotope for PET imaging and radiotherapy. In addition, the well-established coordination chemistry of copper allows for its reaction with a wide variety of chelator systems that can potentially be linked to antibodies, proteins, peptides, and other biologically relevant molecules. New chelators with greater in vivo stability, such as the cross-bridged (CB) versions of tetraazamacrocyclic 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), are now available. Finally, one of the major aspects of successful imaging is the identification and characterization of a relevant disease biomarker at the cellular and subcellular level and the ensuing development of a highly specific targeting moiety. In this Account, we discuss specific examples of PET imaging with new and improved (64)Cu-based radiopharmaceuticals, highlighting the study of some of the key cancer biomarkers, such as epidermal growth-factor receptor (EGFR), somatostatin receptors (SSRs), and integrin alpha(v)beta(3).
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http://dx.doi.org/10.1021/ar800255qDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748250PMC
July 2009

Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis.

Proc Natl Acad Sci U S A 2009 Jan 7;106(3):685-90. Epub 2009 Jan 7.

College of Chemistry, University of California, Berkeley, CA 94720-1460, USA.

A biodegradable positron-emitting dendritic nanoprobe targeted at alpha(v)beta(3) integrin, a biological marker known to modulate angiogenesis, was developed for the noninvasive imaging of angiogenesis. The nanoprobe has a modular multivalent core-shell architecture consisting of a biodegradable heterobifunctional dendritic core chemoselectively functionalized with heterobifunctional polyethylene oxide (PEO) chains that form a protective shell, which imparts biological stealth and dictates the pharmacokinetics. Each of the 8 branches of the dendritic core was functionalized for labeling with radiohalogens. Placement of radioactive moieties at the core was designed to prevent in vivo dehalogenation, a potential problem for radiohalogens in imaging and therapy. Targeting peptides of cyclic arginine-glycine-aspartic acid (RGD) motifs were installed at the terminal ends of the PEO chains to enhance their accessibility to alpha(v)beta(3) integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to alpha(v)beta(3) integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC(50). Cell-based assays of the (125)I-labeled dendritic nanoprobes using alpha(v)beta(3)-positive cells showed a 6-fold increase in alpha(v)beta(3) receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas alpha(v)beta(3)-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of (76)Br-labeled dendritic nanoprobes showed excellent bioavailability for the targeted and nontargeted nanoprobes. In vivo studies in a murine hindlimb ischemia model for angiogenesis revealed high specific accumulation of (76)Br-labeled dendritic nanoprobes targeted at alpha(v)beta(3) integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.
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http://dx.doi.org/10.1073/pnas.0811757106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630081PMC
January 2009