Weibo Cai

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (158)898.15 Total impact

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    ABSTRACT: To date, there is no effective therapy for triple-negative breast cancer (TNBC), which has a dismal clinical outcome. Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types, including TNBC. Our goal was to employ the Fab fragment of ALT-836, a chimeric anti-human TF mAb, for PET imaging of TNBC, which can be used to guide future TNBC therapy. ALT-836-Fab was generated by enzymatic papain digestion. SDS-PAGE and FACS studies were performed to evaluate the integrity and TF binding affinity of ALT-836-Fab before NOTA conjugation and (64)Cu-labeling. Serial PET imaging and biodistribution studies were carried out to evaluate the tumor targeting efficacy and pharmacokinetics in the MDA-MB-231 TNBC model, which expresses high levels of TF on the tumor cells. Blocking studies, histological assessment, as well as RT-PCR were performed to confirm TF specificity of (64)Cu-NOTA-ALT-836-Fab. ALT-836-Fab was produced with high purity, which exhibited superb TF binding affinity and specificity. Serial PET imaging revealed rapid and persistent tumor uptake of (64)Cu-NOTA-ALT-836-Fab (5.1 ± 0.5 %ID/g at 24 h post-injection; n = 4) and high tumor/muscle ratio (7.0 ± 1.2 at 24 h post-injection; n = 4), several-fold higher than that of the blocking group and tumor models that do not express significant level of TF, which was confirmed by biodistribution studies. TF specificity of the tracer was also validated by histology and RT-PCR. (64)Cu-NOTA-ALT-836-Fab exhibited prominent tissue factor targeting efficiency in MDA-MB-231 TNBC model. The use of a Fab fragment led to fast tumor uptake and good tissue/muscle ratio, which may be translated into same-day immunoPET imaging in the clinical setting to improve TNBC patient management.
    European Journal of Nuclear Medicine 03/2015; DOI:10.1007/s00259-015-3038-1 · 4.53 Impact Factor
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    ABSTRACT: Conspectus Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochemical) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clinical research, only very few have moved to humans. One major reason is the lack of understanding of the biological behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal molecular imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time.
    Accounts of Chemical Research 01/2015; 48(2). DOI:10.1021/ar500362y · 24.35 Impact Factor
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    ABSTRACT: Multifunctional zinc oxide (ZnO) nanoparticles (NPs) with well-integrated multimodality imaging capacities have generated increasing research interest in the last decade. However, limited progress has been made in developing ZnO NP-based multimodality tumor-imaging agents. Here we developed novel red fluorescent ZnO NPs and described the successful conjugation of copper-64 (64Cu, t1/2 = 12.7 h) and TRC105, a human/murine chimeric IgG1 monoclonal antibody, to these ZnO NPs via well-developed surface engineering procedures. The produced dual-modality ZnO NPs were readily applicable for in vivo targeted positron emission tomography (PET) imaging and fluorescence imaging of the tumor vasculature. Their pharmacokinetics and tumor-targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. We conclude that ZnO NPs with dual-modality imaging properties can serve as an attractive candidate for future cancer theranostics.
    ACS Applied Materials & Interfaces 01/2015; 7(5). DOI:10.1021/am508440j · 5.90 Impact Factor
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    ABSTRACT: Hexamodal imaging using simple nanoparticles is demonstrated. Porphyrin-phospholipids are used to coat upconversion nanoparticles in order to generate a new biocompatible material. The nanoparticles are characterized in vitro and in vivo for imaging via fluorescence, upconversion, positron emission tomography, computed tomography, Cerenkov luminescence, and photoacoustic tomography.
    Advanced Materials 01/2015; DOI:10.1002/adma.201404739 · 15.41 Impact Factor
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    ABSTRACT: Follicle-stimulating hormone receptor (FSHR) is selectively overexpressed by the vascular endothelium in a wide variety of tumors and confirmed to play critical roles in angiogenesis, tumor invasion, and metastases. The expression level of FSHR correlates strongly with the response of tumors to antiangiogenic therapies. The goal of this study was to develop an immunoPET tracer for imaging of FSHR in different cancer types. A monoclonal antibody (FSHR-mAb) against FSHR was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and used for 64Cu-labeling. NOTA-FSHR-mAb maintained FSHR specificity/avidity based on flow cytometry. 64Cu-labeling was achieved with decent yields (~ 25%) and high specific activity (0.93 GBq/mg). Serial PET imaging revealed that uptake of 64Cu-NOTA-FSHR-mAb was 3.6 ± 0.8, 13.2 ± 0.7, and 14.6 ± 0.4%ID/g in FSHR-positive CAOV-3 tumors at 4, 24, and 48 h post-injection, respectively (n = 3), significantly higher (p<0.05) than that in FSHR-negative SKOV-3 tumors (2.3 ± 1.2, 8.0 ± 0.9, and 9.1 ± 1.3 %ID/g at 4, 24, and 48 h post-injection, respectively (n = 3)) except at 4 h p.i. FSHR-relevant uptake of 64Cu-NOTA-FSHR-mAb was also readily observed in other tumor types (e.g. triple-negative breast tumor MDA-MB-231 or prostate tumor PC-3). Histology studies showed universal FSHR expression in microvasculature of these four tumor types and also prominent expression in tumor cells of CAOV-3, PC-3, and MDA-MB-231. Strong correlations between FSHR expression level in the tumor tissues and tumor uptake of 64Cu-NOTA-FSHR-mAb were witnessed in this study. Prominent, persistent, and FSHR-specific uptake of 64Cu-NOTA-FSHR mAb in different tumors holds strong potential for future cancer diagnosis, prognosis, and therapy using this antibody and establishes FSHR as a promising clinical target for cancer.
    Molecular Pharmaceutics 01/2015; DOI:10.1021/mp500766x · 4.57 Impact Factor
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    ABSTRACT: Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites which are then modified with dual types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, 64Cu, a commonly used positron emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon intravenous injection, in vivo photothermal therapy is finally conducted, achieving effective tumor ablation in an animal tumor model. Our study highlights the promise of constructing multifunctional theranostic nanocomposites based on 2D transitional metal dichalcogenides (TMDCs) for multimodal imaging-guided cancer therapy.
    ACS Nano 01/2015; 9(1). DOI:10.1021/nn506757x · 12.03 Impact Factor
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    ABSTRACT: There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of 52Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. 52Mn was produced via proton irradiation of a natural chromium target. In a comparison of two 52Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher 52Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents (52Mn2+ and Mn2+, respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique.
    Theranostics 01/2015; 5(3):227-239. DOI:10.7150/thno.10185 · 7.83 Impact Factor
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    ABSTRACT: Theranostic nanoparticles hold the potential to revolutionize disease management. Over the last decade, there has been growing interest in the engineering of various kinds of theranostic nanoparticles for simultaneous cancer imaging and therapy in small animals. Efficient targeting of theranostic nanoparticles to the tumor site is critical for both diagnosis and therapy. However, difficulties still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor-targeting capabilities. Here, we discuss the current and prospective status of theranostic nanoparticles that actively target tumors, as well as the challenges that still exist. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 11/2014; DOI:10.2967/jnumed.114.146019 · 5.56 Impact Factor
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    ABSTRACT: Although graphene oxide (GO) has recently been considered as a highly attractive nanomaterial for future cancer imaging and therapy, it is still a major challenge to improve its in vivo tumor active targeting efficiency. Here in this full article, we demonstrated the successful and significantly enhanced in vivo tumor vasculature targeting efficacy of well-functionalized GO nanoconjugates by using vascular endothelial growth factor 121 (VEGF121) as the targeting ligand. As-developed GO nanoconjugate exhibits excellent in vivo stability, specific in vitro and in vivo vascular endothelial growth factor receptor (VEGFR) targeting, significantly enhanced tumor accumulation (>8 %ID/g) as well as high tumor-to-muscle contrast, showing great potential for future tumor targeted imaging and therapy.
    Biomaterials 11/2014; DOI:10.1016/j.biomaterials.2014.10.061 · 8.31 Impact Factor
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    ABSTRACT: Scandium-44 (t½ = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report for the first time the room temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR) was generated and conjugated with N-[(R)-2-Amino-3-(p-isothiocyanato-phenyl) propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ~12 %ID/g at 4 h post-injection) of 44Sc-CHX-A″-DTPA-Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc-CHX-A″-DTPA-Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also monitor the therapeutic efficacy of anti-EGFR treatments.
    Bioconjugate Chemistry 11/2014; 25(12). DOI:10.1021/bc500415x · 4.82 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling cascade plays a critical role in tumor angiogenesis and metastasis and has been correlated with several poorly prognostic cancers such as malignant gliomas. Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raise concerns of potential side effects. In the present work, we propose the use of uniform mesoporous silica nanoparticles (MSNs) for VEGFR targeted positron emission tomography imaging and delivery of the anti-VEGFR drug, i.e. sunitinib, in human glioblastoma (U87MG) bearing murine models. MSNs were synthesized, characterized and modified with the polyethylene glycol, anti-VEGFR ligands VEGF121 and radioisotope 64Cu, followed by extensive in vitro, in vivo and ex vivo studies. Our results demonstrated that significantly higher amount of sunitinib could be delivered to U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts. As developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.
    ACS Applied Materials & Interfaces 10/2014; DOI:10.1021/am506849p · 5.90 Impact Factor
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    ABSTRACT: Although chelator-based radiolabeling techniques have been used for decades, concerns about the complexity of coordination chemistry, possible altering of pharmacokinetics of carriers, and potential detachment of radioisotopes during imaging have driven the need for developing a simple yet better technique for future radiolabeling. Here, the emerging concept of intrinsically radiolabeled nanoparticles, which could be synthesized using methods such as hot-plus-cold precursors, specific trapping, cation exchange, and proton beam activation, is introduced. Representative examples of using these multifunctional nanoparticles for multimodality molecular imaging are highlighted together with current challenges and future research directions. Although still in the early stages, design and synthesis of intrinsically radiolabeled nanoparticles has shown attractive potential to offer easier, faster, and more specific radiolabeling possibilities for the next generation of molecular imaging.
    Small 10/2014; 10(19). DOI:10.1002/smll.201401048 · 7.51 Impact Factor
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    ABSTRACT: Intrinsically radiolabeled nanoparticles are an emerging paradigm for nanotechnology and nanomedicine. On page 3825, F. Chen, W. Cai, and co-workers summarize the state-of-the-art techniques for the preparation of intrinsically radiolabeled nanoparticles, with a focus on the formation mechanism, in vivo stability, and multimodality molecular imaging.
    Small 10/2014; 10(19). DOI:10.1002/smll.201470117 · 7.51 Impact Factor
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    ABSTRACT: Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called 'image-guided drug delivery' (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for treatment of cancer but might also find utility in management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field.
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    ABSTRACT: Insulin-like growth factor 1 receptor (IGF1R) plays an important role in proliferation, apoptosis, angiogenesis, and tumor invasion. The expression level of IGF1R is related to resistance to several targeted therapies. The goal of this study was to develop an immunoPET tracer for imaging of IGF1R in prostate cancer. Murine antibodies against human IGF1R were generated in BALB/c mice, which were screened in IGF1R-positive MCF-7 cells using flow cytometry as well as biodistribution studies with multiple 64Cu-labeled antibody clones. The antibody production method we adopted could readily produce milligram quantities of anti-IGF1R antibodies for in vivo studies. One antibody clone (1A2G11) with the highest affinity for IGF1R was selected and conjugated to NOTA for 64Cu-labeling. NOTA-1A2G11 maintained IGF1R specificity/avidity based on flow cytometry. 64Cu-labeling was achieved with good yield (>50%) and high specific activity (> 1 Ci/μmol). Serial PET imaging revealed that uptake of 64Cu-NOTA-1A2G11 was 2.8 ± 0.7, 10.2 ± 2.6, and 9.6 ± 1.7 %ID/g in IGF1R-positive DU-145 tumors at 4, 24, and 48 h post-injection, respectively (n = 3), significantly higher than that in IGF1R-negative LNCaP tumors (< 3%ID/g at each time point) except at 4 h post-injection. Histology studies showed strong correlations between IGF1R expression level in the prostate cancer tumor tissues and tumor uptake of 64Cu-NOTA-1A2G11. Prominent, persistent, and IGF1R-specific uptake of 64Cu-NOTA-1A2G11 in IGF1R-positive prostate tumors holds strong potential for future cancer diagnosis, prognosis, and therapy using this antibody.
    Molecular Pharmaceutics 08/2014; 11(10). DOI:10.1021/mp5003637 · 4.79 Impact Factor
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    ABSTRACT: Graphene-based nanomaterials have attracted tremendous interest over the last decade due to their unique electronic, optical, mechanical and chemical properties. However, the biomedical applications of these intriguing nanomaterials are still limited due to their suboptimal solubility/biocompatibility, potential toxicity, and difficulties in achieving active tumor targeting, just to name a few. In this review article, we will discuss in detail the important role of surface engineering (i.e. bioconjugation) in improving the in vitro/in vivo stability and enriching the functionality of graphene-based nanomaterials, which can enable single-/multi-modality imaging (e.g. optical imaging, positron emission tomography, magnetic resonance imaging) and therapy (e.g. photothermal therapy, photodynamic therapy, and drug/gene delivery) of cancer. Current challenges and future research directions are also discussed and we believe that graphene-based nanomaterials are attractive nanoplatforms for a broad array of future biomedical applications.
    Bioconjugate Chemistry 08/2014; 25(9). DOI:10.1021/bc500332c · 4.82 Impact Factor
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    ABSTRACT: Intrinsically germanium-69-labeled super-paramagnetic iron oxide nanoparticles are synthesized via a newly developed, fast and highly specific chelator-free approach. The biodistribution pattern and the feasibility of (69) Ge-SPION@PEG for in vivo dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging and lymph-node mapping are investigated, which represents the first example of the successful utilization of a (69) Ge-based agent for PET/MR imaging.
    Advanced Materials 08/2014; 26(30). DOI:10.1002/adma.201401372 · 15.41 Impact Factor
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    ABSTRACT: Tremendous advances over the last several decades in positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for targeted imaging of molecular and cellular events in the living systems. Angiogenesis, a multistep process regulated by the network of different angiogenic factors, has attracted world-wide interests, due to its pivotal role in the formation and progression of different diseases including cancer, cardiovascular diseases (CVD), and inflammation. In this review article, we will summarize the recent progress in PET or SPECT imaging of a wide variety of vascular targets in three major angiogenesis-related diseases: cancer, cardiovascular diseases, and inflammation. Faster drug development and patient stratification for a specific therapy will become possible with the facilitation of PET or SPECT imaging and it will be critical for the maximum benefit of patients.
    Advanced Drug Delivery Reviews 07/2014; 76. DOI:10.1016/j.addr.2014.07.011 · 12.71 Impact Factor
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    ABSTRACT: The overexpression of integrin αvβ3 has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine-glycine-aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin αvβ3 expression and for targeted radionuclide therapy. In this study, we aim to develop a (44)Sc-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin αvβ3 expression in a preclinical cancer model. High quality (44)Sc (t1/2, 3.97 h; β(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated (44)Sc-DOTA-(cRGD)2 uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with (64)Cu or (68)Ga. Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.
    Molecular Pharmaceutics 07/2014; 11(8). DOI:10.1021/mp500343j · 4.57 Impact Factor

Publication Stats

7k Citations
898.15 Total Impact Points


  • 2008–2015
    • University of Wisconsin–Madison
      • • Department of Radiology
      • • Department of Medical Physics
      • • School of Medicine and Public Health
      Madison, Wisconsin, United States
  • 2012
    • University of Wisconsin - Stout
      Menominee, Wisconsin, United States
  • 2006–2009
    • Stanford Medicine
      • Department of Radiology
      Stanford, California, United States
  • 2006–2008
    • Stanford University
      • Department of Medicine
      Palo Alto, CA, United States