In Vivo Tumor Vasculature Targeted PET/NIRF Imaging with TRC105(Fab)-Conjugated, Dual-Labeled Mesoporous Silica NanoparticlesClick to copy article linkArticle link copied!
- Feng Chen
- Tapas R. Nayak
- Shreya Goel
- Hector F. Valdovinos
- Hao Hong
- Charles P. Theuer
- Todd E. Barnhart
- Weibo Cai
Abstract
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0009.gif)
Multifunctional mesoporous silica nanoparticles (MSN) with well-integrated multimodality imaging properties have generated increasing research interest in the past decade. However, limited progress has been made in developing MSN-based multimodality imaging agents to image tumors. We describe the successful conjugation of, copper-64 (64Cu, t1/2 = 12.7 h), 800CW (a near-infrared fluorescence [NIRF] dye), and TRC105 (a human/murine chimeric IgG1 monoclonal antibody) to the surface of MSN via well-developed surface engineering procedures, resulting in a dual-labeled MSN for in vivo targeted positron emission tomography (PET) imaging/NIRF imaging of the tumor vasculature. 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. Dual-labeled MSN is an attractive candidate for future cancer theranostics.
SPECIAL ISSUE
This article is part of the
Introduction
Experimental Section
Materials
Generation of TRC105(Fab)
Synthesis of MSN
Synthesis of NOTA-MSN-800CW-PEG-TRC105(Fab)
Flow Cytometry
Radiolabeling with 64Cu
4T1 Murine Breast Cancer Model
PET/NIRF Imaging and Biodistribution Studies
Results and Discussion
Synthesis and Characterizations of Thiolated TRC105(Fab)
Figure 1
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0002.gif)
Figure 1. Synthesis and characterization of TRC105(Fab). (a) Schematic illustration showing the generation of TRC105(Fab) and its thiolation. (b) SDS-PAGE of molecular weight markers (lane 1), intact TRC105 antibody (lane 2), and TRC105(Fab) after purification on the Sephadex G-75 column (lane 3).
Synthesis and Characterizations of 64Cu-MSN-800CW-TRC105(Fab)
Scheme 1
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0008.gif)
Scheme aUniform MSN nanoparticle (1) was first modified with −NH2 groups with APS to form MSN-NH2 (2). As-synthesized MSN-NH2 was then subjected to 800CW and NOTA conjugation to yield NOTA-MSN-800CW-NH2 (3). Afterwards, PEGylation step was introduced to render the stability of NOTA-MSN-800CW-PEG-Mal (4) in PBS, at the same time adding maleimide groups. NOTA-MSN-800CW-PEG-TRC105(Fab) (5) could be obtained by reacting TRC105(Fab)-SH with 4 at room temperature. 64Cu-labeling was performed in the last step to generate 64Cu-NOTA-MSN-800CW-PEG-TRC105(Fab) (6), short for 64Cu-MSN-800CW-TRC105(Fab).
Figure 2
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0003.gif)
Figure 2. Synthesis and characterization of MSN and MSN-800CW-TRC105(Fab). TEM images of (a) pure MSN, (b) MSN-800CW-TRC105(Fab). Insets in (a) and (b) show the schemes of MSN and MSN-800CW-TRC105(Fab). An optical image of MSN-800CW-TRC105(Fab) acquired from IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm) is also shown in the upper right portion of (b).
In Vitro CD105 Targeting of MSN-800CW-TRC105(Fab)
Figure 3
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0004.gif)
Figure 3. Flow cytometry analysis of MSN nanoconjugates in HUVECs (CD105 positive) after 30 min incubation and subsequent washing. Targeted group: fluorescein conjugated MSN-800CW-TRC105(Fab). Non-targeted group: fluorescein conjugated MSN-800CW. Blocking group: fluorescein conjugated MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (500 μg/mL).
In Vivo PET/NIRF Dual Modal CD105-Targeted Imaging of 64Cu-MSN-800CW-TRC105(Fab)
Figure 4
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0005.gif)
Figure 4. Serial coronal PET images of 4T1 tumor-bearing mice at different time points postinjection of (a) 64Cu-MSN-800CW-TRC105(Fab), (b) 64Cu-MSN-800CW, and (c) 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads.
Figure 5
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0006.gif)
Figure 5. In vivo NIRF imaging of 4T1 tumor-bearing mice at 4 h postinjection. (a) Targeted group, 64Cu-MSN-800CW-TRC105(Fab); (b) non-targeted group, 64Cu-MSN-800CW; (c) blocking group, 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads. Each mouse was iv injected with MSN nanoconjugates with equal amounts of 800CW dyes (∼400 pmol). All images were acquired by using IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm).
Figure 6
![](/cms/10.1021/mp500306k/asset/images/medium/mp-2014-00306k_0007.gif)
Figure 6. Quantitative analysis of the PET data. (a) Time–activity curve of the liver, 4T1 tumor, blood, and muscle upon iv injection of 64Cu-MSN-800CW-TRC105(Fab) (targeted group, n = 3). (b) Time–activity curve of tumor-to-muscle (T/M), tumor-to-blood (T/B), and tumor-to-liver (T/L) ratios from the same targeted group (n = 3). (c) Comparison of 4T1 tumor uptake among the three groups. The differences between 4T1 tumor uptake of 64Cu-MSN-800CW-TRC105(Fab) and the two control groups were statistically significant (**P < 0.01) in all cases. (d) Biodistribution of three groups in 4T1 tumor-bearing mice at the end of the PET scans at 48 h pi (n = 3).
Conclusion
Supporting Information
Ninhydrin testing, tables of PET region-of-interest quantifications, quantitative analysis of PET imaging data from non-targeted and blocking groups. This material is available free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment
This work is supported, in part, by the University of Wisconsin—Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, P30CA014520), the Department of Defense (W81XWH-11-1-0644), and the American Cancer Society (125246-RSG-13-099-01-CCE).
References
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- 5Shi, S.; Yang, K.; Hong, H.; Valdovinos, H. F.; Nayak, T. R.; Zhang, Y.; Theuer, C. P.; Barnhart, T. E.; Liu, Z.; Cai, W. Tumor Vasculature Targeting and Imaging in Living Mice with Reduced Graphene Oxide Biomaterials 2013, 34, 3002– 3009Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yjurs%253D&md5=84da19a32f2b9e0a784f9b92c9bfc486Tumor vasculature targeting and imaging in living mice with reduced graphene oxideShi, Sixiang; Yang, Kai; Hong, Hao; Valdovinos, Hector F.; Nayak, Tapas R.; Zhang, Yin; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, WeiboBiomaterials (2013), 34 (12), 3002-3009CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Graphene-based nanomaterials have attracted tremendous attention in the field of biomedicine due to their intriguing properties. Herein, we report tumor vasculature targeting and imaging in living mice using reduced graphene oxide (RGO), which was conjugated to the anti-CD105 antibody TRC105. The RGO conjugate, 64Cu-NOTA-RGO-TRC105, exhibited excellent stability in vitro and in vivo. Serial positron emission tomog. (PET) imaging studies non-invasively assessed the pharmacokinetics and demonstrated specific targeting of 64Cu-NOTA-RGO-TRC105 to 4T1 murine breast tumors in vivo, compared to non-targeted RGO conjugate (64Cu-NOTA-RGO). In vivo (e.g., blocking 4T1 tumor uptake with excess TRC105), in vitro (e.g., flow cytometry), and ex vivo (e.g., histol.) expts. confirmed the specificity of 64Cu-NOTA-RGO-TRC105 for tumor vascular CD105. Since RGO exhibits desirable properties for photothermal therapy, the tumor-specific RGO conjugate developed in this work may serve as a promising theranostic agent that integrates imaging and therapeutic components.
- 6Rosen, L. S.; Hurwitz, H. I.; Wong, M. K.; Goldman, J.; Mendelson, D. S.; Figg, W. D.; Spencer, S.; Adams, B. J.; Alvarez, D.; Seon, B. K.; Theuer, C. P.; Leigh, B. R.; Gordon, M. S. A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer Clin. Cancer Res. 2012, 18, 4820– 9Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ygsbzI&md5=a0d4274e0bed7c700deaa54229c8cb12A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced CancerRosen, Lee S.; Hurwitz, Herbert I.; Wong, Michael K.; Goldman, Jonathan; Mendelson, David S.; Figg, William D.; Spencer, Shawn; Adams, Bonne J.; Alvarez, Delia; Seon, Ben K.; Theuer, Charles P.; Leigh, Bryan R.; Gordon, Michael S.Clinical Cancer Research (2012), 18 (17), 4820-4829CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of i.v. TRC105 until disease progression or unacceptable toxicity using a std. 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The max. tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concns. that sat. CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 wk. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 mo. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 wk, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clin. activity was seen in a refractory patient population. Ongoing clin. trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820-9. ©2012 AACR.
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- 9Hong, H.; Yang, Y.; Zhang, Y.; Engle, J. W.; Barnhart, T. E.; Nickles, R. J.; Leigh, B. R.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression During Tumor Angiogenesis Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 1335– 1343Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvVais7g%253D&md5=e247f60e04d12e4b4255a5e2f17c1f77Positron emission tomography imaging of CD105 expression during tumor angiogenesisHong, Hao; Yang, Yunan; Zhang, Yin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, Robert J.; Leigh, Bryan R.; Cai, WeiboEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (7), 1335-1343CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel d. (MVD) assessed by CD105 staining is the current gold std. for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomog. (PET) tracer for imaging CD105 expression. Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS anal. and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histol. studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. Results: FACS anal. of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, resp. (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking expts., control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histol. all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105. Conclusion: This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was obsd. Further studies are warranted and currently underway.
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- 18Zhou, J.; Yu, M.; Sun, Y.; Zhang, X.; Zhu, X.; Wu, Z.; Wu, D.; Li, F. Fluorine-18-Labeled Gd3+/Yb3+/Er3+ Co-Doped NaYF4 Nanophosphors for Multimodality PET/MR/UCL Imaging Biomaterials 2011, 32, 1148– 1156Google ScholarThere is no corresponding record for this reference.
- 19Huang, X.; Zhang, F.; Lee, S.; Swierczewska, M.; Kiesewetter, D. O.; Lang, L.; Zhang, G.; Zhu, L.; Gao, H.; Choi, H. S.; Niu, G.; Chen, X. Long-Term Multimodal Imaging of Tumor Draining Sentinel Lymph Nodes Using Mesoporous Silica-Based Nanoprobes Biomaterials 2012, 33, 4370– 4378Google ScholarThere is no corresponding record for this reference.
- 20Zhang, Y.; Hong, H.; Engle, J. W.; Yang, Y.; Barnhart, T. E.; Cai, W. Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Vascular Endothelial Growth Factor with Dual-Labeled Bevacizumab Am. J. Nucl. Med. Mol. Imaging 2012, 2, 1– 13Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrtLs%253D&md5=081ff1f5be3c91058bb4c98bbc86f3a4Positron emission tomography and near-infrared fluorescence imaging of vascular endothelial growth factor with dual-labeled bevacizumabZhang, Yin; Hong, Hao; Engle, Jonathan W.; Yang, Yunan; Barnhart, Todd E.; Cai, WeiboAmerican Journal of Nuclear Medicine and Molecular Imaging (2012), 2 (1), 1-13CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)The pivotal role of vascular endothelial growth factor (VEGF) in cancer is underscored by the approval of bevacizumab (Bev, a humanized anti-VEGF monoclonal antibody) for first line treatment of cancer patients. The aim of this study was to develop a dual-labeled Bev for both positron emission tomog. (PET) and near-IR fluorescence (NIRF) imaging of VEGF. Bev was conjugated to a NIRF dye (i.e. 800CW) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) before 64Cu-labeling. Flow cytometry anal. of U87MG human glioblastoma cells revealed no difference in VEGF binding affinity/specificity between Bev and NOTA-Bev-800CW. 64Cu-labeling of NOTA-Bev-800CW was achieved with high yield. Serial PET imaging of U87MG tumor-bearing female nude mice revealed that tumor uptake of 64Cu-NOTA-Bev-800CW was 4.6 ± 0.7, 16.3 ± 1.6, 18.1 ± 1.4 and 20.7 ± 3.7 % ID/g at 4, 24, 48 and 72 h post-injection resp. (n = 4), corroborated by in vivo/ex vivo NIRF imaging and biodistribution studies. Tumor uptake as measured by ex vivo NIRF imaging had a good linear correlation with the % ID/g values obtained from PET (R2 = 0.93). Blocking expts. and histol. both confirmed the VEGF specificity of 64Cu-NOTA-Bev-800CW. The persistent, prominent, and VEGF-specific uptake of 64Cu-NOTA-Bev-800CW in the tumor, obsd. by both PET and NIRF imaging, warrants further investigation and future clin. translation of such Bev-based imaging agents.
- 21Vallet-Regi, M.; Rámila, A.; del Real, R. P.; Pérez-Pariente, J. A New Property of Mcm-41: Drug Delivery System Chem. Mater. 2000, 13, 308– 311Google ScholarThere is no corresponding record for this reference.
- 22Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals Small 2010, 6, 1794– 1805Google ScholarThere is no corresponding record for this reference.
- 23Meng, H.; Xue, M.; Xia, T.; Ji, Z.; Tarn, D. Y.; Zink, J. I.; Nel, A. E. Use of Size and a Copolymer Design Feature to Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model ACS Nano 2011, 5, 4131– 4144Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltlaqtro%253D&md5=7a297aaa7fdb6c96f8ebe5686a0a7f97Use of Size and a Copolymer Design Feature To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor ModelMeng, Huan; Xue, Min; Xia, Tian; Ji, Zhaoxia; Tarn, Derrick Y.; Zink, Jeffrey I.; Nel, Andre E.ACS Nano (2011), 5 (5), 4131-4144CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size redn. and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after i.v. injection. Using near-IR fluorescence imaging and elemental Si anal., we demonstrate passive accumulation of ∼ 12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant redn. in systemic side effects such as animal wt. loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size redn. as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.
- 24Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles J. Am. Chem. Soc. 2012, 134, 5722– 5725Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktVyntLs%253D&md5=d3c0b442624c819703f88f6c46ef217cNuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica NanoparticlesPan, Limin; He, Qianjun; Liu, Jianan; Chen, Yu; Ma, Ming; Zhang, Linlin; Shi, JianlinJournal of the American Chemical Society (2012), 134 (13), 5722-5725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diam. of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.
- 25Wang, K.; He, X.; Yang, X.; Shi, H. Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal Levels Acc. Chem. Res. 2013, 46, 1367– 1376Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVOgtr8%253D&md5=7ef5408d06507eb5b5740de637593ea6Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal LevelsWang, Kemin; He, Xiaoxiao; Yang, XiaoHai; Shi, HuiAccounts of Chemical Research (2013), 46 (7), 1367-1376CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Going in vivo, including living cells and the whole body, is very important for gaining a better understanding of the mystery of life and requires specialized imaging techniques. The diversity, compn., and temporal-spatial variation of life activities from cells to the whole body require the anal. techniques to be fast-response, noninvasive, highly sensitive, and stable, in situ and in real-time. Functionalized nanoparticle-based fluorescence imaging techniques have the potential to meet such needs through real-time and noninvasive visualization of biol. events in vivo. Functionalized silica nanoparticles (SiNPs) doped with fluorescent dyes appear to be an ideal and flexible platform for developing fluorescence imaging techniques used in living cells and the whole body. The authors can select and incorporate different dyes inside the silica matrix either noncovalently or covalently. These form the functionalized hybrid SiNPs, which support multiplex labeling and ratiometric sensing in living systems. Since the silica matrix protects dyes from outside quenching and degrading factors, this enhances the photostability and biocompatibility of the SiNP-based probes. This makes them ideal for real-time and long-time tracking. One nanoparticle can encapsulate large nos. of dye mols., which amplifies their optical signal and temporal-spatial resoln. response. Integrating fluorescent dye-doped SiNPs with targeting ligands using various surface modification techniques can greatly improve selective recognition. Along with the endocytosis, functionalized SiNPs can be efficiently internalized into cells for noninvasive localization, assessment, and monitoring. These unique characteristics of functionalized SiNPs substantially support their applications in fluorescence imaging in vivo. In this Account, the authors summarize their efforts to develop functionalized dye-doped SiNPs for fluorescence imaging at the cell and small animal levels. The authors first discuss how to design and construct various functionalized dye-doped SiNPs. Then the authors describe their properties and imaging applications in cell surface receptor recognition, intracellular labeling, tracking, sensing, and controlled release. Addnl., the authors demonstrated the promising application of dye-doped SiNPs as contrast imaging agents for in vivo fluorescence imaging in small animals. The authors expect these functionalized dye-doped SiNPs to open new opportunities for biol. and medical research and applications.
- 26Lee, C. H.; Cheng, S. H.; Wang, Y. J.; Chen, Y. C.; Chen, N. T.; Souris, J.; Chen, C. T.; Mou, C. Y.; Yang, C. S.; Lo, L. W. Near-Infrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and in Vivo Biodistribution Adv. Funct. Mater. 2009, 19, 215– 222Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhslequ7s%253D&md5=1df6373665d1b4855117e38709ebe377Near-infrared mesoporous silica nanoparticles for optical imaging: characterization and in vivo biodistributionLee, Chia-Hung; Cheng, Shih-Hsun; Wang, Yu-Jing; Chen, Yu-Ching; Chen, Nai-Tzu; Souris, Jeffrey; Chen, Chin-Tu; Mou, Chung-Yuan; Yang, Chung-Shi; Lo, Leu-WeiAdvanced Functional Materials (2009), 19 (2), 215-222CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)The characterization of near-IR (NIR) mesoporous silica nanoparticles (MSN) suitable for in vivo optical imaging with high efficiency is presented. Trimethylammonium groups modified MSN (MSN-TA) with the av. size of 50-100 nm was synthesized with incorporation of the TA groups into the framework of MSN. It was further adsorbed with indocyanine green (ICG) by electrostatic attraction to render MSN-TA-ICG as an efficient NIR contrast agent for in vivo optical imaging. The studies in stability of MSN-TA-ICG against pH indicated the bonding is stable over the range from acidic to physiol. pH. The in vivo biodistribution of MSN-TA-ICG in anesthetized rat demonstrated a rather strong and stable fluorescence of MSN-TA-ICG that prominent in the organ of liver. Transmission electron microscopy (TEM) imaging and elemental anal. of silicon further manifested the phys. and quant. residences of MSN-TA-ICG in major organs. This is the first report of MSN functionalized with NIR-ICG capable of optical imaging in vivo.
- 27Pan, J.; Wan, D.; Gong, J. Pegylated Liposome Coated QDs/Mesoporous Silica Core–Shell Nanoparticles for Molecular Imaging Chem. Commun. 2011, 47, 3442– 3444Google ScholarThere is no corresponding record for this reference.
- 28Liu, J.; Bu, W.; Zhang, S.; Chen, F.; Xing, H.; Pan, L.; Zhou, L.; Peng, W.; Shi, J. Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal Imaging Chemistry 2012, 18, 2335– 2341Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVelsg%253D%253D&md5=1a17cf05814e38d50af54bbfa0778f15Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal ImagingLiu, Jianan; Bu, Wenbo; Zhang, Shengjian; Chen, Feng; Xing, Huaiyong; Pan, Limin; Zhou, Liangping; Peng, Weijun; Shi, JianlinChemistry - A European Journal (2012), 18 (8), 2335-2341, S2335/1-S2335/5CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Here the authors report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO2 nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO2) on upconversion nanocrystals NaYF4:Tm/Yb/Gd (UCNPs), which can be used as near-IR fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amt. of CTAB, and temp.-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-IR fluorescence and magnetic resonance imaging was also demonstrated.
- 29Zhang, Y.; Hong, H.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Pet Imaging of CD105/Endoglin Expression with a (6)(1)/(6)(4)Cu-Labeled Fab Antibody Fragment Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 759– 767Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1Ohu7c%253D&md5=2a63cf74218ea45208b2b960042e73d5PET imaging of CD105/endoglin expression with a 61/64Cu-labeled Fab antibody fragmentZhang, Yin; Hong, Hao; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Theuer, Charles P.; Barnhart, Todd E.; Cai, WeiboEuropean Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (5), 759-767CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after 61/64Cu labeling. Methods: TRC105-Fab was generated by enzymic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and 61/64Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of 61/64Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. Results TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/μmol). PET imaging revealed rapid uptake of 64Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, resp.; n = 4). Since tumor uptake peaked soon after tracer injection, 61Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histol. examn. Conclusion: We report PET imaging of CD105 expression using 61/64Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clin. investigation.
- 30Chen, F.; Hong, H.; Zhang, Y.; Valdovinos, H. F.; Shi, S.; Kwon, G. S.; Theuer, C. P.; Barnhart, T. E.; Cai, W. In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles ACS Nano 2013, 7, 9027– 9039Google ScholarThere is no corresponding record for this reference.
- 31Orbay, H.; Zhang, Y.; Valdovinos, H. F.; Song, G.; Hernandez, R.; Theuer, C. P.; Hacker, T. A.; Nickles, R. J.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression in a Rat Myocardial Infarction Model with (64)Cu-Nota-TRC105 Am. J. Nucl. Med. Mol. Imaging 2013, 4, 1– 9Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czhtFekuw%253D%253D&md5=4a20b4fbdef77b015c2fce1771fad30aPositron emission tomography imaging of CD105 expression in a rat myocardial infarction model with (64)Cu-NOTA-TRC105Orbay Hakan; Zhang Yin; Valdovinos Hector F; Hernandez Reinier; Nickles Robert J; Song Guoqing; Hacker Timothy A; Theuer Charles P; Cai WeiboAmerican journal of nuclear medicine and molecular imaging (2013), 4 (1), 1-9 ISSN:.Biological changes following myocardial infarction (MI) lead to increased secretion of angiogenic factors that subsequently stimulate the formation of new blood vessels as a compensatory mechanism to reverse ischemia. The goal of this study was to assess the role of CD105 expression during MI-induced angiogenesis by positron emission tomography (PET) imaging using (64)Cu-labeled TRC105, an anti-CD105 monoclonal antibody. MI was induced by ligation of the left anterior descending (LAD) artery in female rats. Echocardiography and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET scans were performed on post-operative day 3 to confirm the presence of MI in the infarct group and intact heart in the sham group, respectively. Ischemia-induced angiogenesis was non-invasively monitored with (64)Cu-NOTA-TRC105 (an extensively validated PET tracer in our previous studies) PET on post-operative days 3, 10, and 17. Tracer uptake in the infarct zone was highest on day 3 following MI, which was significantly higher than that in the sham group (1.41 ± 0.45 %ID/g vs 0.57 ± 0.07 %ID/g; n=3, p<0.05). Subsequently, tracer uptake in the infarct zone decreased over time to the background level on day 17, whereas tracer uptake in the heart of sham rats remained low at all time points examined. Histopathology documented increased CD105 expression following MI, which corroborated in vivo findings. This study indicated that PET imaging of CD105 can be a useful tool for MI-related research, which can potentially improve MI patient management in the future upon clinical translation of the optimized PET tracers.
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Abstract
Figure 1
Figure 1. Synthesis and characterization of TRC105(Fab). (a) Schematic illustration showing the generation of TRC105(Fab) and its thiolation. (b) SDS-PAGE of molecular weight markers (lane 1), intact TRC105 antibody (lane 2), and TRC105(Fab) after purification on the Sephadex G-75 column (lane 3).
Scheme 1
Scheme 1. Schematic Illustration of the Synthesis of 64Cu-MSN-800CW-TRC105(Fab)aScheme aUniform MSN nanoparticle (1) was first modified with −NH2 groups with APS to form MSN-NH2 (2). As-synthesized MSN-NH2 was then subjected to 800CW and NOTA conjugation to yield NOTA-MSN-800CW-NH2 (3). Afterwards, PEGylation step was introduced to render the stability of NOTA-MSN-800CW-PEG-Mal (4) in PBS, at the same time adding maleimide groups. NOTA-MSN-800CW-PEG-TRC105(Fab) (5) could be obtained by reacting TRC105(Fab)-SH with 4 at room temperature. 64Cu-labeling was performed in the last step to generate 64Cu-NOTA-MSN-800CW-PEG-TRC105(Fab) (6), short for 64Cu-MSN-800CW-TRC105(Fab).
Figure 2
Figure 2. Synthesis and characterization of MSN and MSN-800CW-TRC105(Fab). TEM images of (a) pure MSN, (b) MSN-800CW-TRC105(Fab). Insets in (a) and (b) show the schemes of MSN and MSN-800CW-TRC105(Fab). An optical image of MSN-800CW-TRC105(Fab) acquired from IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm) is also shown in the upper right portion of (b).
Figure 3
Figure 3. Flow cytometry analysis of MSN nanoconjugates in HUVECs (CD105 positive) after 30 min incubation and subsequent washing. Targeted group: fluorescein conjugated MSN-800CW-TRC105(Fab). Non-targeted group: fluorescein conjugated MSN-800CW. Blocking group: fluorescein conjugated MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (500 μg/mL).
Figure 4
Figure 4. Serial coronal PET images of 4T1 tumor-bearing mice at different time points postinjection of (a) 64Cu-MSN-800CW-TRC105(Fab), (b) 64Cu-MSN-800CW, and (c) 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads.
Figure 5
Figure 5. In vivo NIRF imaging of 4T1 tumor-bearing mice at 4 h postinjection. (a) Targeted group, 64Cu-MSN-800CW-TRC105(Fab); (b) non-targeted group, 64Cu-MSN-800CW; (c) blocking group, 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads. Each mouse was iv injected with MSN nanoconjugates with equal amounts of 800CW dyes (∼400 pmol). All images were acquired by using IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm).
Figure 6
Figure 6. Quantitative analysis of the PET data. (a) Time–activity curve of the liver, 4T1 tumor, blood, and muscle upon iv injection of 64Cu-MSN-800CW-TRC105(Fab) (targeted group, n = 3). (b) Time–activity curve of tumor-to-muscle (T/M), tumor-to-blood (T/B), and tumor-to-liver (T/L) ratios from the same targeted group (n = 3). (c) Comparison of 4T1 tumor uptake among the three groups. The differences between 4T1 tumor uptake of 64Cu-MSN-800CW-TRC105(Fab) and the two control groups were statistically significant (**P < 0.01) in all cases. (d) Biodistribution of three groups in 4T1 tumor-bearing mice at the end of the PET scans at 48 h pi (n = 3).
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- 3Liu, Z.; Cai, W.; He, L.; Nakayama, N.; Chen, K.; Sun, X.; Chen, X.; Dai, H. In Vivo Biodistribution and Highly Efficient Tumour Targeting of Carbon Nanotubes in Mice Nature Nanotechnol. 2007, 2, 47– 523https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVWqtbc%253D&md5=f444d31cc38e3d7031d346bd1dd9418aIn vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in miceLiu, Zhuang; Cai, Weibo; He, Lina; Nakayama, Nozomi; Chen, Kai; Sun, Xiaoming; Chen, Xiaoyuan; Dai, HongjieNature Nanotechnology (2007), 2 (1), 47-52CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Single-walled carbon nanotubes (SWNTs) exhibit unique size, shape and phys. properties that make them promising candidates for biol. applications. Here, the authors investigate the biodistribution of radio-labeled SWNTs in mice by in vivo positron emission tomog. (PET), ex vivo biodistribution and Raman spectroscopy. It is found that SWNTs that are functionalized with phospholipids bearing polyethylene-glycol (PEG) are surprisingly stable in vivo. The effect of PEG chain length on the biodistribution and circulation of the SWNTs is studied. Effectively PEGylated SWNTs exhibit relatively long blood circulation times and low uptake by the reticuloendothelial system (RES). Efficient targeting of integrin pos. tumor in mice is achieved with SWNTs coated with PEG chains linked to an arginine-glycine-aspartic acid (RGD) peptide. A high tumor accumulation is attributed to the multivalent effect of the SWNTs. The Raman signatures of SWNTs are used to directly probe the presence of nanotubes in mice tissues and confirm the radio-label-based results.
- 4Hong, H.; Yang, K.; Zhang, Y.; Engle, J. W.; Feng, L.; Yang, Y.; Nayak, T. R.; Goel, S.; Bean, J.; Theuer, C. P.; Barnhart, T. E.; Liu, Z.; Cai, W. In Vivo Targeting and Imaging of Tumor Vasculature with Radiolabeled, Antibody-Conjugated Nanographene ACS Nano 2012, 6, 2361– 23704https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitlOlu70%253D&md5=babc5f1db7afd04a2c66978ad6baa327In Vivo Targeting and Imaging of Tumor Vasculature with Radiolabeled, Antibody-Conjugated NanographeneHong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W.; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R.; Goel, Shreya; Bean, Jero; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, WeiboACS Nano (2012), 6 (3), 2361-2370CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomog. imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo expts. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine.
- 5Shi, S.; Yang, K.; Hong, H.; Valdovinos, H. F.; Nayak, T. R.; Zhang, Y.; Theuer, C. P.; Barnhart, T. E.; Liu, Z.; Cai, W. Tumor Vasculature Targeting and Imaging in Living Mice with Reduced Graphene Oxide Biomaterials 2013, 34, 3002– 30095https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yjurs%253D&md5=84da19a32f2b9e0a784f9b92c9bfc486Tumor vasculature targeting and imaging in living mice with reduced graphene oxideShi, Sixiang; Yang, Kai; Hong, Hao; Valdovinos, Hector F.; Nayak, Tapas R.; Zhang, Yin; Theuer, Charles P.; Barnhart, Todd E.; Liu, Zhuang; Cai, WeiboBiomaterials (2013), 34 (12), 3002-3009CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Graphene-based nanomaterials have attracted tremendous attention in the field of biomedicine due to their intriguing properties. Herein, we report tumor vasculature targeting and imaging in living mice using reduced graphene oxide (RGO), which was conjugated to the anti-CD105 antibody TRC105. The RGO conjugate, 64Cu-NOTA-RGO-TRC105, exhibited excellent stability in vitro and in vivo. Serial positron emission tomog. (PET) imaging studies non-invasively assessed the pharmacokinetics and demonstrated specific targeting of 64Cu-NOTA-RGO-TRC105 to 4T1 murine breast tumors in vivo, compared to non-targeted RGO conjugate (64Cu-NOTA-RGO). In vivo (e.g., blocking 4T1 tumor uptake with excess TRC105), in vitro (e.g., flow cytometry), and ex vivo (e.g., histol.) expts. confirmed the specificity of 64Cu-NOTA-RGO-TRC105 for tumor vascular CD105. Since RGO exhibits desirable properties for photothermal therapy, the tumor-specific RGO conjugate developed in this work may serve as a promising theranostic agent that integrates imaging and therapeutic components.
- 6Rosen, L. S.; Hurwitz, H. I.; Wong, M. K.; Goldman, J.; Mendelson, D. S.; Figg, W. D.; Spencer, S.; Adams, B. J.; Alvarez, D.; Seon, B. K.; Theuer, C. P.; Leigh, B. R.; Gordon, M. S. A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer Clin. Cancer Res. 2012, 18, 4820– 96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1ygsbzI&md5=a0d4274e0bed7c700deaa54229c8cb12A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced CancerRosen, Lee S.; Hurwitz, Herbert I.; Wong, Michael K.; Goldman, Jonathan; Mendelson, David S.; Figg, William D.; Spencer, Shawn; Adams, Bonne J.; Alvarez, Delia; Seon, Ben K.; Theuer, Charles P.; Leigh, Bryan R.; Gordon, Michael S.Clinical Cancer Research (2012), 18 (17), 4820-4829CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of i.v. TRC105 until disease progression or unacceptable toxicity using a std. 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The max. tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concns. that sat. CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 wk. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 mo. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 wk, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clin. activity was seen in a refractory patient population. Ongoing clin. trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820-9. ©2012 AACR.
- 7Seon, B. K.; Haba, A.; Matsuno, F.; Takahashi, N.; Tsujie, M.; She, X.; Harada, N.; Uneda, S.; Tsujie, T.; Toi, H.; Tsai, H.; Haruta, Y. Endoglin-Targeted Cancer Therapy Curr. Drug Delivery 2011, 8, 135– 143There is no corresponding record for this reference.
- 8Fonsatti, E.; Nicolay, H. J.; Altomonte, M.; Covre, A.; Maio, M. Targeting Cancer Vasculature Via Endoglin/CD105: A Novel Antibody-Based Diagnostic and Therapeutic Strategy in Solid Tumours Cardiovasc. Res. 2010, 86, 12– 19There is no corresponding record for this reference.
- 9Hong, H.; Yang, Y.; Zhang, Y.; Engle, J. W.; Barnhart, T. E.; Nickles, R. J.; Leigh, B. R.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression During Tumor Angiogenesis Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 1335– 13439https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvVais7g%253D&md5=e247f60e04d12e4b4255a5e2f17c1f77Positron emission tomography imaging of CD105 expression during tumor angiogenesisHong, Hao; Yang, Yunan; Zhang, Yin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, Robert J.; Leigh, Bryan R.; Cai, WeiboEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (7), 1335-1343CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel d. (MVD) assessed by CD105 staining is the current gold std. for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomog. (PET) tracer for imaging CD105 expression. Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS anal. and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histol. studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. Results: FACS anal. of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, resp. (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking expts., control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histol. all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105. Conclusion: This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was obsd. Further studies are warranted and currently underway.
- 10Hong, H.; Zhang, Y.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Bean, J.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Positron Emission Tomography Imaging of Tumor Angiogenesis with a (61/64)Cu-Labeled F(ab′)(2) Antibody Fragment Mol. Pharm. 2013, 10, 709– 71610https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXotl2ntg%253D%253D&md5=1d3b0b0563717419ebaf33ca19fe43acPositron Emission Tomography Imaging of Tumor Angiogenesis with a 61/64Cu-Labeled F(ab')2 Antibody FragmentHong, Hao; Zhang, Yin; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Bean, Jero; Theuer, Charles P.; Barnhart, Todd E.; Cai, WeiboMolecular Pharmaceutics (2013), 10 (2), 709-716CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)The objective of this study was to characterize the in vitro and in vivo properties of the F(ab')2 fragment of TRC105, a human/murine chimeric IgG1 monoclonal antibody that binds with high avidity to human and murine CD105 (i.e., endoglin), and investigate its potential for positron emission tomog. (PET) imaging of tumor angiogenesis after 61/64Cu-labeling. TRC105-F(ab')2 of high purity was produced by pepsin digestion of TRC105, which was confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu-labeling of NOTA-TRC105-F(ab')2 (NOTA denotes 1,4,7-triazacyclononane-1,4,7-triacetic acid) was achieved with yields of >75% (specific activity: ∼115 GBq/μmol). PET imaging revealed rapid tumor uptake of 64Cu-NOTA-TRC105-F(ab')2 in the 4T1 murine breast cancer model (5.8 ± 0.8, 7.6 ± 0.6, 5.6 ± 0.4, 5.0 ± 0.6, and 3.8 ± 0.7% ID/g at 0.5, 3, 16, 24, and 48 h postinjection resp.; n = 4). Since tumor uptake peaked at 3 h postinjection, 61Cu-NOTA-TRC105-F(ab')2 also gave good tumor contrast at 3 and 8 h postinjection. CD105 specificity of the tracers was confirmed by blocking studies and histopathol. In conclusion, the use of a F(ab')2 fragment led to more rapid tumor uptake (which peaked at 3 h postinjection) than radiolabeled intact antibody (which often peaked after 24 h postinjection), which may allow for same day immunoPET imaging in future clin. studies.
- 11James, M. L.; Gambhir, S. S. A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications Physiol. Rev. 2012, 92, 897– 96511https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptF2kuro%253D&md5=ac41f9148a6e867416060e04fcdff630A molecular imaging primer: modalities, imaging agents, and applicationsJames, Michelle L.; Gambhir, Sanjiv S.Physiological Reviews (2012), 92 (2), 897-965CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. Mol. imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochem. processes involved in normal physiol. and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on mol. imaging of intact living subjects. We provide a basic primer for those who are new to mol. imaging, and a resource for those involved in the field. We begin by describing classical mol. imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of mol. imaging agents (i.e., small mols., peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how mol. imaging is being applied in oncol., neuroscience, cardiol., gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biol. and/or clin. questions using the tools of mol. imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
- 12Gambhir, S. S. Molecular Imaging of Cancer with Positron Emission Tomography Nature Rev. Cancer 2002, 2, 683– 69312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xmslanu7c%253D&md5=228f99ad777626e7763eeaf5f2a4e4cbMolecular imaging of cancer with positron emission tomographyGambhir, Sanjiv SamNature Reviews Cancer (2002), 2 (9), 683-693CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. The imaging of specific mol. targets that are assocd. with cancer should allow earlier diagnosis and better management of oncol. patients. Positron emission tomog. (PET) is a highly sensitive non-invasive technol. that is ideally suited for pre-clin. and clin. imaging of cancer biol., in contrast to anatomical approaches. By using radiolabeled tracers, which are injected in non-pharmacol. doses, three-dimensional images can be reconstructed by a computer to show the concn. and location(s) of the tracer of interest. PET should become increasingly important in cancer imaging in the next decade.
- 13Cai, W.; Chen, K.; Li, Z. B.; Gambhir, S. S.; Chen, X. Dual-Function Probe for PET and Near-Infrared Fluorescence Imaging of Tumor Vasculature J. Nucl. Med. 2007, 48, 1862– 1870There is no corresponding record for this reference.
- 14Chen, K.; Li, Z. B.; Wang, H.; Cai, W.; Chen, X. Dual-Modality Optical and Positron Emission Tomography Imaging of Vascular Endothelial Growth Factor Receptor on Tumor Vasculature Using Quantum Dots Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 2235– 224414https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVyls73E&md5=644ac277398856b7515add2a3f30ceaaDual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dotsChen, Kai; Li, Zi-Bo; Wang, Hui; Cai, Weibo; Chen, XiaoyuanEuropean Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (12), 2235-2244CODEN: EJNMA6; ISSN:1619-7070. (Springer)To date, the in vivo imaging of quantum dots (QDs) has been mostly qual. or semiquant. The development of a dual-function positron emission tomog. (PET)/near-IR fluorescence (NIRF) probe might allow the accurate assessment of the tumor-targeting efficacy of QDs. An amine-functionalized QD was conjugated with VEGF protein and DOTA chelator for VEGFR-targeted PET/NIRF imaging after 64Cu-labeling. The targeting efficacy of this dual functional probe was evaluated in vitro and in vivo through cell-binding assay, cell staining, in vivo optical/PET imaging, ex vivo optical/PET imaging, and histol. The DOTA-QD-VEGF exhibited VEGFR-specific binding in both cell-binding assay and cell staining expt. Both NIR fluorescence imaging and microPET showed VEGFR-specific delivery of conjugated DOTA-QD-VEGF nanoparticle and prominent reticuloendothelial system uptake. The U87MG tumor uptake of 64Cu-labeled DOTA-QD was less than one percentage injected dose per g (%ID/g), significantly lower than that of 64Cu-labeled DOTA-QD-VEGF (1.52 ± 0.6%ID/g, 2.81 ± 0.3%ID/g, 3.84 ± 0.4%ID/g, and 4.16 ± 0.5%ID/g at 1, 4, 16, and 24 h post injection, resp.; n = 3). Good correlation was also obsd. between the results measured by ex vivo PET and NIRF organ imaging. Histol. examn. revealed that DOTA-QD-VEGF primarily targets the tumor vasculature through a VEGF-VEGFR interaction. We have successfully developed a QD-based nanoprobe for dual PET and NIRF imaging of tumor VEGFR expression. The success of this bifunctional imaging approach may render higher degree of accuracy for the quant. targeted NIRF imaging in deep tissue.
- 15Lee, J.; Lee, T. S.; Ryu, J.; Hong, S.; Kang, M.; Im, K.; Kang, J. H.; Lim, S. M.; Park, S.; Song, R. RGD Peptide-Conjugated Multimodal NaDdF4:Yb3+/Er3+ Nanophosphors for Upconversion Luminescence, MR, and PET Imaging of Tumor Angiogenesis J. Nucl. Med. 2013, 54, 96– 103There is no corresponding record for this reference.
- 16Sun, Y.; Yu, M.; Liang, S.; Zhang, Y.; Li, C.; Mou, T.; Yang, W.; Zhang, X.; Li, B.; Huang, C.; Li, F. Fluorine-18 Labeled Rare-Earth Nanoparticles for Positron Emission Tomography (PET) Imaging of Sentinel Lymph Node Biomaterials 2011, 32, 2999– 3007There is no corresponding record for this reference.
- 17Xie, J.; Chen, K.; Huang, J.; Lee, S.; Wang, J.; Gao, J.; Li, X.; Chen, X. PET/NIRF/MRI Triple Functional Iron Oxide Nanoparticles Biomaterials 2010, 31, 3016– 3022There is no corresponding record for this reference.
- 18Zhou, J.; Yu, M.; Sun, Y.; Zhang, X.; Zhu, X.; Wu, Z.; Wu, D.; Li, F. Fluorine-18-Labeled Gd3+/Yb3+/Er3+ Co-Doped NaYF4 Nanophosphors for Multimodality PET/MR/UCL Imaging Biomaterials 2011, 32, 1148– 1156There is no corresponding record for this reference.
- 19Huang, X.; Zhang, F.; Lee, S.; Swierczewska, M.; Kiesewetter, D. O.; Lang, L.; Zhang, G.; Zhu, L.; Gao, H.; Choi, H. S.; Niu, G.; Chen, X. Long-Term Multimodal Imaging of Tumor Draining Sentinel Lymph Nodes Using Mesoporous Silica-Based Nanoprobes Biomaterials 2012, 33, 4370– 4378There is no corresponding record for this reference.
- 20Zhang, Y.; Hong, H.; Engle, J. W.; Yang, Y.; Barnhart, T. E.; Cai, W. Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Vascular Endothelial Growth Factor with Dual-Labeled Bevacizumab Am. J. Nucl. Med. Mol. Imaging 2012, 2, 1– 1320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrtLs%253D&md5=081ff1f5be3c91058bb4c98bbc86f3a4Positron emission tomography and near-infrared fluorescence imaging of vascular endothelial growth factor with dual-labeled bevacizumabZhang, Yin; Hong, Hao; Engle, Jonathan W.; Yang, Yunan; Barnhart, Todd E.; Cai, WeiboAmerican Journal of Nuclear Medicine and Molecular Imaging (2012), 2 (1), 1-13CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)The pivotal role of vascular endothelial growth factor (VEGF) in cancer is underscored by the approval of bevacizumab (Bev, a humanized anti-VEGF monoclonal antibody) for first line treatment of cancer patients. The aim of this study was to develop a dual-labeled Bev for both positron emission tomog. (PET) and near-IR fluorescence (NIRF) imaging of VEGF. Bev was conjugated to a NIRF dye (i.e. 800CW) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) before 64Cu-labeling. Flow cytometry anal. of U87MG human glioblastoma cells revealed no difference in VEGF binding affinity/specificity between Bev and NOTA-Bev-800CW. 64Cu-labeling of NOTA-Bev-800CW was achieved with high yield. Serial PET imaging of U87MG tumor-bearing female nude mice revealed that tumor uptake of 64Cu-NOTA-Bev-800CW was 4.6 ± 0.7, 16.3 ± 1.6, 18.1 ± 1.4 and 20.7 ± 3.7 % ID/g at 4, 24, 48 and 72 h post-injection resp. (n = 4), corroborated by in vivo/ex vivo NIRF imaging and biodistribution studies. Tumor uptake as measured by ex vivo NIRF imaging had a good linear correlation with the % ID/g values obtained from PET (R2 = 0.93). Blocking expts. and histol. both confirmed the VEGF specificity of 64Cu-NOTA-Bev-800CW. The persistent, prominent, and VEGF-specific uptake of 64Cu-NOTA-Bev-800CW in the tumor, obsd. by both PET and NIRF imaging, warrants further investigation and future clin. translation of such Bev-based imaging agents.
- 21Vallet-Regi, M.; Rámila, A.; del Real, R. P.; Pérez-Pariente, J. A New Property of Mcm-41: Drug Delivery System Chem. Mater. 2000, 13, 308– 311There is no corresponding record for this reference.
- 22Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals Small 2010, 6, 1794– 1805There is no corresponding record for this reference.
- 23Meng, H.; Xue, M.; Xia, T.; Ji, Z.; Tarn, D. Y.; Zink, J. I.; Nel, A. E. Use of Size and a Copolymer Design Feature to Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model ACS Nano 2011, 5, 4131– 414423https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltlaqtro%253D&md5=7a297aaa7fdb6c96f8ebe5686a0a7f97Use of Size and a Copolymer Design Feature To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor ModelMeng, Huan; Xue, Min; Xia, Tian; Ji, Zhaoxia; Tarn, Derrick Y.; Zink, Jeffrey I.; Nel, Andre E.ACS Nano (2011), 5 (5), 4131-4144CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size redn. and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after i.v. injection. Using near-IR fluorescence imaging and elemental Si anal., we demonstrate passive accumulation of ∼ 12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant redn. in systemic side effects such as animal wt. loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size redn. as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.
- 24Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles J. Am. Chem. Soc. 2012, 134, 5722– 572524https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktVyntLs%253D&md5=d3c0b442624c819703f88f6c46ef217cNuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica NanoparticlesPan, Limin; He, Qianjun; Liu, Jianan; Chen, Yu; Ma, Ming; Zhang, Linlin; Shi, JianlinJournal of the American Chemical Society (2012), 134 (13), 5722-5725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diam. of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.
- 25Wang, K.; He, X.; Yang, X.; Shi, H. Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal Levels Acc. Chem. Res. 2013, 46, 1367– 137625https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVOgtr8%253D&md5=7ef5408d06507eb5b5740de637593ea6Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal LevelsWang, Kemin; He, Xiaoxiao; Yang, XiaoHai; Shi, HuiAccounts of Chemical Research (2013), 46 (7), 1367-1376CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Going in vivo, including living cells and the whole body, is very important for gaining a better understanding of the mystery of life and requires specialized imaging techniques. The diversity, compn., and temporal-spatial variation of life activities from cells to the whole body require the anal. techniques to be fast-response, noninvasive, highly sensitive, and stable, in situ and in real-time. Functionalized nanoparticle-based fluorescence imaging techniques have the potential to meet such needs through real-time and noninvasive visualization of biol. events in vivo. Functionalized silica nanoparticles (SiNPs) doped with fluorescent dyes appear to be an ideal and flexible platform for developing fluorescence imaging techniques used in living cells and the whole body. The authors can select and incorporate different dyes inside the silica matrix either noncovalently or covalently. These form the functionalized hybrid SiNPs, which support multiplex labeling and ratiometric sensing in living systems. Since the silica matrix protects dyes from outside quenching and degrading factors, this enhances the photostability and biocompatibility of the SiNP-based probes. This makes them ideal for real-time and long-time tracking. One nanoparticle can encapsulate large nos. of dye mols., which amplifies their optical signal and temporal-spatial resoln. response. Integrating fluorescent dye-doped SiNPs with targeting ligands using various surface modification techniques can greatly improve selective recognition. Along with the endocytosis, functionalized SiNPs can be efficiently internalized into cells for noninvasive localization, assessment, and monitoring. These unique characteristics of functionalized SiNPs substantially support their applications in fluorescence imaging in vivo. In this Account, the authors summarize their efforts to develop functionalized dye-doped SiNPs for fluorescence imaging at the cell and small animal levels. The authors first discuss how to design and construct various functionalized dye-doped SiNPs. Then the authors describe their properties and imaging applications in cell surface receptor recognition, intracellular labeling, tracking, sensing, and controlled release. Addnl., the authors demonstrated the promising application of dye-doped SiNPs as contrast imaging agents for in vivo fluorescence imaging in small animals. The authors expect these functionalized dye-doped SiNPs to open new opportunities for biol. and medical research and applications.
- 26Lee, C. H.; Cheng, S. H.; Wang, Y. J.; Chen, Y. C.; Chen, N. T.; Souris, J.; Chen, C. T.; Mou, C. Y.; Yang, C. S.; Lo, L. W. Near-Infrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and in Vivo Biodistribution Adv. Funct. Mater. 2009, 19, 215– 22226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhslequ7s%253D&md5=1df6373665d1b4855117e38709ebe377Near-infrared mesoporous silica nanoparticles for optical imaging: characterization and in vivo biodistributionLee, Chia-Hung; Cheng, Shih-Hsun; Wang, Yu-Jing; Chen, Yu-Ching; Chen, Nai-Tzu; Souris, Jeffrey; Chen, Chin-Tu; Mou, Chung-Yuan; Yang, Chung-Shi; Lo, Leu-WeiAdvanced Functional Materials (2009), 19 (2), 215-222CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)The characterization of near-IR (NIR) mesoporous silica nanoparticles (MSN) suitable for in vivo optical imaging with high efficiency is presented. Trimethylammonium groups modified MSN (MSN-TA) with the av. size of 50-100 nm was synthesized with incorporation of the TA groups into the framework of MSN. It was further adsorbed with indocyanine green (ICG) by electrostatic attraction to render MSN-TA-ICG as an efficient NIR contrast agent for in vivo optical imaging. The studies in stability of MSN-TA-ICG against pH indicated the bonding is stable over the range from acidic to physiol. pH. The in vivo biodistribution of MSN-TA-ICG in anesthetized rat demonstrated a rather strong and stable fluorescence of MSN-TA-ICG that prominent in the organ of liver. Transmission electron microscopy (TEM) imaging and elemental anal. of silicon further manifested the phys. and quant. residences of MSN-TA-ICG in major organs. This is the first report of MSN functionalized with NIR-ICG capable of optical imaging in vivo.
- 27Pan, J.; Wan, D.; Gong, J. Pegylated Liposome Coated QDs/Mesoporous Silica Core–Shell Nanoparticles for Molecular Imaging Chem. Commun. 2011, 47, 3442– 3444There is no corresponding record for this reference.
- 28Liu, J.; Bu, W.; Zhang, S.; Chen, F.; Xing, H.; Pan, L.; Zhou, L.; Peng, W.; Shi, J. Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal Imaging Chemistry 2012, 18, 2335– 234128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvVelsg%253D%253D&md5=1a17cf05814e38d50af54bbfa0778f15Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal ImagingLiu, Jianan; Bu, Wenbo; Zhang, Shengjian; Chen, Feng; Xing, Huaiyong; Pan, Limin; Zhou, Liangping; Peng, Weijun; Shi, JianlinChemistry - A European Journal (2012), 18 (8), 2335-2341, S2335/1-S2335/5CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)Here the authors report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO2 nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO2) on upconversion nanocrystals NaYF4:Tm/Yb/Gd (UCNPs), which can be used as near-IR fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amt. of CTAB, and temp.-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-IR fluorescence and magnetic resonance imaging was also demonstrated.
- 29Zhang, Y.; Hong, H.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Pet Imaging of CD105/Endoglin Expression with a (6)(1)/(6)(4)Cu-Labeled Fab Antibody Fragment Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 759– 76729https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmt1Ohu7c%253D&md5=2a63cf74218ea45208b2b960042e73d5PET imaging of CD105/endoglin expression with a 61/64Cu-labeled Fab antibody fragmentZhang, Yin; Hong, Hao; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Theuer, Charles P.; Barnhart, Todd E.; Cai, WeiboEuropean Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (5), 759-767CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after 61/64Cu labeling. Methods: TRC105-Fab was generated by enzymic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and 61/64Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of 61/64Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. Results TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/μmol). PET imaging revealed rapid uptake of 64Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, resp.; n = 4). Since tumor uptake peaked soon after tracer injection, 61Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histol. examn. Conclusion: We report PET imaging of CD105 expression using 61/64Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clin. investigation.
- 30Chen, F.; Hong, H.; Zhang, Y.; Valdovinos, H. F.; Shi, S.; Kwon, G. S.; Theuer, C. P.; Barnhart, T. E.; Cai, W. In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles ACS Nano 2013, 7, 9027– 9039There is no corresponding record for this reference.
- 31Orbay, H.; Zhang, Y.; Valdovinos, H. F.; Song, G.; Hernandez, R.; Theuer, C. P.; Hacker, T. A.; Nickles, R. J.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression in a Rat Myocardial Infarction Model with (64)Cu-Nota-TRC105 Am. J. Nucl. Med. Mol. Imaging 2013, 4, 1– 931https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czhtFekuw%253D%253D&md5=4a20b4fbdef77b015c2fce1771fad30aPositron emission tomography imaging of CD105 expression in a rat myocardial infarction model with (64)Cu-NOTA-TRC105Orbay Hakan; Zhang Yin; Valdovinos Hector F; Hernandez Reinier; Nickles Robert J; Song Guoqing; Hacker Timothy A; Theuer Charles P; Cai WeiboAmerican journal of nuclear medicine and molecular imaging (2013), 4 (1), 1-9 ISSN:.Biological changes following myocardial infarction (MI) lead to increased secretion of angiogenic factors that subsequently stimulate the formation of new blood vessels as a compensatory mechanism to reverse ischemia. The goal of this study was to assess the role of CD105 expression during MI-induced angiogenesis by positron emission tomography (PET) imaging using (64)Cu-labeled TRC105, an anti-CD105 monoclonal antibody. MI was induced by ligation of the left anterior descending (LAD) artery in female rats. Echocardiography and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET scans were performed on post-operative day 3 to confirm the presence of MI in the infarct group and intact heart in the sham group, respectively. Ischemia-induced angiogenesis was non-invasively monitored with (64)Cu-NOTA-TRC105 (an extensively validated PET tracer in our previous studies) PET on post-operative days 3, 10, and 17. Tracer uptake in the infarct zone was highest on day 3 following MI, which was significantly higher than that in the sham group (1.41 ± 0.45 %ID/g vs 0.57 ± 0.07 %ID/g; n=3, p<0.05). Subsequently, tracer uptake in the infarct zone decreased over time to the background level on day 17, whereas tracer uptake in the heart of sham rats remained low at all time points examined. Histopathology documented increased CD105 expression following MI, which corroborated in vivo findings. This study indicated that PET imaging of CD105 can be a useful tool for MI-related research, which can potentially improve MI patient management in the future upon clinical translation of the optimized PET tracers.
Supporting Information
Supporting Information
Ninhydrin testing, tables of PET region-of-interest quantifications, quantitative analysis of PET imaging data from non-targeted and blocking groups. This material is available free of charge via the Internet at http://pubs.acs.org.
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