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Duraiyarasu M, Senthil Kumaran S, Mayilmurugan R. Biotin Conjugated Fe(III)-Triscatecholate Complex as Tumour Targeting T 1 MRI Contrast Agent via Second Sphere Water Relaxation. Chemistry 2025; 31:e202403619. [PMID: 39658512 DOI: 10.1002/chem.202403619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/23/2024] [Accepted: 12/10/2024] [Indexed: 12/12/2024]
Abstract
The biotin-conjugated Fe(III) catecholate complex [Fe(BioL)3]3-, Fe(BioL)3 (BioLH2=N-(3,4-dihydroxyphenethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide) is reported as targeted magnetic resonance imaging (MRI) contrast agents (CAs) to increase the payload for early-stage imaging of tumours. The high spin state and octahedral coordination of the Fe(III) complex are confirmed by EPR spectra and DFT optimized structure, respectively. The overall formation constant (log K) of Fe(BioL)3 is determined as 45, which is higher than the known, more stable complex [Fe(EDTA)]. The complex Fe(BioL)3 exhibited r1 relaxivity of 3.09±0.10 and 1.95±0.09 mM-1 s-1 at 25 °C and 37 °C, respectively, at 1.41 T and pH 7.35 via second-sphere water interactions as due to the absence of inner water coordination. The interaction of Fe(BioL)3 with bovine serum albumin (BSA) and human serum albumin (HSA) displayed enhanced relaxivity of 5.16±0.15 and 10.0±0.19 mM-1 s-1, respectively, at 25 °C and pH 7.3 possibly via lengthening of rotational correlational time. The complex Fe(BioL)3 uptake studies with the avidin, a biotin-binding protein pocket, showed 46 and 37 % enhancements of r1 and r2 relaxivities. Complex Fe(BioL)3 showed 80 % cell viability of the human gastric adenocarcinoma (AGS) cells, and 89 % of iron has been uptaken into cells.
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Affiliation(s)
- Maheshwaran Duraiyarasu
- Department of Chemistry, & Department of Bioscience & Biomedical Engineering, Indian Institute of Technology Bhilai, Durg, 491002, Chattisgarh, India
- Current Institution, School of Biological and Health Systems Engineering, Arizona State University, Tempe, 85281, Arizona, USA
| | - S Senthil Kumaran
- Department of NMR, All India Institute of Medical Sciences Ansari Nagar, New Delhi, 110 029, India
| | - Ramasamy Mayilmurugan
- Department of Chemistry, & Department of Bioscience & Biomedical Engineering, Indian Institute of Technology Bhilai, Durg, 491002, Chattisgarh, India
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Fathi M, Taher HJ, Al-Rubiae SJ, Yaghoobpoor S, Bahrami A, Eshraghi R, Sadri H, Asadi Anar M, Gholamrezanezhad A. Role of molecular imaging in prognosis, diagnosis, and treatment of gastrointestinal cancers: An update on new therapeutic methods. World J Methodol 2024; 14:93461. [PMID: 39712556 PMCID: PMC11287540 DOI: 10.5662/wjm.v14.i4.93461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/31/2024] [Accepted: 07/15/2024] [Indexed: 07/26/2024] Open
Abstract
One of the leading causes of cancer-related death is gastrointestinal cancer, which has a significant morbidity and mortality rate. Although preoperative risk assessment is essential for directing patient care, its biological behavior cannot be accurately predicted by conventional imaging investigations. Potential pathophysiological information in anatomical imaging that cannot be visually identified can now be converted into high-dimensional quantitative image features thanks to the developing discipline of molecular imaging. In order to enable molecular tissue profile in vivo, molecular imaging has most recently been utilized to phenotype the expression of single receptors and targets of biological therapy. It is expected that molecular imaging will become increasingly important in the near future, driven by the expanding range of biological therapies for cancer. With this live molecular fingerprinting, molecular imaging can be utilized to drive expression-tailored customized therapy. The technical aspects of molecular imaging are first briefly discussed in this review, followed by an examination of the most recent research on the diagnosis, prognosis, and potential future clinical methods of molecular imaging for GI tract malignancies.
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Affiliation(s)
- Mobina Fathi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | | | | | - Shirin Yaghoobpoor
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Ashkan Bahrami
- Faculty of Medicine, Kashan University of Medical Sciences, Kashan 1617768911, Iran
| | - Reza Eshraghi
- Faculty of Medicine, Kashan University of Medical Sciences, Kashan 1617768911, Iran
| | - Hossein Sadri
- Faculty of Medicine, Kashan University of Medical Sciences, Kashan 1617768911, Iran
| | - Mahsa Asadi Anar
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Ali Gholamrezanezhad
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
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Shang K, Xu C, Cao Z, Cui M, Sun J, Xiao H, Zhang L, Wang Y, Han H. Polymer-based delivery systems with metal complexes as contrast agents for medical imaging. Coord Chem Rev 2024; 518:216071. [DOI: 10.1016/j.ccr.2024.216071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Meng Q, Wu M, Shang Z, Zhang Z, Zhang R. Responsive gadolinium(III) complex-based small molecule magnetic resonance imaging probes: Design, mechanism and application. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2021.214398] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Campbell J, Tung MT, Diaz-Rodriguez RM, Robertson KN, Beharry AA, Thompson A. Introducing the Tellurophene-Appended BODIPY: PDT Agent with Mass Cytometry Tracking Capabilities. ACS Med Chem Lett 2021; 12:1925-1931. [PMID: 34917256 PMCID: PMC8667306 DOI: 10.1021/acsmedchemlett.1c00492] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/17/2021] [Indexed: 12/20/2022] Open
Abstract
The synthesis and characterization of the first BODIPY appended to the five-membered heterocylic tellurophene [Te] moiety is reported. By incorporating tellurophene at the meso position, the tellurophene-appended boron-dipyrromethene dye (BODIPY) acts as a multimodal agent, becoming a potent photosensitizer with a mass cytometry tag. To synthesize the compound, we developed a method to enable late-stage Suzuki-Miyaura coupling by preparing and isolating tellurophene-2-BPin in a one-step procedure from the parent tellurophene. Coupling to a meso-substituted BODIPY functionalized with a pendant aryl bromide provides the desired tellurophene-appended BODIPY. This compound demonstrated a singlet oxygen quantum yield of 0.26 ± 0.01 and produced a light dose-dependent cytotoxicity with nanomolar IC50 values against 2D cultured HeLa cells and high efficacy against 3D cultured HeLa tumor spheroids, proving to be a strong photosensitizer. The presence of the tellurophene moiety could be detected using mass cytometry, thus showcasing the ability of a tellurophene-appended BODIPY as a novel photodynamic-therapy-mass-cytometry theranostic agent.
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Affiliation(s)
- Jacob
W. Campbell
- Department
of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia B3H 4J3, Canada
| | - Matthew T. Tung
- Department
of Chemistry and Physical Sciences, University
of Toronto, Mississauga, Ontario L5L 1C6, Canada
| | | | | | - Andrew A. Beharry
- Department
of Chemistry and Physical Sciences, University
of Toronto, Mississauga, Ontario L5L 1C6, Canada
| | - Alison Thompson
- Department
of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia B3H 4J3, Canada
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Ag Seleci D, Maurer V, Barlas FB, Porsiel JC, Temel B, Ceylan E, Timur S, Stahl F, Scheper T, Garnweitner G. Transferrin-Decorated Niosomes with Integrated InP/ZnS Quantum Dots and Magnetic Iron Oxide Nanoparticles: Dual Targeting and Imaging of Glioma. Int J Mol Sci 2021; 22:ijms22094556. [PMID: 33925347 PMCID: PMC8123697 DOI: 10.3390/ijms22094556] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/19/2022] Open
Abstract
The development of multifunctional nanoscale systems that can mediate efficient tumor targeting, together with high cellular internalization, is crucial for the diagnosis of glioma. The combination of imaging agents into one platform provides dual imaging and allows further surface modification with targeting ligands for specific glioma detection. Herein, transferrin (Tf)-decorated niosomes with integrated magnetic iron oxide nanoparticles (MIONs) and quantum dots (QDs) were formulated (PEGNIO/QDs/MIONs/Tf) for efficient imaging of glioma, supported by magnetic and active targeting. Transmission electron microscopy confirmed the complete co-encapsulation of MIONs and QDs in the niosomes. Flow cytometry analysis demonstrated enhanced cellular uptake of the niosomal formulation by glioma cells. In vitro imaging studies showed that PEGNIO/QDs/MIONs/Tf produces an obvious negative-contrast enhancement effect on glioma cells by magnetic resonance imaging (MRI) and also improved fluorescence intensity under fluorescence microscopy. This novel platform represents the first niosome-based system which combines magnetic nanoparticles and QDs, and has application potential in dual-targeted imaging of glioma.
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Affiliation(s)
- Didem Ag Seleci
- Institute for Particle Technology (iPAT), Technische Universität Braunschweig, 38104 Braunschweig, Germany; (D.A.S.); (V.M.); (J.C.P.); (B.T.)
- Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig, 38106 Braunschweig, Germany
| | - Viktor Maurer
- Institute for Particle Technology (iPAT), Technische Universität Braunschweig, 38104 Braunschweig, Germany; (D.A.S.); (V.M.); (J.C.P.); (B.T.)
- Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig, 38106 Braunschweig, Germany
| | - Firat Baris Barlas
- Faculty of Science Biochemistry Department, Ege University, 35100 Izmir, Turkey; (F.B.B.); (E.C.); (S.T.)
| | - Julian Cedric Porsiel
- Institute for Particle Technology (iPAT), Technische Universität Braunschweig, 38104 Braunschweig, Germany; (D.A.S.); (V.M.); (J.C.P.); (B.T.)
| | - Bilal Temel
- Institute for Particle Technology (iPAT), Technische Universität Braunschweig, 38104 Braunschweig, Germany; (D.A.S.); (V.M.); (J.C.P.); (B.T.)
| | - Elcin Ceylan
- Faculty of Science Biochemistry Department, Ege University, 35100 Izmir, Turkey; (F.B.B.); (E.C.); (S.T.)
| | - Suna Timur
- Faculty of Science Biochemistry Department, Ege University, 35100 Izmir, Turkey; (F.B.B.); (E.C.); (S.T.)
| | - Frank Stahl
- Institute for Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (F.S.); (T.S.)
| | - Thomas Scheper
- Institute for Technical Chemistry, Leibniz University Hannover, 30167 Hannover, Germany; (F.S.); (T.S.)
| | - Georg Garnweitner
- Institute for Particle Technology (iPAT), Technische Universität Braunschweig, 38104 Braunschweig, Germany; (D.A.S.); (V.M.); (J.C.P.); (B.T.)
- Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig, 38106 Braunschweig, Germany
- Correspondence:
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7
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盛 荟, 梁 磊, 周 童, 贾 彦, 王 彤, 袁 兰, 韩 鸿. [Improved synthesis process of optical-magnetic bimodal probe of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2020; 52:959-963. [PMID: 33047737 PMCID: PMC7653407 DOI: 10.19723/j.issn.1671-167x.2020.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Indexed: 06/11/2023]
Abstract
OBJECTIVE To improve the methods to synthesize and purify of optical-magnetic bimodal molecular probe of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluorescein thioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes. METHODS Target compound (7), optical-magnetic bimodal molecular molecular probe, was synthesized by the use of 1, 4, 7, 10-tetraazacyclododecane (1) as starting material via substitution reaction, hydrolysis reaction, coupling reaction and complexation reaction with metal. RESULTS The synthetic route of Gd-[4, 7-Bis-carboxymethyl-10-(2-fluoresceinthioureaethyl)-1, 4, 7, 10-tetraaza-cyclododec-1-yl]-acetic acid complexes was improved. The optical-magnetic bimodal molecular probes were synthesized by substitution reaction, hydrolysis reaction, coupling reaction and complex reaction with metal respectively. For the improved route, the total yield could reach 34.6% which was higher than the original route (18.0%). The structures of those compounds were identified by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and mass spectrometry. The improved route could avoid the uncontrollable disadvantage of the substitution reaction, this process could reduce the formation of impurities and made the purification process easier, and in the aspect of purification and separation, the preparative high-performance liquid chromatography with less sample loading and high cost was improved to a column chromatography with many sample loads and being easy to operate. Therefore, the use of column chromatography could be more conducive to mass production of the optical-magnetic bimodal molecular molecular probe. CONCLUSION The improved synthetic route improves the controllability of the reaction conditions and makes it easier to purify and separate the compounds. At the same time, the improved synthetic route can increase the total yield significantly. The optical-magnetic bimodal molecular probe can combine the living magnetic resonance imaging with the in vitro optical imaging to realize the dual synchronous detection of magneto-optics, so that the detection results of the living magnetic resonance imaging and the in vitro optical imaging are mutually verified. In other words, this synthetic optical-magnetic bimodal molecular probe will make the experimental results more accurate and reliable. In subsequent biological experimental studies, the optical-magnetic bimodal molecular probe can be applied to related research of brain structure and function, and the probe can be used for the brain-related diseases researches, such as brain tumors. after intravenous administration, and thus the optical-magnetic bimodal molecular probe can play an important role in medical treatment of brain tumors and cerebrovascular diseases.
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Affiliation(s)
- 荟 盛
- 北京大学药学院化学生物学系，北京 100191Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
- 北京大学医药卫生分析中心，北京 100191Peking University Medical and Health Analysis Center, Beijng 100191, China
- 北京市磁共振成像设备与技术重点实验室，北京 100191Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
| | - 磊 梁
- 北京大学药学院药物化学系，北京 100191Department of Medicinal Chemistry, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
| | - 童亮 周
- 北京大学药学院药物化学系，北京 100191Department of Medicinal Chemistry, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
| | - 彦兴 贾
- 北京大学药学院药物化学系，北京 100191Department of Medicinal Chemistry, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
| | - 彤 王
- 北京大学药学院化学生物学系，北京 100191Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
- 北京大学医药卫生分析中心，北京 100191Peking University Medical and Health Analysis Center, Beijng 100191, China
- 北京市磁共振成像设备与技术重点实验室，北京 100191Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
| | - 兰 袁
- 北京大学药学院化学生物学系，北京 100191Department of Chemical Biology, Peking University School of Pharmaceutical Sciences, Beijng 100191, China
- 北京大学医药卫生分析中心，北京 100191Peking University Medical and Health Analysis Center, Beijng 100191, China
| | - 鸿宾 韩
- 北京市磁共振成像设备与技术重点实验室，北京 100191Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
- 北京大学第三医院放射科，北京 100191Department of Radiology, Peking University Third Hospital, Beijing 100191, China
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Morse SV, Boltersdorf T, Harriss BI, Chan TG, Baxan N, Jung HS, Pouliopoulos AN, Choi JJ, Long NJ. Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound. Am J Cancer Res 2020; 10:2659-2674. [PMID: 32194827 PMCID: PMC7052893 DOI: 10.7150/thno.42665] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/01/2020] [Indexed: 12/14/2022] Open
Abstract
Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles. Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes. Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right control hemisphere. Cellular uptake of Gd(rhodamine-pip-DO3A) was observed in all the treated regions with a uniform distribution (coefficient of variation = 0.4 ± 0.05). Uptake was confirmed within neurons, whereas the probe did not co-localize with microglia and astrocytes. Compared to the dextran molecule, Gd(rhodamine-pip-DO3A) distributed more homogeneously and was less concentrated around blood vessels. Furthermore, the dextran molecule was found to accumulate unselectively in microglia as well as neurons, whereas our probe was only taken up by neurons. Gd(rhodamine-pip-DO3A) was detected via magnetic resonance imaging ex vivo in similar regions to where fluorescence was detected. Conclusion: We have introduced a method to image neurons with a dual-modal imaging agent delivered non-invasively and locally to the brain using focused ultrasound and microbubbles. When delivered to the mouse brain, the agent distributed homogeneously and was only uptaken by neurons; in contrast, conventionally used dextran distributed heterogeneously and was uptaken by microglia as well as neurons. This result indicates that our probe labels neurons without microglial involvement and in addition the probe was found to be detectable via both ex vivo MRI and fluorescence. Labeling neurons with such dual-modal agents could facilitate the study of neuronal morphology and physiology using the advantages of both imaging modalities.
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Deng Y, Xu A, Yu Y, Fu C, Liang G. Biomedical Applications of Fluorescent and Magnetic Resonance Imaging Dual‐Modality Probes. Chembiochem 2018; 20:499-510. [DOI: 10.1002/cbic.201800450] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Yun Deng
- Institute for Interdisciplinary & Research Key Laboratory of, Optoelectronic Chemical Materials and Devices of Ministry of EducationJianghan University Wuhan 430056 P.R. China
| | - Aifei Xu
- School of Tobacco Science and EngineeringZhengzhou University of Light Industry Zhengzhou 450002 P.R. China
| | - Yanhua Yu
- Institute for Interdisciplinary & Research Key Laboratory of, Optoelectronic Chemical Materials and Devices of Ministry of EducationJianghan University Wuhan 430056 P.R. China
| | - Cheng Fu
- Institute for Interdisciplinary & Research Key Laboratory of, Optoelectronic Chemical Materials and Devices of Ministry of EducationJianghan University Wuhan 430056 P.R. China
| | - Gaolin Liang
- CAS Key Laboratory of Soft Matter ChemistryDepartment of ChemistryUniversity of Science and Technology of China Hefei 230026 P.R. China
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Miao X, Xu W, Cha H, Chang Y, Oh IT, Chae KS, Lee GH. Application of Dye-coated Ultrasmall Gadolinium Oxide Nanoparticles for Biomedical Dual Imaging. B KOREAN CHEM SOC 2017. [DOI: 10.1002/bkcs.11220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Xu Miao
- Department of Chemistry, College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
- Department of Nanoscience and Nanotechnology (DNN), College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
| | - Wenlong Xu
- Department of Chemistry, College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
- Department of Nanoscience and Nanotechnology (DNN), College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
| | - Hyunsil Cha
- Department of Molecular Medicine and Medical & Biological Engineering and DNN; School of Medicine and Hospital; Taegu 702-701 South Korea
| | - Yongmin Chang
- Department of Nanoscience and Nanotechnology (DNN), College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
- Department of Molecular Medicine and Medical & Biological Engineering and DNN; School of Medicine and Hospital; Taegu 702-701 South Korea
| | - In Taek Oh
- Department of Biology Education and DNN; Teacher's College; Taegu 41566 South Korea
| | - Kwon Seok Chae
- Department of Nanoscience and Nanotechnology (DNN), College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
- Department of Biology Education and DNN; Teacher's College; Taegu 41566 South Korea
| | - Gang Ho Lee
- Department of Chemistry, College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
- Department of Nanoscience and Nanotechnology (DNN), College of Natural Sciences; Kyungpook National University (KNU); Taegu 702-701 South Korea
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Vultos F, Fernandes C, Mendes F, Marques F, Correia JDG, Santos I, Gano L. A Multifunctional Radiotheranostic Agent for Dual Targeting of Breast Cancer Cells. ChemMedChem 2017. [PMID: 28628723 DOI: 10.1002/cmdc.201700287] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A straightforward synthetic route for a new multifunctional 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivative is described. To demonstrate the versatility of this pro-chelator for the preparation of radiolabeled hybrid compounds containing two different biological targeting moieties, an antitumor agent (e.g., a DNA-intercalating agent) and an estrogen receptor (ER) ligand (e.g., LXXLL-based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabeled with the auger electron emitter indium-111, and the resulting radioconjugate was demonstrated to induce DNA damage in vitro, which, along with the nuclear internalization exhibited in breast cancer cells, might enhance its therapeutic activity. This favorable in vitro performance suggests that these hybrid compounds could be attractive probes for theranostic applications.
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Affiliation(s)
- Filipe Vultos
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - Célia Fernandes
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - Filipa Mendes
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - Fernanda Marques
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - João D G Correia
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - Isabel Santos
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
| | - Lurdes Gano
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066, Bobadela, LRS, Portugal
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12
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Chilla SNM, Henoumont C, Elst LV, Muller RN, Laurent S. Importance of DOTA derivatives in bimodal imaging. Isr J Chem 2017. [DOI: 10.1002/ijch.201700024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
| | - Céline Henoumont
- General Organic and Biomedical chemistry University of Mons; Avenue Victor Maistriau, 19 7000 Mons Belgium
| | - Luce Vander Elst
- General Organic and Biomedical chemistry University of Mons; Avenue Victor Maistriau, 19 7000 Mons Belgium
| | - Robert N. Muller
- General Organic and Biomedical chemistry University of Mons; Avenue Victor Maistriau, 19 7000 Mons Belgium
- Center for Microscopy and Molecular Imaging (CMMI); Institution Rue Adrienne Bolland 8 Gosselies 6041 Belgium
| | - Sophie Laurent
- General Organic and Biomedical chemistry University of Mons; Avenue Victor Maistriau, 19 7000 Mons Belgium
- Center for Microscopy and Molecular Imaging (CMMI); Institution Rue Adrienne Bolland 8 Gosselies 6041 Belgium
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13
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Karki K, Ewing JR, Ali MM. Targeting Glioma with a Dual Mode Optical and Paramagnetic Nanoprobe across the Blood-brain Tumor Barrier. ACTA ACUST UNITED AC 2016; 7. [PMID: 27695645 PMCID: PMC5042151 DOI: 10.4172/2157-7439.1000395] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
In brain tumors, delivering nanoparticles across the blood-tumor barrier presents major hurdles. A clinically relevant MRI contrast agent, GdDOTA and a near-infrared (NIR) fluorescent dye, DL680 were conjugated to a G5 PAMAM dendrimer, thus producing a dual-mode MRI and NIR imaging agent. Systemic delivery of the subsequent nano-sized agent demonstrated glioma-specific accumulation, probably due to the enhanced permeability and retention effect. In vivo MRI detected the agent in glioma tissue, but not in normal contralateral tissue; this observation was validated with in vivo and ex vivo fluorescence imaging. A biodistribution study showed the agent to have accumulated in the glioma tumor and the liver, the latter being the excretion path for a G5 dendrimer-based agent.
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Affiliation(s)
- Kishor Karki
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
| | - James R Ewing
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Meser M Ali
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
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14
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Singh S, Tiwari AK, Varshney R, Mathur R, Shukla G, Bag N, Singh B, Mishra AK. Comparative evaluation of Bis(thiosemicarbazone)- Biotin and Met-ac-TE3A for tumor imaging. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2016; 153:566-571. [PMID: 26436844 DOI: 10.1016/j.saa.2015.08.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 08/19/2015] [Accepted: 08/31/2015] [Indexed: 06/05/2023]
Abstract
2,2',2″-(11-(2-((4-mercapto-1-methoxy-1-oxobutan-2-yl)amino)-2-oxoethyl)-1,4,8,11-tetraaza cyclotetradecane-1,4,8-triyl)triacetic acid, Met-ac-TE3A and (E)-N-methyl-2-((E)-3-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)hydrazinecarbono-thioyl)hydrazonobutan-2-ylidene)hydrazinecarbothioamide, Bis(thiosemicarbazone)- Biotin were synthesized and evaluated for imaging application. The pharmacokinetics of these ligands were determined by tracer methods. In vitro human serum stability of (99m)Tc Met-ac-TE3A/(99m)Tc Bis(thiosemicarbazone)-Biotin after 24h was found to be 96.5% and 97.0% respectively. Blood kinetics of both ligands in normal rabbits showed biphasic clearance pattern. Ex vivo biodistribution study revealed significant initial tumor uptake and high tumor/muscles ratio which is a pre-requisite condition for a ligand to work as SPECT-radiopharmaceutical for tumor imaging.
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Affiliation(s)
- Sweta Singh
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India; Department of Chemistry, Banaras Hindu University, Varanasi 221005, India
| | - Anjani K Tiwari
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India
| | - Raunak Varshney
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India
| | - R Mathur
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India
| | - Gauri Shukla
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India
| | - N Bag
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India
| | - B Singh
- Department of Chemistry, Banaras Hindu University, Varanasi 221005, India
| | - Anil K Mishra
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India.
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15
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Esser L, Truong NP, Karagoz B, Moffat BA, Boyer C, Quinn JF, Whittaker MR, Davis TP. Gadolinium-functionalized nanoparticles for application as magnetic resonance imaging contrast agents via polymerization-induced self-assembly. Polym Chem 2016. [DOI: 10.1039/c6py01797e] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Polymerization-induced self-assembly (PISA) is an easily applied synthetic technique for the preparation of polymer nanoparticles with various shapes and at high concentrations.
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Affiliation(s)
- Lars Esser
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology
- Monash Institute of Pharmaceutical Sciences
- Monash University
- Parkville
- Australia
| | - Nghia P. Truong
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology
- Monash Institute of Pharmaceutical Sciences
- Monash University
- Parkville
- Australia
| | - Bunyamin Karagoz
- Istanbul Technical University
- Department of Chemistry
- Istanbul
- Turkey
| | | | - Cyrille Boyer
- Australian Centre for Nanomedicine
- The University of New South Wales
- Sydney
- Australia
| | - John F. Quinn
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology
- Monash Institute of Pharmaceutical Sciences
- Monash University
- Parkville
- Australia
| | - Michael R. Whittaker
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology
- Monash Institute of Pharmaceutical Sciences
- Monash University
- Parkville
- Australia
| | - Thomas P. Davis
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology
- Monash Institute of Pharmaceutical Sciences
- Monash University
- Parkville
- Australia
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16
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Gadolinium(III)-DOTA Complex Functionalized with BODIPY as a Potential Bimodal Contrast Agent for MRI and Optical Imaging. INORGANICS 2015. [DOI: 10.3390/inorganics3040516] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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17
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Carron S, Li QY, Vander Elst L, Muller RN, Parac-Vogt TN, Capobianco JA. Assembly of near infra-red emitting upconverting nanoparticles and multiple Gd(III)-chelates as a potential bimodal contrast agent for MRI and optical imaging. Dalton Trans 2015; 44:11331-9. [PMID: 26011519 DOI: 10.1039/c5dt00919g] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Linking multiple paramagnetic gadolinium(III)-chelates based on the 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (DOTA) ligand to the surface of NaGdF4:Yb(3+),Tm(3+) upconverting nanoparticles with an average particle size of 20 nm resulted in an assembly that has favorable properties for bimodal Magnetic Resonance Imaging (MRI) and Optical Imaging (OI). An improved synthetic pathway was used to couple the paramagnetic precursor to the nanoparticles. The nanoparticles were rendered water dispersible via citrate capping, leaving one acid group free for amide coupling with the mono-amino precursor of the DOTA ligand. Luminescence spectroscopy measurements have shown that the excitation of the nanoconstruct at 980 nm resulted in intense upconverted emission of thulium(III) at 800 nm. The assembly of several paramagnetic centers on the nanoparticle scaffold reduces the overall tumbling rate, resulting in enhanced longitudinal relaxation times and improved relaxivity. The proton NMRD profiles show a characteristic hump at higher frequencies, which is caused by the slow rotation of the nanoconstruct, resulting in r1 values of 25 mM(-1) s(-1) per gadolinium(III)-ion at 60 MHz and 310 K. This is a significant improvement compared to the Gd-DO3A-ethylamine precursor (4) for which a value of r1 of 3.23 mM(-1) s(-1) was observed under the same conditions. Theoretical fitting by two different approaches showed an increase of τR from 57.3 ps for the Gd-DO3A-ethylamine precursor (4) to 392.0 ps for the nanoconstruct, which is responsible for the overall substantial increase in relaxivity.
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Affiliation(s)
- Sophie Carron
- Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
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18
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Harrison VSR, Carney CE, MacRenaris KW, Waters EA, Meade TJ. Multimeric Near IR-MR Contrast Agent for Multimodal In Vivo Imaging. J Am Chem Soc 2015; 137:9108-16. [PMID: 26083313 PMCID: PMC4512902 DOI: 10.1021/jacs.5b04509] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR-MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging.
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Affiliation(s)
- Victoria S R Harrison
- †Department of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
| | - Christiane E Carney
- †Department of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
| | - Keith W MacRenaris
- †Department of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
| | - Emily A Waters
- ‡Center for Advanced Molecular Imaging, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
| | - Thomas J Meade
- †Department of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.,‡Center for Advanced Molecular Imaging, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
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19
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Liu Y, Miao Q, Zou P, Liu L, Wang X, An L, Zhang X, Qian X, Luo S, Liang G. Enzyme-Controlled Intracellular Self-Assembly of (18)F Nanoparticles for Enhanced MicroPET Imaging of Tumor. Am J Cancer Res 2015. [PMID: 26199645 PMCID: PMC4508496 DOI: 10.7150/thno.11758] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Herein, we report the development of a new "smart" radioactive probe (i.e., 1) which can undergo furin-controlled condensation and self-assembly of radioactive nanoparticles (i.e., 1-NPs) in tumor cells and its application for enhanced microPET imaging of tumors in nude mice co-injected with its cold analog (i.e., 1-Cold). Furin-controlled condensation of 1-Cold and self-assembly of its nanoparticles (i.e., 1-Cold-NPs) in vitro were validated and characterized with HPLC, mass spectra, SEM, and TEM analyses. Cell uptake studies showed that both 1 and 1-Cold have good cell permeability. TEM images of 1-Cold-treated MDA-MB-468 cells directly uncovered that the intracellular 1-Cold-NPs were at/near the location of furin (i.e., Golgi bodies). MTT results indicated that 50 µM 1-Cold did not impose cytotoxicity to MDA-MB-468 cells up to 12 hours. MicroPET imaging of MDA-MB-468 tumor-bearing mice indicated that mice co-injected with 1 and 1-Cold showed higher uptake and longer attenuation of the radioactivity in tumors than those mice only injected with same dosage of 1. Tumor uptake ratios of 1 between these two groups of mice reached the maximum of 8.2 folds at 240 min post injection. Biodistribution study indicated that the uptake ratios of 1 in kidneys between these two groups continuously increased and reached 81.9 folds at 240 min post injection, suggesting the formation of radioactive NPs (i.e., 1-NPs) in MDA-MB-468 tumors of mice co-injected with 1 and 1-Cold. And the nanoparticles were slowly digested and secreted from the tumors, accumulating in the kidneys. Our ''smart'' probe (i.e., 1), together with the strategy of co-injection, might help researchers trace the biomarkers of interest within a longer time window.
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20
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Stasiuk GJ, Minuzzi F, Sae-Heng M, Rivas C, Juretschke HP, Piemonti L, Allegrini PR, Laurent D, Duckworth AR, Beeby A, Rutter GA, Long NJ. Dual-modal magnetic resonance/fluorescent zinc probes for pancreatic β-cell mass imaging. Chemistry 2015; 21:5023-33. [PMID: 25736590 PMCID: PMC4464533 DOI: 10.1002/chem.201406008] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Indexed: 11/11/2022]
Abstract
Despite the contribution of changes in pancreatic β-cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic-resonance imaging (MRI) provides a potentially useful technique, targeting MRI-active probes to the β cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual-modal probes based on transition-metal chelates capable of binding zinc. The first of these, Gd⋅1, binds Zn(II) directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from λem =410 to 500 nm with an increase in relaxivity from r1 =4.2 up to 4.9 mM(-1) s(-1) . The probe is efficiently accumulated into secretory granules in β-cell-derived lines and isolated islets, but more poorly by non-endocrine cells, and leads to a reduction in T1 in human islets. In vivo murine studies of Gd⋅1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes.
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Affiliation(s)
- Graeme J Stasiuk
- Department of Chemistry, Imperial College LondonSouth Kensington Campus, London SW7 2AZ (UK)
| | - Florencia Minuzzi
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of MedicineImperial College London, Hammersmith Hospital, London W12 0NN (UK)
| | - Myra Sae-Heng
- Department of Chemistry, Imperial College LondonSouth Kensington Campus, London SW7 2AZ (UK)
| | - Charlotte Rivas
- Department of Chemistry, Imperial College LondonSouth Kensington Campus, London SW7 2AZ (UK)
| | - Hans-Paul Juretschke
- Sanofi-Aventis Deutschland GmbH, R&D DSAR/BiomakersBiom & Biol Ass, FF, Industriepark Hoechst, Building H825, 65926 Frankfurt (Germany)
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific InstituteVia Olgettina 60, 20132 Milano (Italy)
| | | | - Didier Laurent
- Novartis Institute for Biomedical Research, Fabrikstrasse10-2.40.4, 4056, Basel (Switzerland)
| | - Andrew R Duckworth
- Department of Chemistry, Durham University, South RoadDurham, DH1 3LE (UK)
| | - Andrew Beeby
- Department of Chemistry, Durham University, South RoadDurham, DH1 3LE (UK)
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of MedicineImperial College London, Hammersmith Hospital, London W12 0NN (UK)
| | - Nicholas J Long
- Department of Chemistry, Imperial College LondonSouth Kensington Campus, London SW7 2AZ (UK)
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21
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Rivas C, Stasiuk GJ, Sae-Heng M, J. Long N. Towards understanding the design of dual-modal MR/fluorescent probes to sense zinc ions. Dalton Trans 2015; 44:4976-85. [DOI: 10.1039/c4dt02981j] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A series of new gadolinium complexes have been synthesised to test the design of dual-modal probes that can display a change in fluorescence or relaxivity response upon zinc binding. By an iterative change in parameters of the probes, the compounds give insight into the design protocols required for successful imaging of zinc ions.
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Affiliation(s)
- Charlotte Rivas
- Department of Chemistry
- Imperial College London
- South Kensington Campus
- London
- UK
| | - Graeme J. Stasiuk
- Department of Chemistry
- Imperial College London
- South Kensington Campus
- London
- UK
| | - Myra Sae-Heng
- Department of Chemistry
- Imperial College London
- South Kensington Campus
- London
- UK
| | - Nicholas J. Long
- Department of Chemistry
- Imperial College London
- South Kensington Campus
- London
- UK
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22
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Singh S, Tiwari AK, Varshney R, Mathur R, Hazari PP, Singh B, Mishra AK. Evaluation of methionine and tryptophan derivatised vehicles: Met-ac-TE3A/Trp-ac-TE3A for tumor imaging. RSC Adv 2015. [DOI: 10.1039/c5ra07138k] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Two novel amino acid (methionine and tryptophan) appended 1,4,8,11-tetraazacyclotetradecane triacetate (TE3A) compounds Met-ac-TE3A and Trp-ac-TE3A were synthesized and evaluated for imaging applications.
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Affiliation(s)
- Sweta Singh
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
- Department of Chemistry
| | - Anjani K. Tiwari
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
| | - Raunak Varshney
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
| | - Rashi Mathur
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
| | - Puja P. Hazari
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
| | - B. Singh
- Department of Chemistry
- Banaras Hindu University
- Varanasi-221005
- India
| | - Anil K. Mishra
- Division of Cyclotron and Radiopharmaceutical Sciences
- Institute of Nuclear Medicine and Allied Sciences
- Delhi-110054
- India
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23
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Shi W, Song B, Tan M, Ye Z, Yuan J. A novel heterobimetallic Ru(ii)–Gd(iii) complex-based magnetoluminescent agent for MR and luminescence imaging. RSC Adv 2015. [DOI: 10.1039/c5ra18544k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
A novel heterobimetallic ruthenium(II)–gadolinium(III) complex, Ru–Gd, has been developed for luminescence and an vivo T1-weighted MR imaging agent.
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Affiliation(s)
- Wenbo Shi
- State Key Laboratory of Fine Chemicals
- Department of Chemistry
- Dalian University of Technology
- Dalian 116024
- China
| | - Bo Song
- State Key Laboratory of Fine Chemicals
- Department of Chemistry
- Dalian University of Technology
- Dalian 116024
- China
| | - Mingqian Tan
- Liaoning Key Laboratory of Food Biological Technology
- School of Food Science and Technology
- Dalian Polytechnic University
- Dalian 116034
- China
| | - Zhiqiang Ye
- State Key Laboratory of Fine Chemicals
- Department of Chemistry
- Dalian University of Technology
- Dalian 116024
- China
| | - Jingli Yuan
- State Key Laboratory of Fine Chemicals
- Department of Chemistry
- Dalian University of Technology
- Dalian 116024
- China
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24
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Martins AF, Eliseeva SV, Carvalho HF, Teixeira JMC, Paula CTB, Hermann P, Platas-Iglesias C, Petoud S, Tóth E, Geraldes CFGC. A bis(pyridine N-oxide) analogue of DOTA: relaxometric properties of the Gd(III) complex and efficient sensitization of visible and NIR-emitting lanthanide(III) cations including Pr(III) and Ho(III). Chemistry 2014; 20:14834-45. [PMID: 25236257 DOI: 10.1002/chem.201403856] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Indexed: 11/07/2022]
Abstract
We report the synthesis of a cyclen-based ligand (4,10-bis[(1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid=L1) containing two acetate and two 2-methylpyridine N-oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the Gd(III) complex may be sufficient for biological applications. A detailed structural study of the complexes by (1) H NMR spectroscopy and DFT calculations indicates that they adopt an anti-Δ(λλλλ) conformation in aqueous solution, that is, an anti-square antiprismatic (anti-SAP) isomeric form, as demonstrated by analysis of the (1) H NMR paramagnetic shifts induced by Yb(III) . The water-exchange rate of the Gd(III) complex is ${k{{298\hfill \atop {\rm ex}\hfill}}}$=6.7×10(6) s(-1) , about a quarter of that for the mono-oxidopyridine analogue, but still about 50 % higher than the ${k{{298\hfill \atop {\rm ex}\hfill}}}$ of GdDOTA (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The 2-methylpyridine N-oxide chromophores can be used to sensitize a wide range of Ln(III) ions emitting in both the visible (Eu(III) and Tb(III) ) and NIR (Pr(III) , Nd(III) , Ho(III) , Yb(III) ) spectral regions. The emission quantum yield determined for the Yb(III) complex (${Q{{{\rm L}\hfill \atop {\rm Yb}\hfill}}}$=7.3(1)×10(-3) ) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.
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Affiliation(s)
- André F Martins
- Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, P. O. Box 3046, 3001-401 Coimbra (Portugal); Coimbra Chemistry Center, Rua Larga, University of Coimbra, 3004-535 Coimbra (Portugal); Centre de Biophysique Moléculaire, CNRS, Rue Charles Sadron, 45071 Orléans (France)
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25
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Lim EK, Kang B, Choi Y, Jang E, Han S, Lee K, Suh JS, Haam S, Huh YM. Gadolinium-based nanoparticles for highly efficient T1-weighted magnetic resonance imaging. NANOTECHNOLOGY 2014; 25:245103. [PMID: 24872113 DOI: 10.1088/0957-4484/25/24/245103] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
We developed Pyrene-Gadolinium (Py-Gd) nanoparticles as pH-sensitive magnetic resonance imaging (MRI) contrast agents capable of showing a high-Mr signal in cancer-specific environments, such as acidic conditions. Py-Gd nanoparticles were prepared by coating Py-Gd, which is a complex of gadolinium with pyrenyl molecules, with pyrenyl polyethyleneglycol PEG using a nano-emulsion method. These particles show better longitudinal relaxation time (T1) MR signals in acidic conditions than they do in neutral conditions. Furthermore, the particles exhibit biocompatibility and MR contrast effects in both in vitro and in vivo studies. From these results, we confirm that Py-Gd nanoparticles have the potential to be applied for accurate cancer diagnosis and therapy.
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26
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Krchová T, Kotek J, Jirák D, Havlíčková J, Císařová I, Hermann P. Lanthanide(III) complexes of aminoethyl-DO3A as PARACEST contrast agents based on decoordination of the weakly bound amino group. Dalton Trans 2014; 42:15735-47. [PMID: 24051547 DOI: 10.1039/c3dt52031e] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
2-Aminoethyl DOTA analogues with unsubstituted (H3L1), monomethylated (H3L2) and dimethylated (H3L3) amino groups were prepared by improved synthetic procedures. Their solid-state structures exhibit an extensive system of intramolecular hydrogen bonds, which is probably present in solution and leads to the rather high value of the last dissociation constant. The protonation sequence of H3L1 in solution corresponds to that found in the solid state. The stability constants of the H3L1 complexes with La(3+) and Gd(3+) (20.02 and 22.23, respectively) are similar to those of DO3A and the reduction of the pK(A) value of the pendant amino group from 10.51 in the free ligand to 6.06 and 5.83 in the La(3+) and Gd(3+) complexes, respectively, points to coordination of the amino group. It was confirmed in the solid state structure of the [Yb(L1)] complex, where disorder between the SA' and TSA' isomers was found. A similar situation is expected in solution, where a fast equilibration among the isomers hampers the unambiguous determination of the isomer ratio in solution. The PARACEST effect was observed in Eu(III)-H3L1/H3L2 and Yb(III)-H3L1/H3L2 complexes, being dependent on pH in the region of 4.5-7.5 and pH-independent in more alkaline solutions. The decrease of the PARACEST effect parallels with the increasing abundance of the complex protonated species, where the pendant amino group is not coordinating. Surprisingly, a small PARACEST effect was also observed in solutions of Eu(III)/Yb(III)-H3L3 complexes, where the pendant amino group is dimethylated. The effect is detectable in a narrow pH region, where both protonated and deprotonated complex species are present in equilibrium. The data points to the new mechanism of the PARACEST effect, where the slow coordination-decoordination of the pendant amine is coupled with the fast proton exchange between the free amino group and bulk water mediates the magnetization transfer. The pH-dependence of the effect was proved to be measurable by MRI and, thus, the complexes extend the family of pH-sensitive probes.
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Affiliation(s)
- Tereza Krchová
- Department of Inorganic Chemistry, Universita Karlova (Charles University), Hlavova 2030, 128 40 Prague 2, Czech Republic.
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Gottschalk S, Engelmann J, Rolla GA, Botta M, Parker D, Mishra A. Comparative in vitro studies of MR imaging probes for metabotropic glutamate subtype-5 receptor targeting. Org Biomol Chem 2014; 11:6131-41. [PMID: 23925571 DOI: 10.1039/c3ob41297k] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A series of magnetic resonance imaging probes has been evaluated to target selectively the metabotropic glutamate receptor subtype 5 (mGluR5). Eight imaging probes based on the contrast agent [Gd·DOTA], previously derived by linking it to a series of specific and selective mGluR5 antagonists, have been extensively tested for their functionality in vitro. The Nuclear Magnetic Relaxation Dispersion (NMRD) profiles of selected probes have been examined via field-cycling relaxometry in the presence and absence of a model protein. The properties of the targeted contrast agents were evaluated using a primary astrocyte model, as these cells mimic the in vivo situation effectively. The probes were non-toxic (up to 200 μM) to these mGluR5 expressing primary cells. Cellular proton longitudinal relaxation rate enhancements of up to 35% were observed by MRI at 200 μM of probe concentration. The antagonistic effect of all compounds was tested using an assay measuring changes of intracellular calcium levels. Furthermore, treatment at two different temperatures (4 °C vs. 37 °C) and of an mGluR5-negative cell line provided further insight into the selectivity and specificity of these probes towards cell surface mGluR5. Finally, two out of eight probes demonstrated an antagonistic effect as well as significant enhancement of receptor mediated cellular relaxation rates, strongly suggesting that they would be viable probes for the mapping of mGluR5 by MRI in vivo.
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Affiliation(s)
- Sven Gottschalk
- High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Spemannstrasse 41, Tuebingen, D-72076, Germany.
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Mishra A, Mishra R, Gottschalk S, Pal R, Sim N, Engelmann J, Goldberg M, Parker D. Microscopic visualization of metabotropic glutamate receptors on the surface of living cells using bifunctional magnetic resonance imaging probes. ACS Chem Neurosci 2014; 5:128-37. [PMID: 24251400 DOI: 10.1021/cn400175m] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
A series of bimodal metabotropic glutamate-receptor targeted MRI contrast agents has been developed and evaluated, based on established competitive metabotropic Glu receptor subtype 5 (mGluR5) antagonists. In order to directly visualize mGluR5 binding of these agents on the surface of live astrocytes, variations in the core structure were made. A set of gadolinium conjugates containing either a cyanine dye or a fluorescein moiety was accordingly prepared, to allow visualization by optical microscopy in cellulo. In each case, surface receptor binding was compromised and cell internalization observed. Another approach, examining the location of a terbium analogue via sensitized emission, also exhibited nonspecific cell uptake in neuronal cell line models. Finally, biotin derivatives of two lead compounds were prepared, and the specificity of binding to the mGluR5 cell surface receptors was demonstrated with the aid of their fluorescently labeled avidin conjugates, using both total internal reflection fluorescence (TIRF) and confocal microscopy.
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Affiliation(s)
| | | | - Sven Gottschalk
- High Field MR Centre, Max Planck Institute for Biological Cybernetics, Spemannstrasse 41, Tuebingen 72076, Germany
| | | | | | - Joern Engelmann
- High Field MR Centre, Max Planck Institute for Biological Cybernetics, Spemannstrasse 41, Tuebingen 72076, Germany
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Germeroth AI, Hanna JR, Karim R, Kundel F, Lowther J, Neate PGN, Blackburn EA, Wear MA, Campopiano DJ, Hulme AN. Triazole biotin: a tight-binding biotinidase-resistant conjugate. Org Biomol Chem 2013; 11:7700-4. [PMID: 24108311 DOI: 10.1039/c3ob41837e] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The natural amide bond found in all biotinylated proteins has been replaced with a triazole through CuAAC reaction of an alkynyl biotin derivative. The resultant triazole-linked adducts are shown to be highly resistant to the ubiquitous hydrolytic enzyme biotinidase and to bind avidin with dissociation constants in the low pM range. Application of this strategy to the production of a series of biotinidase-resistant biotin-Gd-DOTA contrast agents is demonstrated.
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Affiliation(s)
- Anne I Germeroth
- EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK.
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Hu Z, Ahrén M, Selegård L, Skoglund C, Söderlind F, Engström M, Zhang X, Uvdal K. Highly Water-Dispersible Surface-Modified Gd2O3Nanoparticles for Potential Dual-Modal Bioimaging. Chemistry 2013; 19:12658-67. [DOI: 10.1002/chem.201301687] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Stasiuk GJ, Long NJ. The ubiquitous DOTA and its derivatives: the impact of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid on biomedical imaging. Chem Commun (Camb) 2013; 49:2732-46. [PMID: 23392443 DOI: 10.1039/c3cc38507h] [Citation(s) in RCA: 157] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Over the last twenty-five years 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has made a significant impact on the field of diagnostic imaging. DOTA is not the only metal chelate in use in medical diagnostics, but it is the only one to significantly impact on all of the major imaging modalities Magnetic Resonance (MR), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Fluorescence imaging. This crossover of modalities has been possible due to the versatility of DOTA firstly, to complex a variety of metal ions and secondly, the ease with which it can be modified for different disease states. This has driven research over the last two decades into the chemistry of DOTA and the modification of the substituent pendant arms of this macrocycle to create functional, targeted and dual-modal imaging agents. The primary use of DOTA has been with the lanthanide series of metals, gadolinium for MRI, europium and terbium for fluorescence and neodymium for near infra-red imaging. There are now many research groups dedicated to the use of lanthanides with DOTA although other chelates such as DTPA and NOTA are being increasingly employed. The ease with which DOTA can be conjugated to peptides has given rise to targeted imaging agents seen in the PET, SPECT and radiotherapy fields. These modalities use a variety of radiometals that complex with DOTA, e.g.(64)Cu and (68)Ga which are used in clinical PET scans, (111)In, and (90)Y for SPECT and radiotherapy. In this article, we will demonstrate the remarkable versatility of DOTA, how it has crossed the imaging modality boundaries and how it has been successfully transferred into the clinic.
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Affiliation(s)
- Graeme J Stasiuk
- Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
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Calce E, Monfregola L, De Luca S. Synthetic Strategy to Prepare DOTA-Based Bifunctional Chelating Agent Ready to Bind Biomolecular Probes. Int J Pept Res Ther 2013. [DOI: 10.1007/s10989-013-9348-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Tan M, Ye Z, Lindner D, Brady-Kalnay SM, Lu ZR. Synthesis and evaluation of a targeted nanoglobular dual-modal imaging agent for MR imaging and image-guided surgery of prostate cancer. Pharm Res 2013; 31:1469-76. [PMID: 23471641 DOI: 10.1007/s11095-013-1008-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 02/07/2013] [Indexed: 11/27/2022]
Abstract
PURPOSE To synthesize and evaluate a peptide targeted nanoglobular dual modal imaging agent specific to a cancer biomarker in tumor stroma for MRI and fluorescence visualization of prostate tumor in image-guided surgery. METHODS A peptide (CGLIIQKNEC, CLT1) targeted generation 2 nanoglobular (polylysine dendrimer with a silsesquioxane core) dual modal imaging agent, CLT1-G2-(Gd-DOTA-MA)-Cy5, was synthesized by stepwise conjugation of Gd-DOTA-MA, Cy5 and peptide to the dendrimer. Contrast enhanced MR imaging of the targeted dual imaging agent was evaluated on a Bruker 7T animal scanner with male athymic nude mice bearing orthotopic PC3-GFP prostate tumor. Fluorescence tumor imaging of the agent was carried out on a Maestro fluorescence imaging system. RESULTS The targeted agent CLT1-G2-(Gd-DOTA-MA)-Cy5 produced greater contrast enhancement in the tumor tissue than the control agent KAREC-G2-(Gd-DOTA-MA)-Cy5 at a dose of 30 μmol-Gd/kg in the MR images of the tumor bearing mice. Signal-to-noise ratio (SNR) of CLT1-G2-(Gd-DOTA-MA)-Cy5 in the tumor tissue was approximately 2 fold of that of the control agent in the first 15 min post-injection. The targeted agent also resulted in bright fluorescence signals in the tumor tissue. CONCLUSION The CLT1 peptide targeted nanoglobular dual-imaging agent CLT1-G2-(Gd-DOTA-MA)-Cy5 has a potential for MRI and fluorescence visualization of prostate tumor.
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Affiliation(s)
- Mingqian Tan
- Department of Biomedical Engineering, Case Western Reserve University, Wickenden Building, Room 427, 10900 Euclid Avenue, Cleveland, Ohio, 44106-7207, USA
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de la Reberdière A, Lachaud F, Chuburu F, Cadiou C, Lemercier G. Synthesis of a new family of protected 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives with thioctic acid pending arms. Tetrahedron Lett 2012. [DOI: 10.1016/j.tetlet.2012.08.150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Laakso J, Rosser GA, Szíjjártó C, Beeby A, Borbas KE. Synthesis of chlorin-sensitized near infrared-emitting lanthanide complexes. Inorg Chem 2012; 51:10366-74. [PMID: 22978627 DOI: 10.1021/ic3015354] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Lanthanide (Yb(3+), Nd(3+)) complexes equipped with red-absorbing hydroporphyrin (chlorin) antennae were synthesized and characterized. The syntheses are scalable, highly modular, and enable the introduction of different chlorins functionalized with a single reactive group (COOH or NH(2)). Absorption maxima were dependent on chlorin substitution pattern (monomeso aryl or dimeso aryl) and metalation state (free base or zinc chelate). The complexes benefit from dual chlorin (610-639 nm) and lanthanide (980 or 1065 nm for Yb- or Nd-complexes, respectively) emission in the biologically relevant red and near IR region of the spectrum.
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Affiliation(s)
- Johanna Laakso
- Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691, Stockholm, Sweden
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36
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Luo J, Li WS, Xu P, Zhang LY, Chen ZN. Zn2+ Responsive Bimodal Magnetic Resonance Imaging and Fluorescent Imaging Probe Based on a Gadolinium(III) Complex. Inorg Chem 2012; 51:9508-16. [PMID: 22880548 DOI: 10.1021/ic301308z] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Jian Luo
- State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002,
China
| | - Wei-Sheng Li
- State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002,
China
| | - Peng Xu
- State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002,
China
| | - Li-Yi Zhang
- State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002,
China
| | - Zhong-Ning Chen
- State Key Laboratory of Structural Chemistry, Fujian Institute
of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002,
China
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37
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James ML, Gambhir SS. A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 2012; 92:897-965. [PMID: 22535898 DOI: 10.1152/physrev.00049.2010] [Citation(s) in RCA: 736] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Molecular 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 biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular 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 molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular 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.
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Affiliation(s)
- Michelle L James
- Molecular Imaging Program, Department of Radiology, Stanford University, Palo Alto, CA 94305, USA
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38
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Pinho SLC, Faneca H, Geraldes CFGC, Rocha J, Carlos LD, Delville MH. Silica Nanoparticles for Bimodal MRI-Optical Imaging by Grafting Gd3+ and Eu3+/Tb3+ Complexes. Eur J Inorg Chem 2012. [DOI: 10.1002/ejic.201101110] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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39
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Mishra A, Gottschalk S, Engelmann J, Parker D. Responsive imaging probes for metabotropic glutamate receptors. Chem Sci 2012. [DOI: 10.1039/c1sc00418b] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Yamane T, Hanaoka K, Muramatsu Y, Tamura K, Adachi Y, Miyashita Y, Hirata Y, Nagano T. Method for Enhancing Cell Penetration of Gd3+-based MRI Contrast Agents by Conjugation with Hydrophobic Fluorescent Dyes. Bioconjug Chem 2011; 22:2227-36. [DOI: 10.1021/bc200127t] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- Takehiro Yamane
- Graduate School of
Pharmaceutical
Sciences, The University of Tokyo, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- CREST, Japan Science and Technology Agency, 5, Sanbancho, Chiyoda-ku, Tokyo,
102-0075, Japan
| | - Kenjiro Hanaoka
- Graduate School of
Pharmaceutical
Sciences, The University of Tokyo, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- CREST, Japan Science and Technology Agency, 5, Sanbancho, Chiyoda-ku, Tokyo,
102-0075, Japan
| | - Yasuaki Muramatsu
- Graduate School of
Pharmaceutical
Sciences, The University of Tokyo, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- CREST, Japan Science and Technology Agency, 5, Sanbancho, Chiyoda-ku, Tokyo,
102-0075, Japan
| | - Keita Tamura
- Department
of Physiology, The University of Tokyo School of Medicine, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yusuke Adachi
- Department
of Physiology, The University of Tokyo School of Medicine, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yasushi Miyashita
- Department
of Physiology, The University of Tokyo School of Medicine, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yasunobu Hirata
- Department of Cardiovascular
Medicine, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Tetsuo Nagano
- Graduate School of
Pharmaceutical
Sciences, The University of Tokyo, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
- CREST, Japan Science and Technology Agency, 5, Sanbancho, Chiyoda-ku, Tokyo,
102-0075, Japan
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De M, Chou SS, Joshi HM, Dravid VP. Hybrid magnetic nanostructures (MNS) for magnetic resonance imaging applications. Adv Drug Deliv Rev 2011; 63:1282-99. [PMID: 21851844 DOI: 10.1016/j.addr.2011.07.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 06/29/2011] [Accepted: 07/02/2011] [Indexed: 12/13/2022]
Abstract
The development of MRI contrast agents has experienced its version of the gilded age over the past decade, thanks largely to the rapid advances in nanotechnology. In addition to progress in single mode contrast agents, which ushered in unprecedented R(1) or R(2) sensitivities, there has also been a boon in the development of agents covering more than one mode of detection. These include T(1)-PET, T(2)-PET T(1)-optical, T(2)-optical, T(1)-T(2) agents and many others. In this review, we describe four areas which we feel have experienced particular growth due to nanotechnology, specifically T(2) magnetic nanostructure development, T(1)/T(2)-optical dual mode agents, and most recently the T(1)-T(2) hybrid imaging systems. In each of these systems, we describe applications including in vitro, in vivo usage and assay development. In all, while the benefits and drawbacks of most MRI contrast agents depend on the application at hand, the recent development in multimodal nanohybrids may curtail the shortcomings of single mode agents in diagnostic and clinical settings by synergistically incorporating functionality. It is hoped that as nanotechnology advances over the next decade, it will produce agents with increased diagnostics and assay relevant capabilities in streamlined packages that can meaningfully improve patient care and prognostics. In this review article, we focus on T(2) materials, its surface functionalization and coupling with optical and/or T(1) agents.
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Pinho SLC, Faneca H, Geraldes CFGC, Delville MH, Carlos LD, Rocha J. Lanthanide-DTPA grafted silica nanoparticles as bimodal-imaging contrast agents. Biomaterials 2011; 33:925-35. [PMID: 22035824 DOI: 10.1016/j.biomaterials.2011.09.086] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 09/23/2011] [Indexed: 01/09/2023]
Abstract
The design and synthesis of a combined MRI-optical probe for bio-imaging are reported. The materials studied join the properties of lanthanide (Ln(3+)) complexes and nanoparticles (NPs), offering an excellent solution for bimodal imaging. The hybrid SiO(2)@APS/DTPA:Gd:Ln (Ln = Eu(3+) or Tb(3+)) (APS: 3-aminopropyltriethoxysilane, DTPA: diethylenetriamine pentaacetic acid) system increases the payload of the active magnetic centre (Gd(3+)) and introduces a Ln(3+) long-life excited state (Eu(3+): 0.35 ± 0.02 ms, Tb(3+): 1.87 ± 0.02 ms), with resistance to photobleaching and sharp emission bands. The Eu(3+) ions reside in a single low-symmetry site. Although the photoluminescence emission is not influenced by the simultaneous presence of Gd(3+) and Eu(3+), a moderate r(1) increase and a larger enhancement of r(2) are observed, particularly at high fields, due to susceptibility effects on r(2). The presence of Tb(3+) instead of Eu(3+) further raises r(1) but decreases r(2). These values are constant over a wide (5-13) pH range, indicating the paramagnetic NPs stability and absence of leaching. The uptake of NPs by living cells is fast and results in an intensity increase in the T(1)-weighted MRI images. The optical properties of the NPs in cellular pellets are also studied, confirming their potential as bimodal imaging agents.
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Affiliation(s)
- Sonia L C Pinho
- Department of Chemistry, CICECO, University of Aveiro, 3810-193 Aveiro, Portugal.
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Mishra A, Schüz A, Engelmann J, Beyerlein M, Logothetis NK, Canals S. Biocytin-derived MRI contrast agent for longitudinal brain connectivity studies. ACS Chem Neurosci 2011; 2:578-87. [PMID: 22860157 DOI: 10.1021/cn200022m] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 08/03/2011] [Indexed: 11/28/2022] Open
Abstract
To investigate the connectivity of brain networks noninvasively and dynamically, we have developed a new strategy to functionalize neuronal tracers and designed a biocompatible probe that can be visualized in vivo using magnetic resonance imaging (MRI). Furthermore, the multimodal design used allows combined ex vivo studies with microscopic spatial resolution by conventional histochemical techniques. We present data on the functionalization of biocytin, a well-known neuronal tract tracer, and demonstrate the validity of the approach by showing brain networks of cortical connectivity in live rats under MRI, together with the corresponding microscopic details, such as fibers and neuronal morphology under light microscopy. We further demonstrate that the developed molecule is the first MRI-visible probe to preferentially trace retrograde connections. Our study offers a new platform for the development of multimodal molecular imaging tools of broad interest in neuroscience, that capture in vivo the dynamics of large scale neural networks together with their microscopic characteristics, thereby spanning several organizational levels.
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Affiliation(s)
| | | | | | | | - Nikos K. Logothetis
- Imaging Science and Biomedical Engineering, University of Manchester, Manchester M13 9PL, England
| | - Santiago Canals
- Instituto de Neurociencias CSIC-UMH, Campus de San Juan, 03550 San Juan de Alicante, Spain
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Kobayashi H, Longmire MR, Ogawa M, Choyke PL. Rational chemical design of the next generation of molecular imaging probes based on physics and biology: mixing modalities, colors and signals. Chem Soc Rev 2011; 40:4626-48. [PMID: 21607237 PMCID: PMC3417232 DOI: 10.1039/c1cs15077d] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In recent years, numerous in vivo molecular imaging probes have been developed. As a consequence, much has been published on the design and synthesis of molecular imaging probes focusing on each modality, each type of material, or each target disease. More recently, second generation molecular imaging probes with unique, multi-functional, or multiplexed characteristics have been designed. This critical review focuses on (i) molecular imaging using combinations of modalities and signals that employ the full range of the electromagnetic spectra, (ii) optimized chemical design of molecular imaging probes for in vivo kinetics based on biology and physiology across a range of physical sizes, (iii) practical examples of second generation molecular imaging probes designed to extract complementary data from targets using multiple modalities, color, and comprehensive signals (277 references).
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Affiliation(s)
- Hisataka Kobayashi
- Molecular Imaging Program, National Cancer Institute/NIH, Bldg. 10, Room B3B69, MSC 1088, 10 Center Dr Bethesda, Maryland 20892-1088, USA.
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Abstract
A number of medical imaging techniques are used heavily in the provision of spatially resolved information on disease and physiological status and accordingly play a critical role in clinical diagnostics and subsequent treatment. Though, for most imaging modes, contrast is potentially enhanced through the use of contrast agents or improved hardware or imaging protocols, no single methodology provides, in isolation, a detailed mapping of anatomy, disease markers or physiological status. In recent years, the concept of complementing the strengths of one imaging modality with those of another has come to the fore and been further bolstered by the development of fused instruments such as PET/CT and PET/MRI stations. Coupled with the continual development in imaging hardware has been a surge in reports of contrast agents bearing multiple functionality, potentially providing not only a powerful and highly sensitised means of co-localising physiological/disease status and anatomy, but also the tracking and delineation of multiple markers and indeed subsequent or simultaneous highly localized therapy ("theragnostics").
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Affiliation(s)
- Wen-Yen Huang
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, OX1 3QR, UK
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Ultra Convenient Synthesis of Lanthanide Based Magnetic-Fluorescent Hydrogels for Multimodal Cellular Imaging. ACTA ACUST UNITED AC 2011. [DOI: 10.4028/www.scientific.net/amr.266.118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A simple approach has been developed to synthesize lanthanide based multifunctional magnetic-fluorescent hydrogels for cellular imaging via MRI and optical imaging synchronously. The multifunctional hydrogels are prepared by covalently conjugating gadolinium and europium chelate with biocompatible chitosan. The room temperature photoluminescence (PL) spectrum shows that the hydrogels have a strong PL emission, which is characteristic of Eu3+ transitions from the excited 5D0 to 7FJ levels. Moreover, in vitro magnetic resonance imaging (MRI) analysis shows that the hydrogels exhibit powerful T1-weighted MRI signal in water. As a result, the hydrogels combine magnetic and fluorescent properties and can be expected to act as a promising multimodal MRI/optical imaging probe.
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Mishra G, Hazari PP, Kumar N, Mishra AK. In vitroandin vivoevaluation of99mTc-DO3A-EA-Folate for receptor-mediated targeting of folate positive tumors. J Drug Target 2011; 19:761-9. [DOI: 10.3109/1061186x.2011.561857] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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48
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SHE W, LUO K, HE B, AI H, GU ZH. FUNCTIONAL PEPTIDE DENDRIMERS AS MAGNETIC RESONANCE IMAGING PROBES. ACTA POLYM SIN 2011. [DOI: 10.3724/sp.j.1105.2011.10027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Liu Y, Yu G, Tian M, Zhang H. Optical probes and the applications in multimodality imaging. CONTRAST MEDIA & MOLECULAR IMAGING 2011; 6:169-77. [PMID: 21246711 DOI: 10.1002/cmmi.428] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Revised: 09/23/2010] [Accepted: 10/08/2010] [Indexed: 11/11/2022]
Abstract
Optical imaging essentially refers to in vivo fluorescence imaging and bioluminescence imaging. These types of imaging are widely used visualization methods in biomedical research and are important in molecular imaging. A new generation of imaging agents called multimodal probes have emerged in the past few years. These probes can be detected by two or more imaging modalities, which harnesses the strengths of the different modalities and enables researchers to obtain more information than can be achieved using only one modality. Owing to its low cost and the large number of probes available, the optical method plays an important role in multimodality imaging. In this mini-review, we describe the available multimodal imaging probes for in vivo imaging that combine optical imaging with other modalities.
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Affiliation(s)
- Yang Liu
- Department of Nuclear Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Lattuada L, Barge A, Cravotto G, Giovenzana GB, Tei L. The synthesis and application of polyamino polycarboxylic bifunctional chelating agents. Chem Soc Rev 2011; 40:3019-49. [DOI: 10.1039/c0cs00199f] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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