Weibo Cai

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

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Publications (207)1174.52 Total impact


  • No preview · Article · Jan 2016 · European journal of nuclear medicine and molecular imaging
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    ABSTRACT: Over the last decade, radiolabeled iron oxide nanoparticles have been developed as promising contrast agents for dual-modality positron emission tomography/magnetic resonance imaging (PET/MRI) or single-photon emission computed tomography/magnetic resonance imaging (SPECT/MRI). The combination of PET (or SPECT) with MRI can offer synergistic advantages for noninvasive, sensitive, high-resolution, and quantitative imaging, which is suitable for early detection of various diseases such as cancer. Here, we summarize the recent advances on radiolabeled iron oxide nanoparticles for dual-modality imaging, through the use of a variety of PET (and SPECT) isotopes by using both chelator-based and chelator-free radiolabeling techniques.
    No preview · Article · Dec 2015 · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology
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    ABSTRACT: Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched 72Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure 72As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming 72Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.
    No preview · Article · Dec 2015 · Bioconjugate Chemistry
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    ABSTRACT: Development of novel imaging probes for cancer diagnostics remains critical for early detection of disease, yet most imaging agents are hindered by high off-target accumulation (e.g. liver, spleen) and suboptimal tumor accumulation. To overcome these limitations, researchers have adapted antibodies for imaging purposes. As cancerous malignancies express atypical patterns of cell surface proteins in comparison to non-cancerous tissues, novel antibody-based imaging agents can be constructed to target individual cancer cells or surrounding vasculature. Using molecular imaging techniques, these agents may be utilized for detection of malignancies and monitoring of therapeutic response. Currently, there are several imaging modalities commonly employed for molecular imaging. These imaging modalities include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance (MR) imaging, optical imaging (fluorescence and bioluminescence), and photoacoustic (PA) imaging. While antibody-based imaging agents may be employed for a broad range of diseases, this review focuses on the molecular imaging of pancreatic cancer, as there are limited resources for imaging and treatment of pancreatic malignancies. Additionally, pancreatic cancer remains the most lethal cancer with an overall 5-year survival rate of approximately 7%, despite significant advances in the imaging and treatment of many other cancers. In this review, we discuss recent advances in molecular imaging of pancreatic cancer using antibody-based imaging agents. This task is accomplished by summarizing the current progress in each type of molecular imaging modality described above. Also, several considerations for designing and synthesizing novel antibody-based imaging agents are discussed. Lastly, the future directions of antibody-based imaging agents are discussed, emphasizing the potential applications for personalized medicine.
    Full-text · Article · Nov 2015 · Molecular Pharmaceutics
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    ABSTRACT: Layered double hydroxide (LDH) nanomaterial has emerged as a novel delivery agent for biomedical applications due to its unique structure and properties. However, in vivo positron emission tomography (PET) imaging with LDH nanoparticles has not been achieved. The aim of this study is to explore chelator-free labeling of LDH nanoparticles with radioisotopes for in vivo PET imaging. Bivalent cation (64)Cu(2+) and trivalent cation (44)Sc(3+) were found to readily label LDH nanoparticles with excellent labeling efficiency and stability, whereas tetravalent cation (89)Zr(4+) could not label LDH since it does not fit into the LDH crystal structure. PET imaging shows that prominent tumor uptake was achieved in 4T1 breast cancer with (64)Cu-LDH-BSA via passive targeting alone (7.7 ± 0.1%ID/g at 16 h post-injection; n = 3). These results support that LDH is a versatile platform that can be labeled with various bivalent and trivalent radiometals without comprising the native properties, highly desirable for PET image-guided drug delivery.
    Full-text · Article · Nov 2015 · Scientific Reports
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    ABSTRACT: Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. (64)Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ(2) = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.
    Full-text · Article · Nov 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Objective: Lung cancer accounts for 17% of cancer-related deaths worldwide and most patients present with locally advanced or metastatic disease. Novel positron emission tomography (PET) imaging agents for assessing vascular endothelial growth factor receptor-2 (VEGFR-2) expression can be utilized for detecting VEGFR-2+ malignancies and subsequent monitoring of therapeutic response to VEGFR-2-targeted therapies. Here we report the synthesis and characterization of the antibody-based imaging agent for detection of VEGFR-2 expression in vivo. Methods: Ramucirumab (named RamAb), a fully humanized IgG1 monoclonal antibody, 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. Flow cytometry analysis and microscopy studies were performed to compare VEGFR-2 binding affinity of RamAb and NOTA-RamAb. PET imaging and biodistribution studies were performed in nude mice bearing HCC4006 and A549 xenograft tumors. Ex vivo histopathology were performed to elucidate the expression patterns of VEGFR-2 in different tissues and organs to validate in vivo results. Results: Flow cytometry examination revealed the specific binding capacity of FITC-RamAb to VEGFR-2 and no difference in VEGFR-2 binding affinity was seen between RamAb and NOTA-RamAb. After labeled with (64)Cu, PET imaging revealed specific and prominent uptake of (64)Cu-NOTA-RamAb in VEGFR-2 positive HCC4006 tumors (9.4 ± 0.5 %ID/g at 48 h post-injection; n = 4) and significantly lower uptake in VEGFR-2 negative A549 tumors (4.3 ± 0.2 %ID/g at 48 h post-injection; n = 3). Blocking experiments revealed significantly lower uptake in HCC4006 tumors, along with histology analysis, further confirming the VEGFR-2 specificity of (64)Cu-NOTA-RamAb. Conclusion: This study provides initial evidence that (64)Cu-NOTA-RamAb can function as a PET imaging agent for visualizing VEGFR-2 expression in vivo, which may also find potential applications in monitoring the treatment response of VEGFR-2 targeted cancer therapy.
    Full-text · Article · Nov 2015 · Journal of Nuclear Medicine
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    ABSTRACT: Tetracarboxylic porphyrins and polyethylene glycol (PEG) diamines were crosslinked in conditions that gave rise to a water-soluble porphyrin polyamide. Using PEG linkers 2 kDa or larger prevented fluorescence self-quenching. This networked porphyrin mesh was retained during dialysis with membranes with a 100 kDa pore size, yet passed through the membrane when centrifugal filtration was applied. Following intravenous administration, the porphyrin mesh, but not the free porphyrin, was rapidly cleared via renal excretion. The process could be monitored by fluorescence analysis of collected urine, with minimal background due to the large Stokes shift of the porphyrin (230 nm separating excitation and emission peaks). In a rhabdomyolysis mouse model of renal failure, porphyrin mesh urinary clearance was significantly impaired. This led to slower accumulation in the bladder, which could be visualized non-invasively via fluorescence imaging. Without further modification, the porphyrin mesh was chelated with (64)Cu for dynamic whole body positron emission tomography imaging of renal clearance. Together, these data show that small porphyrin-PEG polymers can serve as effective multimodal markers of renal function.
    No preview · Article · Oct 2015 · Biomaterials
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    ABSTRACT: Interleukin-15 (IL-15), a potent stimulant of CD8+ T and NK cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL-15 superagonist mutant and a dimeric IL-15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo with a substantially longer serum half-life than recombinant IL-15. A single intravenous dose of ALT-803, but not IL-15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL-15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared to IL-15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well-tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil and monocyte counts by >8-fold. ALT-803 dose-dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4+, and CD8+ memory T cell subsets. In vitro studies demonstrated ALT-803-mediated stimulation of mouse and human immune cell proliferation and IFN-γ production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans.
    Full-text · Article · Oct 2015
  • Emily B. Ehlerding · Feng Chen · Weibo Cai

    No preview · Article · Oct 2015
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    ABSTRACT: Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)2] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal "click" ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105(+/+)) tumors with (64)Cu-labeled Bs-F(ab)2 revealed a significantly enhanced tumor uptake [42.9 ± 9.5 percentage injected dose per gram (%ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 ± 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of (64)Cu-NOTA-Bs-F(ab)2. (64)Cu-NOTA-Bs-F(ab)2 was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 ± 10.8%ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 ± 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1-labeled Bs-F(ab)2 for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions.
    Full-text · Article · Sep 2015 · Proceedings of the National Academy of Sciences
  • Emily B Ehlerding · Weibo Cai

    No preview · Article · Sep 2015 · Journal of Nuclear Medicine
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    ABSTRACT: (52)Mn (t1/2 =5.59 d, ß+ = 29.6%, Eßave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high specific activity (52)Mn in a state suitable for macromolecule labeling. To that end a (52)Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate (52)Mn-DOTA-TRC105. (52)Mn is produced by 60 µA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semi-organic mobile phase, 97:3 (v:v) ethanol: HCl (11M, aqueous). The method is 62 ± 14% efficient (n=7) in (52)Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) x10(6) (n = 4), and an average effective specific activity of 0.8 GBq/µmol (n = 4) in titration against DOTA. (52)Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7 %ID/g at 24 hours post injection and ex vivo (52)Mn biodistribution validates the in vivo PET data. Free (52)Mn(2+)(as chloride or acetate) is used as a control in additional mice to evaluate the non-targeted biodistribution in the tumor model.
    Full-text · Article · Aug 2015 · Bioconjugate Chemistry
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    ABSTRACT: Traditional chelator-based radio-labeled nanoparticles and positron emission tomography (PET) imaging are playing vital roles in the field of nano-oncology. However, their long-term in vivo integrity and potential mismatch of the biodistribution patterns between nanoparticle and radioisotope are two major concerns for this approach. Here, we present a chelator-free zirconium-89 (89Zr, t1/2=78.4 h) labeling of mesoporous silica nanoparticle (MSN) with significantly enhanced in vivo long-term (>20 Days) stability. Successful radio-labeling and in vivo stability are demonstrated to be highly dependent on both the concentration and location of deprotonated silanol groups (-Si-O-) from two types of silica nanoparticles investigated. This work reports on 89Zr-labeled MSN with detailed labeling mechanism investigation and long-term stability study. With its attractive radio-stability and the simplicity of chelator-free radio-labeling, 89Zr-MSN offers a novel, simple, and accurate way for studying the in vivo long-term fate and PET image-guided drug delivery of MSN in the near future.
    Full-text · Article · Jul 2015 · ACS Nano
  • Weibo Cai · Feng Chen

    No preview · Article · Jul 2015 · Current drug targets
  • Sarah Yang · Shreya Goel · Weibo Cai

    No preview · Chapter · Jul 2015
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    Shreya Goel · Feng Chen · Weibo Cai

    Full-text · Article · Jun 2015 · Nanomedicine
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    ABSTRACT: Our goal was to demonstrate that suitably derivatized monomeric RGD peptide-based PET tracers, targeting integrin αvβ3, may offer advantages in image contrast, time for imaging, and low uptake in nontarget tissues. Two cyclic RGDfK derivatives, (PEG)2-c(RGDfK) and PEG4-SAA4-c(RGDfK), were constructed and conjugated to NOTA for (64)Cu labeling. Their integrin αvβ3-binding properties were determined via a competitive cell binding assay. Mice bearing U87MG tumors were intravenously injected with each of the (64)Cu-labeled peptides, and PET scans were acquired during the first 30 min, and 2 and 4 h after injection. Blocking and ex vivo biodistribution studies were carried out to validate the PET data and confirm the specificity of the tracers. The IC50 values of NOTA-(PEG)2-c(RGDfK) and NOTA-PEG4-SAA4-c(RGDfK) were 444 ± 41 nM and 288 ± 66 nM, respectively. Dynamic PET data of (64)Cu-NOTA-(PEG)2-c(RGDfK) and (64)Cu-NOTA-PEG4-SAA4-c(RGDfK) showed similar circulation t 1/2 and peak tumor uptake of about 4 %ID/g for both tracers. Due to its marked hydrophilicity, (64)Cu-NOTA-PEG4-SAA4-c(RGDfK) provided faster clearance from tumor and normal tissues yet maintained excellent tumor-to-background ratios. Static PET scans at later time-points corroborated the enhanced excretion of the tracer, especially from abdominal organs. Ex vivo biodistribution and receptor blocking studies confirmed the accuracy of the PET data and the integrin αvβ3-specificity of the peptides. Our two novel RGD-based radiotracers with optimized pharmacokinetic properties allowed fast, high-contrast PET imaging of tumor-associated integrin αvβ3. These tracers may facilitate the imaging of abdominal malignancies, normally precluded by high background uptake.
    Full-text · Article · May 2015 · European Journal of Nuclear Medicine
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    ABSTRACT: Exploration of protein function and interaction is critical for discovering links between genomics, proteomics, and disease state; yet the immense complexity of proteomics found in biological systems currently limit our investigational capacities. While affinity and auto-fluorescent tags are widely employed for protein analysis, these methods have limited success as they lack specificity and require multiple fusion tags and genetic constructs. As an alternative approach, the innovative HaloTag protein fusion platform allows for comprehensive analysis of protein function and interaction using a single genetic construct with multiple capabilities. This is accomplished using a simplified process, in which a variable HaloTag ligand binds rapidly to the HaloTag protein (usually linked to the protein of interest) with high affinity and specificity. In this review article, we examine all current applications of the HaloTag technology platform for biomedical applications such as the study of protein isolation and purification, protein function, protein-protein and protein-DNA interactions, biological assays, in vitro cellular imaging, and in vivo molecular imaging. In addition, novel uses of the HaloTag platform are briefly discussed with potential future applications.
    Full-text · Article · May 2015 · Bioconjugate Chemistry

  • No preview · Conference Paper · May 2015

Publication Stats

9k Citations
1,174.52 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
  • 2006-2009
    • Stanford University
      • • Department of Medicine
      • • Department of Radiology
      Palo Alto, California, United States
  • 2006-2008
    • Stanford Medicine
      • • Department of Radiology
      • • Department of Neurosurgery
      Stanford, California, United States