Weibo Cai

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

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Publications (165)940.77 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The critical challenge in abdominal aortic aneurysm (AAA) research is the accurate diagnosis and assessment of AAA progression. Angiogenesis is a pathological hallmark of AAA, and CD105 is highly expressed on newly formed vessels. Our goal was to use (64)Cu-labeled anti-CD105 antibody Fab fragment for noninvasive assessment of angiogenesis in the aortic wall in a murine model of AAA. Fab fragment of TRC105, a mAb that specifically binds to CD105, was generated by enzymatic papain digestion and conjugated to NOTA for (64)Cu-labeling. Binding affinity/specificity of NOTA-TRC105-Fab was evaluated by flow cytometry and various ex vivo studies. BALB/c mice were anesthetized and treated with calcium phosphate to induce AAA, which underwent weekly PET scans using (64)Cu-NOTA-TRC105-Fab. Biodistribution and autoradiography studies were also performed to confirm the accuracy of PET results. NOTA-TRC105-Fab exhibited high purity and specifically bound to CD105 in vitro. Uptake of (64)Cu-NOTA-TRC105-Fab increased from a control level of 3.4 ± 0.1 to 9.5 ± 0.4 %ID/g at 6 h p.i. on Day 5, and decreased to 7.2 ± 1.4 %ID/g on Day 12 which correlated well with biodistribution and autoradiography studies (i.e. much higher tracer uptake in AAA than normal aorta). Of note, enhanced AAA contrast was achieved, due to the minimal background in the abdominal area of mice. Degradation of elastic fibers and highly expressed CD105 were observed in ex vivo studies. (64)Cu-NOTA-TRC105-Fab cleared rapidly through kidneys, which enabled noninvasive PET imaging of the aorta with enhanced contrast and showed increased angiogenesis (CD105 expression) during AAA. (64)Cu-NOTA-TRC105-Fab PET may potentially be used for future diagnosis and prognosis of AAA. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 04/2015; DOI:10.2967/jnumed.114.153098 · 5.56 Impact Factor
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    ABSTRACT: Aptamers are single-stranded oligonucleotides with high affinity and specificity to the target molecules or cells, thus they can serve as an important category of molecular targeting ligand. Since their discovery, aptamers have been rapidly translated into clinical practice. The strong target affinity/selectivity, cost-effectivity, chemical versatility and safety of aptamers are superior to traditional peptides- or proteins-based ligands which make them unique choices for molecular imaging. Therefore, aptamers are considered to be extremely useful to guide various imaging contrast agents to the target tissues or cells for optical, magnetic resonance, nuclear, computed tomography, ultrasound and multimodality imaging. This review aims to provide an overview of aptamers' advantages as targeting ligands and their application in targeted imaging. Further research in synthesis of new types of aptamers and their conjugation with new categories of contrast agents is required to develop clinically translatable aptamer-based imaging agents which will eventually result in improved patient care.
    Current topics in medicinal chemistry 04/2015; · 3.45 Impact Factor
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    ABSTRACT: Actively targeted theranostic nanomedicine may be the key for future personalized cancer management. Although numerous types of theranostic nanoparticles have been developed in the last decade for cancer treatment, challenges still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor targeting capabilities. Here, we report the design, synthesis, surface engineering, and in vivo active vasculature targeting of a new category of theranostic nanoparticle for future cancer management. Water-soluble photothermally sensitive copper sulfide nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed by multi-step surface engineering to form the final theranostic nanoparticle. Systematic in vitro targeting, an in vivo long-term toxicity study, photothermal ablation evaluation, in vivo vasculature targeted imaging, and biodistribution and histology studies were performed to fully explore the potential of these as-developed new theranostic nanoparticles.
    ACS Nano 04/2015; DOI:10.1021/nn507241v · 12.03 Impact Factor
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    ABSTRACT: The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression/metastasis and associated closely with poor prognostic outcome of cancer patients. Thus developing positron emission tomography (PET) agents for assessing c-Met expression would be extremely useful for diagnosis of cancer and subsequent monitoring of responses to c-Met-targeted therapies. Here we report the characterization of recombinant human hepatocyte growth factor (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. rh-HGF was expressed in human embryonic kidney (HEK) 293 cells and purified by nickel-nitrilogriacetic acid (Ni-NTA) affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (64)Cu. c-Met binding evaluation by flow cytometry was performed in both U87MG and MDA-MB-231 cell lines, which have high and low level of c-Met, respectively. PET imaging and biodistribution studies were performed in nude mice bearing U87MG and MDA-MB-231 xenografted tumors. The rh-HGF expression yield was 150-200 μg protein per 5 × 106 cells after 48 h transfection with purity of 85% ~ 90%. Flow cytometry examination confirmed strong and specific binding capacity of rh-HGF to c-Met. After labeled with (64)Cu, PET imaging revealed specific and prominent uptake of (64)Cu-NOTA-rh-HGF in c-Met positive U87MG tumors (6.7 ± 1.8 %ID/g at 9 h post-injection) and significantly lower uptake in c-Met negative MDA-MB-231 tumors (1.8 ± 0.6 %ID/g at 9 h post-injection). The fact that heat-denatured rh-HGF (termed as dnrh-HGF) had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of (64)Cu-NOTA-rh-HGF. The study provided the initial evidence to confirm that (64)Cu-NOTA-rh-HGF is applicable for visualizing c-Met expression in vivo, which may also find potential applications in treatment monitoring of c-Met-targeted cancer therapy. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 04/2015; DOI:10.2967/jnumed.115.154690 · 5.56 Impact Factor
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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
  • Shreya Goel, Feng Chen, Weibo Cai
    Nanomedicine 03/2015; 10(6):897-898. DOI:10.2217/nnm.14.220 · 5.82 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 · 4.79 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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  • Feng Chen, Weibo Cai
    Nanomedicine 01/2015; 10(1):1-3. DOI:10.2217/nnm.14.186 · 5.82 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; 39. 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

Publication Stats

7k Citations
940.77 Total Impact Points

Institutions

  • 2008–2015
    • University of Wisconsin–Madison
      • • Department of Medical Physics
      • • Department of Radiology
      • • 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