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Teitz M, Velarde E, Yang X, Lee S, Lecksell K, Terrillion C, Bibic A, Ngen EJ. Developing Magnetic Resonance Imaging Biomarkers of Neuroinflammation, Cognitive Impairment, and Survival Outcomes for Radiotherapy-Induced Brain Injury in a Preclinical Mouse Model. Invest Radiol 2025:00004424-990000000-00306. [PMID: 40095964 DOI: 10.1097/rli.0000000000001173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
OBJECTIVE Radiotherapy-induced brain injury (RIBI) is a chronic side effect that affects up to 90% of brain tumor survivors treated with radiotherapy. Here, we used multiparametric magnetic resonance imaging (MRI) to identify noninvasive and clinically translatable biomarkers of RIBI. METHOD 8-week-old female, immune competent BALB/c mice were stereotactically irradiated with a single dose of 80 Gy, at a dose rate of 1.7 Gy/minute. The irradiated mice were then monitored longitudinally with MRI, behavioral tests of learning and memory, and immunohistochemistry, in comparison to nonirradiated mice. RESULTS Three types of MRI biomarkers of RIBI were identified. A contrast-enhanced T1-weighted MRI biomarker was identified as being best suited to detect the onset of injury, by detecting changes in the blood-brain barrier (BBB) permeability. Maximum BBB permeability (18.95 ± 1.75) was detected with contrast-enhanced T1-weighted MRI at 1-month postirradiation in irradiated mice (P < 0.0001, n = 3). Interestingly, maximum neuroinflammation (24.14 ± 6.72) was also detected using IBA1 and CD68 immunohistochemistry at 1-month postirradiation in irradiated mice (P = 0.0041, n = 3). This simultaneous maximum BBB permeability and neuroinflammation detection also coincided with the detection of the onset of transient cognitive impairment, detected using the fear-conditioning behavioral test at 1-month postirradiation in irradiated mice compared to nonirradiated mice (P = 0.0017, n = 10). A T2-weighted MRI hyperintensity biomarker was also identified, and determined to be best suited to detect intermediate injury. Maximum T2-weighted MRI hyperintensity (3.97 ± 2.07) was detected at 2-month postirradiation in the irradiated mice compared to nonirradiated mice (P = 0.0368, n = 3). This T2-weighted MRI hyperintensity also correlated with maximum astrogliosis (9.92 ± 4.21), which was also detected at 2-month postirradiation using GFAP immunohistochemistry in the irradiated mice compared to nonirradiated mice (P = 0.0215, n = 3). Finally, T2-weighted and T2*-weighted MRI hypointensity biomarkers were identified as being best suited to detect late injury, from 4-month postirradiation. These biomarkers correlated with increased iron deposition from late vascular damage, which was validated with Perls' Prussian blue histology (P < 0.05, n = 3). These hypointense MRI biomarkers of late injury also preceded significant weight loss, severe cognitive impairment, and decreased survival in the irradiated mice compared to the nonirradiated mice. CONCLUSIONS Here, we identified 3 types of translational MRI biomarkers of RIBI that could enable the noninvasive longitudinal evaluation of potential RIBI prophylactic and therapeutic agents. These translational MRI biomarkers could also play a pivotal role in the management of RIBI in brain tumor survivors.
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Affiliation(s)
- Maya Teitz
- From the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD (M.T., X.Y., A.B., E.J.N.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD (E.V.); Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD (S.L.); Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD (K.L.); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, (C.T.); F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD (A.B.); and Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (E.J.N.)
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You C, Yi JY, Hsu TW, Huang SL. Integration of cellular-resolution optical coherence tomography and Raman spectroscopy for discrimination of skin cancer cells with machine learning. JOURNAL OF BIOMEDICAL OPTICS 2023; 28:096005. [PMID: 37720189 PMCID: PMC10500347 DOI: 10.1117/1.jbo.28.9.096005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 08/28/2023] [Accepted: 09/05/2023] [Indexed: 09/19/2023]
Abstract
Significance An integrated cellular-resolution optical coherence tomography (OCT) module with near-infrared Raman spectroscopy was developed on the discrimination of various skin cancer cells and normal cells. Micron-level three-dimensional (3D) spatial resolution and the spectroscopic capability on chemical component determination can be obtained simultaneously. Aim We experimentally verified the effectiveness of morphology, intensity, and spectroscopy features for discriminating skin cells. Approach Both spatial and spectroscopic features were employed for the discrimination of five types of skin cells, including keratinocytes (HaCaT), the cell line of squamous cell carcinoma (A431), the cell line of basal cell carcinoma (BCC-1/KMC), primary melanocytes, and the cell line of melanoma (A375). The cell volume, compactness, surface roughness, average intensity, and internal intensity standard deviation were extracted from the 3D OCT images. After removing the fluorescence components from the acquired Raman spectra, the entire spectra (600 to 2100 cm - 1 ) were used. Results An accuracy of 85% in classifying five types of skin cells was achieved. The cellular-resolution OCT images effectively differentiate cancer and normal cells, whereas Raman spectroscopy can distinguish the cancer cells with nearly 100% accuracy. Conclusions Among the OCT image features, cell surface roughness, internal average intensity, and standard deviation of internal intensity distribution effectively differentiate the cancerous and normal cells. The three features also worked well in sorting the keratinocyte and melanocyte. Using the full Raman spectra, the melanoma and keratinocyte-based cell carcinoma cancer cells can be discriminated effectively.
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Affiliation(s)
- Cian You
- National Taiwan University, Graduate Institute of Photonics and Optoelectronics, Taipei, Taiwan
| | - Jui-Yun Yi
- National Kaohsiung Normal University, Department of Electrical Engineering, Kaohsiung, Taiwan
| | - Ting-Wei Hsu
- National Taiwan University, Graduate Institute of Photonics and Optoelectronics, Taipei, Taiwan
| | - Sheng-Lung Huang
- National Taiwan University, Graduate Institute of Photonics and Optoelectronics, Taipei, Taiwan
- National Taiwan University, All Vista Healthcare Center, Taipei, Taiwan
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Hejrati N, Wong R, Khazaei M, Fehlings MG. How can clinical safety and efficacy concerns in stem cell therapy for spinal cord injury be overcome? Expert Opin Biol Ther 2023; 23:883-899. [PMID: 37545020 DOI: 10.1080/14712598.2023.2245321] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/03/2023] [Indexed: 08/08/2023]
Abstract
INTRODUCTION Spinal cord injury (SCI) can lead to severe neurological dysfunction. Despite scientific and medical advances, clinically effective regenerative therapies including stem cells are lacking for SCI. AREAS COVERED This paper discusses translational challenges related to the safe, effective use of stem cells for SCI, with a focus on mesenchymal stem cells (MSCs), neural stem cells (NSCs), Schwann cells (SCs), olfactory ensheathing cells (OECs), oligodendrocyte precursor cells (OPCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). We discuss approaches to enhance the efficacy of cell-based strategies by i) addressing patient heterogeneity and enhancing patient selection; ii) selecting cell type, cell source, cell developmental stage, and delivery technique; iii) enhancing graft integration and mitigating immune-mediated graft rejection; and iv) ensuring availability of cells. Additionally, we review strategies to optimize outcomes including combinatorial use of rehabilitation and discuss ways to mitigate potential risks of tumor formation associated with stem cell-based strategies. EXPERT OPINION Basic science research will drive translational advances to develop stem cell-based therapies for SCI. Genetic, serological, and imaging biomarkers may enable individualization of cell-based treatments. Moreover, combinatorial strategies will be required to enhance graft survival, migration and functional integration, to enable precision-based intervention.
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Affiliation(s)
- Nader Hejrati
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Department of Neurosurgery & Spine Center of Eastern Switzerland, Cantonal Hospital St.Gallen, St.Gallen, Switzerland
| | - Raymond Wong
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Mohamad Khazaei
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Michael G Fehlings
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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He XY, Zhou YR, Mu T, Liao YF, Jiang L, Qin Y, Cai JH. Magnetic resonance imaging focused on the ferritin heavy chain 1 reporter gene detects neuronal differentiation in stem cells. Neural Regen Res 2023; 18:1563-1569. [PMID: 36571363 PMCID: PMC10075097 DOI: 10.4103/1673-5374.358608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The neuronal differentiation of mesenchymal stem cells offers a new strategy for the treatment of neurological disorders. Thus, there is a need to identify a noninvasive and sensitive in vivo imaging approach for real-time monitoring of transplanted stem cells. Our previous study confirmed that magnetic resonance imaging, with a focus on the ferritin heavy chain 1 reporter gene, could track the proliferation and differentiation of bone marrow mesenchymal stem cells that had been transduced with lentivirus carrying the ferritin heavy chain 1 reporter gene. However, we could not determine whether or when bone marrow mesenchymal stem cells had undergone neuronal differentiation based on changes in the magnetic resonance imaging signal. To solve this problem, we identified a neuron-specific enolase that can be differentially expressed before and after neuronal differentiation in stem cells. In this study, we successfully constructed a lentivirus carrying the neuron-specific enolase promoter and expressing the ferritin heavy chain 1 reporter gene; we used this lentivirus to transduce bone marrow mesenchymal stem cells. Cellular and animal studies showed that the neuron-specific enolase promoter effectively drove the expression of ferritin heavy chain 1 after neuronal differentiation of bone marrow mesenchymal stem cells; this led to intracellular accumulation of iron and corresponding changes in the magnetic resonance imaging signal. In summary, we established an innovative magnetic resonance imaging approach focused on the induction of reporter gene expression by a neuron-specific promoter. This imaging method can be used to noninvasively and sensitively detect neuronal differentiation in stem cells, which may be useful in stem cell-based therapies.
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Affiliation(s)
- Xiao-Ya He
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yi-Rui Zhou
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Tong Mu
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing; Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yi-Fan Liao
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics; Department of Nuclear Medicine, The Second Hospital of the Army Medical University, Chongqing, China
| | - Li Jiang
- Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Qin
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jin-Hua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
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Dynamic MRI of the Mesenchymal Stem Cells Distribution during Intravenous Transplantation in a Rat Model of Ischemic Stroke. Life (Basel) 2023; 13:life13020288. [PMID: 36836645 PMCID: PMC9962901 DOI: 10.3390/life13020288] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/29/2022] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
Systemic transplantation of mesenchymal stem cells (MSCs) is a promising approach for the treatment of ischemia-associated disorders, including stroke. However, exact mechanisms underlying its beneficial effects are still debated. In this respect, studies of the transplanted cells distribution and homing are indispensable. We proposed an MRI protocol which allowed us to estimate the dynamic distribution of single superparamagnetic iron oxide labeled MSCs in live ischemic rat brain during intravenous transplantation after the transient middle cerebral artery occlusion. Additionally, we evaluated therapeutic efficacy of cell therapy in this rat stroke model. According to the dynamic MRI data, limited numbers of MSCs accumulated diffusely in the brain vessels starting at the 7th minute from the onset of infusion, reached its maximum by 29 min, and gradually eliminated from cerebral circulation during 24 h. Despite low numbers of cells entering brain blood flow and their short-term engraftment, MSCs transplantation induced long lasting improvement of the neurological deficit, but without acceleration of the stroke volume reduction compared to the control animals during 14 post-transplantation days. Taken together, these findings indicate that MSCs convey their positive action by triggering certain paracrine mechanisms or cell-cell interactions or invoking direct long-lasting effects on brain vessels.
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Cell-based drug delivery systems and their in vivo fate. Adv Drug Deliv Rev 2022; 187:114394. [PMID: 35718252 DOI: 10.1016/j.addr.2022.114394] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/17/2022] [Accepted: 06/07/2022] [Indexed: 11/22/2022]
Abstract
Cell-based drug delivery systems (DDSs) have received attention recently because of their unique biological properties and self-powered functions, such as excellent biocompatibility, low immunogenicity, long circulation time, tissue-homingcharacteristics, and ability to cross biological barriers. A variety of cells, including erythrocytes, stem cells, and lymphocytes, have been explored as functional vectors for the loading and delivery of various therapeutic payloads (e.g., small-molecule and nucleic acid drugs) for subsequent disease treatment. These cell-based DDSs have their own unique in vivo fates, which are attributed to various factors, including their biological properties and functions, the loaded drugs and loading process, physiological and pathological circumstances, and the body's response to these carrier cells, which result in differences in drug delivery efficiency and therapeutic effect. In this review, we summarize the main cell-based DDSs and their biological properties and functions, applications in drug delivery and disease treatment, and in vivo fate and influencing factors. We envision that the unique biological properties, combined with continuing research, will enable development of cell-based DDSs as friendly drug vectors for the safe, effective, and even personalized treatment of diseases.
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Moonshi SS, Wu Y, Ta HT. Visualizing stem cells in vivo using magnetic resonance imaging. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 14:e1760. [PMID: 34651465 DOI: 10.1002/wnan.1760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/18/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022]
Abstract
Stem cell (SC) therapies displayed encouraging efficacy and clinical outcome in various disorders. Despite this huge hype, clinical translation of SC therapy has been disheartening due to contradictory results from clinical trials. The ability to monitor migration and engraftment of cells in vivo represents an ideal strategy in cell therapy. Therefore, suitable imaging approach to track MSCs would allow understanding of migratory and homing efficiency, optimal route of delivery and engraftment of cells at targeted location. Hence, longitudinal tracking of SCs is crucial for the optimization of treatment parameters, leading to improved clinical outcome and translation. Magnetic resonance imaging (MRI) represents a suitable imaging modality to observe cells non-invasively and repeatedly. Tracking is achieved when cells are incubated prior to implantation with appropriate contrast agents (CA) or tracers which can then be detected in an MRI scan. This review explores and emphasizes the importance of monitoring the distribution and fate of SCs post-implantation using current contrast agents, such as positive CAs including paramagnetic metals (gadolinium), negative contrast agents such as superparamagnetic iron oxides and 19 F containing tracers, specifically for the in vivo tracking of MSCs using MRI. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Shehzahdi Shebbrin Moonshi
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia
| | - Yuao Wu
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia
| | - Hang Thu Ta
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia.,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia.,School of Environment and Science, Griffith University, Nathan, Queensland, Australia
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Kim IK, Park JH, Kim B, Hwang KC, Song BW. Recent advances in stem cell therapy for neurodegenerative disease: Three dimensional tracing and its emerging use. World J Stem Cells 2021; 13:1215-1230. [PMID: 34630859 PMCID: PMC8474717 DOI: 10.4252/wjsc.v13.i9.1215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases.
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Affiliation(s)
- Il-Kwon Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Jun-Hee Park
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Bomi Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea.
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Ngen EJ, Chen Y, Azad BB, Boinapally S, Jacob D, Lisok A, Shen C, Hossain MS, Jin J, Bhujwalla ZM, Pomper MG, Banerjee SR. Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors. Nanotheranostics 2021; 5:182-196. [PMID: 33564617 PMCID: PMC7868004 DOI: 10.7150/ntno.52361] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/31/2020] [Indexed: 02/03/2023] Open
Abstract
Enhanced vascular permeability in tumors plays an essential role in nanoparticle delivery. Prostate-specific membrane antigen (PSMA) is overexpressed on the epithelium of aggressive prostate cancers (PCs). Here, we evaluated the feasibility of increasing the delivery of PSMA-targeted magnetic nanoparticles (MNPs) to tumors by enhancing vascular permeability in PSMA(+) PC tumors with PSMA-targeted photodynamic therapy (PDT). Method: PSMA(+) PC3 PIP tumor-bearing mice were given a low-molecular-weight PSMA-targeted photosensitizer and treated with fluorescence image-guided PDT, 4 h after. The mice were then given a PSMA-targeted MNP immediately after PDT and monitored with fluorescence imaging and T2-weighted magnetic resonance imaging (T2-W MRI) 18 h, 42 h, and 66 h after MNP administration. Untreated PSMA(+) PC3 PIP tumor-bearing mice were used as negative controls. Results: An 8-fold increase in the delivery of the PSMA-targeted MNPs was detected using T2-W MRI in the pretreated tumors 42 h after PDT, compared to untreated tumors. Additionally, T2-W MRIs revealed enhanced peripheral intra-tumoral delivery of the PSMA-targeted MNPs. That finding is in keeping with two-photon microscopy, which revealed higher vascular densities at the tumor periphery. Conclusion: These results suggest that PSMA-targeted PDT enhances the delivery of PSMA-targeted MNPs to PSMA(+) tumors by enhancing the vascular permeability of the tumors.
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Affiliation(s)
- Ethel J Ngen
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ying Chen
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Babak Behnam Azad
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Srikanth Boinapally
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Desmond Jacob
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Ala Lisok
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Chentian Shen
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Mir S Hossain
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jiefu Jin
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Zaver M Bhujwalla
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.,The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Martin G Pomper
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.,The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Sangeeta R Banerjee
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.,The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.,The F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland 21205, USA
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Almeida AF, Vinhas A, Gonçalves AI, Miranda MS, Rodrigues MT, Gomes ME. Magnetic triggers in biomedical applications - prospects for contact free cell sensing and guidance. J Mater Chem B 2021; 9:1259-1271. [PMID: 33410453 DOI: 10.1039/d0tb02474k] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
In recent years, the inputs from magnetically assisted strategies have been contributing to the development of more sensitive screening methods and precise means of diagnosis to overcome existing and emerging treatment challenges. The features of magnetic materials enabling in vivo traceability, specific targeting and space- and time-controlled delivery of nanomedicines have highlighted the resourcefulness of the magnetic toolbox for biomedical applications and theranostic strategies. The breakthroughs in magnetically assisted technologies for contact-free control of cell and tissue fate opens new perspectives to improve healing and instruct regeneration reaching a wide range of diseases and disorders. In this review, the contribution of magnetic nanoparticles (MNPs) will be explored as sophisticated and versatile nanotriggers, evidencing their unique cues to probe and control cell function. As cells detect and engage external magnetic features, these approaches will be overviewed considering molecular engineering and cell programming perspectives as well as cell and tissue targeting modalities. The therapeutic relevance of MNPs will be also emphasized as key components of nanostructured systems to control the release of nanomedicines and in the context of new therapy technologies.
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Affiliation(s)
- Ana F Almeida
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Adriana Vinhas
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana I Gonçalves
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Margarida S Miranda
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Márcia T Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Kim JH, Dodd S, Ye FQ, Knutsen AK, Nguyen D, Wu H, Su S, Mastrogiacomo S, Esparza TJ, Swenson RE, Brody DL. Sensitive detection of extremely small iron oxide nanoparticles in living mice using MP2RAGE with advanced image co-registration. Sci Rep 2021; 11:106. [PMID: 33420210 PMCID: PMC7794370 DOI: 10.1038/s41598-020-80181-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 12/15/2020] [Indexed: 02/05/2023] Open
Abstract
Magnetic resonance imaging (MRI) is a widely used non-invasive methodology for both preclinical and clinical studies. However, MRI lacks molecular specificity. Molecular contrast agents for MRI would be highly beneficial for detecting specific pathological lesions and quantitatively evaluating therapeutic efficacy in vivo. In this study, an optimized Magnetization Prepared—RApid Gradient Echo (MP-RAGE) with 2 inversion times called MP2RAGE combined with advanced image co-registration is presented as an effective non-invasive methodology to quantitatively detect T1 MR contrast agents. The optimized MP2RAGE produced high quality in vivo mouse brain T1 (or R1 = 1/T1) map with high spatial resolution, 160 × 160 × 160 µm3 voxel at 9.4 T. Test–retest signal to noise was > 20 for most voxels. Extremely small iron oxide nanoparticles (ESIONPs) having 3 nm core size and 11 nm hydrodynamic radius after polyethylene glycol (PEG) coating were intracranially injected into mouse brain and detected as a proof-of-concept. Two independent MP2RAGE MR scans were performed pre- and post-injection of ESIONPs followed by advanced image co-registration. The comparison of two T1 (or R1) maps after image co-registration provided precise and quantitative assessment of the effects of the injected ESIONPs at each voxel. The proposed MR protocol has potential for future use in the detection of T1 molecular contrast agents.
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Affiliation(s)
- Joong H Kim
- Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD, USA.,Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Stephen Dodd
- Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Frank Q Ye
- Neurophysiology Imaging Facility, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Eye Institute, National Institutes of Health, Bethesda, MD, USA
| | - Andrew K Knutsen
- Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD, USA
| | - Duong Nguyen
- Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Haitao Wu
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shiran Su
- Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.,Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Simone Mastrogiacomo
- Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Thomas J Esparza
- Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD, USA.,Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Rolf E Swenson
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - David L Brody
- Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD, USA. .,Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. .,Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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12
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Zhang Y, Zhang H, Huang D, Tan B, Zhang C, Deng Z. Naphthalene-facilitated self-assembly of a Gd-chelate as a novel T2 MRI contrast agent for visualization of stem cell transplants. J Mater Chem B 2021; 9:5729-5737. [PMID: 34231635 DOI: 10.1039/d1tb00424g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Naphthalene is coupled with DOTA via a peptide sequence to yield an amphipathic MRI probe Nap-CFGKTG-DOTA-Gd (Nap-Gd) that can self-assemble into nanofibers. Incubation of NSCs, hMSCs and L929 cells in the presence of Nap-Gd in the μM level can introduce a significant amount of Nap-Gd into the cells as nanoclusters or nanofibers. The resultant intracellular Gd content is 10-60 times that achieved by incubation with Dotarem at the same concentration. The labelled cells exhibit a significant hyperintensive effect under T1-weighted MRI and a significant hypointensive effect under T2-weighted MRI. The hypointensive effect is more persistent than the hyperintensive effect, which allows in vivo tracking of labelled hMSCs for over 12 days under T2-weighted MRI. A comprehensive interpretation of the MRI signal intensity and the associated relaxation times reveals the structure-function relationship between the binding status of Nap-Gd in cells (structure) and the magnetic relaxation processes (function) toward a full understanding of the observed hyperintensive and hypointensive effects.
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Affiliation(s)
- Yanhui Zhang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, P. R. China. and CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
| | - Hailu Zhang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
| | - Dehua Huang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
| | - Bo Tan
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
| | - Chengxing Zhang
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
| | - Zongwu Deng
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, P. R. China. and CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
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13
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Zhang Y, Huang D, Zhang C, Meng J, Tan B, Deng Z. IQF characterization of a cathepsin B-responsive nanoprobe for report of differentiation of HL60 cells into macrophages. RSC Adv 2021; 11:16522-16529. [PMID: 35479137 PMCID: PMC9031808 DOI: 10.1039/d1ra01549d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/18/2021] [Indexed: 12/14/2022] Open
Abstract
Tracking of in vivo fates of exogenous cell transplants in terms of viability, migration, directional differentiation and function delivery by a suitable method of medical imaging is of great significance in the development and application of various cell therapies. In this contribution directional differentiation of HL60 cells into macrophages and granulocytes, and a difference in the associated expression level of cathepsin B (Cat B) among the parent and daughter cells is used as a model to guide and evaluate the development of a Cat B-responsive Abz-FRFK-Dnp@PLGA nanoprobe for an optical report of the differentiation process. A well-documented internally quenched fluorescence (IQF) pair coupled with a peptide substrate FRFK of Cat B was synthesized and imbedded in PLGA to form the nanoprobe. The nanoprobe is resistant to leakage when dispersed in water for 10 days. Degradation of the nanoprobe is dominated by Cat B. HL60 cells were then labelled with the Abz-FRFK-Dnp@PLGA nanoprobe to track the differentiation process. Differentiation of labelled HL60 cells into macrophages exhibited a significantly higher fluorescence relative to the granulocytes or the labelled parent cells. The fluorescence difference allows the differentiation process to be followed. The established characterization and assessment procedure is to be used for the development and evaluation of nanoprobes for other imaging modalities. A Cat B-responsive Abz-FRFK-Dnp@PLGA nanoprobe for an optical report of the differentiation of HL60 cells into macrophages.![]()
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Affiliation(s)
- Yanhui Zhang
- School of Nano-Tech and Nano-Bionics
- University of Science and Technology of China
- Hefei
- P. R. China
- CAS Key Laboratory of Nano-Bio Interface
| | - Dehua Huang
- CAS Key Laboratory of Nano-Bio Interface
- Suzhou Institute of Nano-tech and Nano-bionics
- Chinese Academy of Sciences
- Suzhou
- P. R. China
| | - Chengxing Zhang
- CAS Key Laboratory of Nano-Bio Interface
- Suzhou Institute of Nano-tech and Nano-bionics
- Chinese Academy of Sciences
- Suzhou
- P. R. China
| | - Jingjing Meng
- CAS Key Laboratory of Nano-Bio Interface
- Suzhou Institute of Nano-tech and Nano-bionics
- Chinese Academy of Sciences
- Suzhou
- P. R. China
| | - Bo Tan
- CAS Key Laboratory of Nano-Bio Interface
- Suzhou Institute of Nano-tech and Nano-bionics
- Chinese Academy of Sciences
- Suzhou
- P. R. China
| | - Zongwu Deng
- School of Nano-Tech and Nano-Bionics
- University of Science and Technology of China
- Hefei
- P. R. China
- CAS Key Laboratory of Nano-Bio Interface
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14
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Papan P, Kantapan J, Sangthong P, Meepowpan P, Dechsupa N. Iron (III)-Quercetin Complex: Synthesis, Physicochemical Characterization, and MRI Cell Tracking toward Potential Applications in Regenerative Medicine. CONTRAST MEDIA & MOLECULAR IMAGING 2020; 2020:8877862. [PMID: 33456403 PMCID: PMC7785384 DOI: 10.1155/2020/8877862] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 12/20/2022]
Abstract
In cell therapy, contrast agents T1 and T2 are both needed for the labeling and tracking of transplanted stem cells over extended periods of time through magnetic resonance imaging (MRI). Importantly, the metal-quercetin complex via coordination chemistry has been studied extensively for biomedical applications, such as anticancer therapies and imaging probes. Herein, we report on the synthesis, characterization, and labeling of the iron (III)-quercetin complex, "IronQ," in circulating proangiogenic cells (CACs) and also explore tracking via the use of a clinical 1.5 Tesla (T) MRI scanner. Moreover, IronQ had a paramagnetic T1 positive contrast agent property with a saturation magnetization of 0.155 emu/g at 1.0 T and longitudinal relaxivity (r1) values of 2.29 and 3.70 mM-1s-1 at 1.5 T for water and human plasma, respectively. Surprisingly, IronQ was able to promote CAC growth in conventional cell culture systems without the addition of specific growth factors. Increasing dosages of IronQ from 0 to 200 μg/mL led to higher CAC uptake, and maximum labeling time was achieved in 10 days. The accumulated IronQ in CACs was measured by two methodologies, an inductively coupled plasma optical emission spectrometry (ICP-EOS) and T1-weighted MRI. In our research, we confirmed that IronQ has excellent dual functions with the use of an imaging probe for MRI. IronQ can also act as a stimulating agent by favoring circulating proangiogenic cell differentiation. Optimistically, IronQ is considered beneficial for alternative labeling and in the tracking of circulation proangiogenic cells and/or other stem cells in applications of cell therapy through noninvasive magnetic resonance imaging in both preclinical and clinical settings.
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Affiliation(s)
- Phakorn Papan
- Research Unit of Molecular Imaging Probes and Radiobiology, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Jiraporn Kantapan
- Research Unit of Molecular Imaging Probes and Radiobiology, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Padchanee Sangthong
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Puttinan Meepowpan
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nathupakorn Dechsupa
- Research Unit of Molecular Imaging Probes and Radiobiology, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand
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15
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Pedron S, Pikkemaat JA, Söntjens SH, Janssen HM, Broer DJ. Magnetic Resonance Monitoring of Opaque Temperature-Sensitive Polymeric Scaffolds. ACS APPLIED BIO MATERIALS 2020; 3:7639-7645. [DOI: 10.1021/acsabm.0c00836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Sara Pedron
- Department of Biomolecular Engineering, Philips Research Laboratories, High Tech Campus 11, 5656 AE Eindhoven The Netherlands
| | - Jeroen A. Pikkemaat
- Department of Biomolecular Engineering, Philips Research Laboratories, High Tech Campus 11, 5656 AE Eindhoven The Netherlands
| | | | - Henk M. Janssen
- SyMO-Chem B.V., Den Dolech 2, 5612 AZ Eindhoven The Netherlands
| | - Dirk J. Broer
- Department of Chemistry - Functional Organic Materials & Devices, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven The Netherlands
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16
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Zhang S, Lachance BB, Moiz B, Jia X. Optimizing Stem Cell Therapy after Ischemic Brain Injury. J Stroke 2020; 22:286-305. [PMID: 33053945 PMCID: PMC7568970 DOI: 10.5853/jos.2019.03048] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.
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Affiliation(s)
- Shuai Zhang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Brittany Bolduc Lachance
- Program in Trauma, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bilal Moiz
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, USA.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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17
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Kim K, Kim H, Bae SH, Lee SY, Kim YH, Na J, Lee CH, Lee MS, Ko GB, Kim KY, Lee SH, Song IH, Cheon GJ, Kang KW, Kim SE, Chung JK, Kim EE, Paek SH, Lee JS, Lee BC, Youn H. [ 18F]CB251 PET/MR imaging probe targeting translocator protein (TSPO) independent of its Polymorphism in a Neuroinflammation Model. Am J Cancer Res 2020; 10:9315-9331. [PMID: 32802194 PMCID: PMC7415805 DOI: 10.7150/thno.46875] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 07/12/2020] [Indexed: 01/03/2023] Open
Abstract
The 18 kDa translocator protein (TSPO) has been proposed as a biomarker for the detection of neuroinflammation. Although various PET probes targeting TSPO have been developed, a highly selective probe for detecting TSPO is still needed because single nucleotide polymorphisms in the human TSPO gene greatly affect the binding affinity of TSPO ligands. Here, we describe the visualization of neuroinflammation with a multimodality imaging system using our recently developed TSPO-targeting radionuclide PET probe [18F]CB251, which is less affected by TSPO polymorphisms. Methods: To test the selectivity of [18F]CB251 for TSPO polymorphisms, 293FT cells expressing polymorphic TSPO were generated by introducing the coding sequences of wild-type (WT) and mutant (Alanine → Threonine at 147th Amino Acid; A147T) forms. Competitive inhibition assay was conducted with [3H]PK11195 and various TSPO ligands using membrane proteins isolated from 293FT cells expressing TSPO WT or mutant-A147T, representing high-affinity binder (HAB) or low-affinity binder (LAB), respectively. IC50 values of each ligand to [3H]PK11195 in HAB or LAB were measured and the ratio of IC50 values of each ligand to [3H]PK11195 in HAB to LAB was calculated, indicating the sensitivity of TSPO polymorphism. Cellular uptake of [18F]CB251 was measured with different TSPO polymorphisms, and phantom studies of [18F]CB251-PET using 293FT cells were performed. To test TSPO-specific cellular uptake of [18F]CB251, TSPO expression was regulated with pCMV-TSPO (or shTSPO)/eGFP vector. Intracranial lipopolysaccharide (LPS) treatment was used to induce regional inflammation in the mouse brain. Gadolinium (Gd)-DOTA MRI was used to monitor the disruption of the blood-brain barrier (BBB) and infiltration by immune cells. Infiltration of peripheral immune cells across the BBB, which exacerbates neuroinflammation to produce higher levels of neurotoxicity, was also monitored with bioluminescence imaging (BLI). Peripheral immune cells isolated from luciferase-expressing transgenic mice were transferred to syngeneic inflamed mice. Neuroinflammation was monitored with [18F]CB251-PET/MR and BLI. To evaluate the effects of anti-inflammatory agents on intracranial inflammation, an inflammatory cytokine inhibitor, 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me) was administered in intracranial LPS challenged mice. Results: The ratio of IC50 values of [18F]CB251 in HAB to LAB indicated similar binding affinity to WT and mutant TSPO and was less affected by TSPO polymorphisms. [18F]CB251 was specific for TSPO, and its cellular uptake reflected the amount of TSPO. Higher [18F]CB251 uptake was also observed in activated immune cells. Simultaneous [18F]CB251-PET/MRI showed that [18F]CB251 radioactivity was co-registered with the MR signals in the same region of the brain of LPS-injected mice. Luciferase-expressing peripheral immune cells were located at the site of LPS-injected right striatum. Quantitative evaluation of the anti-inflammatory effect of CDDO-Me on neuroinflammation was successfully monitored with TSPO-targeting [18F]CB251-PET/MR and BLI. Conclusion: Our results indicate that [18F]CB251-PET has great potential for detecting neuroinflammation with higher TSPO selectivity regardless of polymorphisms. Our multimodal imaging system, [18F]CB251-PET/MRI, tested for evaluating the efficacy of anti-inflammatory agents in preclinical studies, might be an effective method to assess the severity and therapeutic response of neuroinflammation.
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18
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Schomann T, Iljas JD, Que I, Li Y, Suidgeest E, Cruz LJ, Frijns JHM, Chan A, Löwik CMWG, Huisman MA, Mezzanotte L. Multimodal imaging of hair follicle bulge-derived stem cells in a mouse model of traumatic brain injury. Cell Tissue Res 2020; 381:55-69. [PMID: 32036485 PMCID: PMC7306043 DOI: 10.1007/s00441-020-03173-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 01/20/2020] [Indexed: 01/01/2023]
Abstract
Traumatic brain injury (TBI) is a devastating event for which current therapies are limited. Stem cell transplantation may lead to recovery of function via different mechanisms, such as cell replacement through differentiation, stimulation of angiogenesis and support to the microenvironment. Adult hair follicle bulge-derived stem cells (HFBSCs) possess neuronal differentiation capacity, are easy to harvest and are relatively immune-privileged, which makes them potential candidates for autologous stem cell-based therapy. In this study, we apply in vivo multimodal, optical and magnetic resonance imaging techniques to investigate the behavior of mouse HFBSCs in a mouse model of TBI. HFBSCs expressed Luc2 and copGFP and were examined for their differentiation capacity in vitro. Subsequently, transduced HFBSCs, preloaded with ferumoxytol, were transplanted next to the TBI lesion (cortical region) in nude mice, 2 days after injury. Brains were fixed for immunohistochemistry 58 days after transplantation. Luc2- and copGFP-expressing, ferumoxytol-loaded HFBSCs showed adequate neuronal differentiation potential in vitro. Bioluminescence of the lesioned brain revealed survival of HFBSCs and magnetic resonance imaging identified their localization in the area of transplantation. Immunohistochemistry showed that transplanted cells stained for nestin and neurofilament protein (NF-Pan). Cells also expressed laminin and fibronectin but extracellular matrix masses were not detected. After 58 days, ferumoxytol could be detected in HFBSCs in brain tissue sections. These results show that HFBSCs are able to survive after brain transplantation and suggest that cells may undergo differentiation towards a neuronal cell lineage, which supports their potential use for cell-based therapy for TBI.
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Affiliation(s)
- Timo Schomann
- Department of Otorhinolaryngology and Head & Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Percuros B.V, Leiden, the Netherlands
| | - Juvita D Iljas
- Percuros B.V, Leiden, the Netherlands
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Ivo Que
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Yuedan Li
- Percuros B.V, Leiden, the Netherlands
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ernst Suidgeest
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Luis J Cruz
- Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Johan H M Frijns
- Department of Otorhinolaryngology and Head & Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Leiden Institute for Brain and Cognition, Leiden University, Leiden, the Netherlands
| | - Alan Chan
- Percuros B.V, Leiden, the Netherlands
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Clemens M W G Löwik
- Optical Molecular Imaging, Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
- Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Margriet A Huisman
- Department of Otorhinolaryngology and Head & Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Hair Science Institute, Maastricht, the Netherlands
| | - Laura Mezzanotte
- Optical Molecular Imaging, Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
- Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
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19
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Bao H, Xia Y, Yu C, Ning X, Liu X, Fu H, Chen Z, Huang J, Zhang Z. CT/Bioluminescence Dual-Modal Imaging Tracking of Mesenchymal Stem Cells in Pulmonary Fibrosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1904314. [PMID: 31565866 DOI: 10.1002/smll.201904314] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/06/2019] [Indexed: 06/10/2023]
Abstract
Human mesenchymal stem cells (hMSCs), due to their immune regulation and collateral secretion effects, are currently explored for potential therapy of idiopathic pulmonary fibrosis (IPF). Understanding the migration, homing, functions, and survival of transplanted hMSCs in vivo is critical to successful IPF treatment. Therefore, it is highly desired to develop noninvasive and effective imaging technologies to track the transplanted hMSCs, providing experimental basis for improving the efficacy of hMSCs in the treatment of IPF. The rational design and development of a dual-labeling strategy are reported by integrating gold nanoparticle (AuNP)-based computed tomography (CT) nanotracers and red-emitting firefly luciferase (RfLuc)-based bioluminescence (BL) tags for CT/BL multimodal imaging tracking of the transplanted hMSCs in a murine model of IPF. In this approach, the CT nanotracer is prepared by sequential coupling of AuNPs with polyethylene glycol and trans-activator of transcription (TAT) peptide (Au@TAT), and employed it to monitor the location and distribution of the transplanted hMSCs in vivo by CT imaging, while RfLuc is used to monitor hMSCs viability by BLI. This facile strategy allows for visualization of the transplanted hMSCs in vivo, thereby enabling profound understanding of the role of hMSCs in the IPF treatment, and advancing stem cell-based regenerative medicine.
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Affiliation(s)
- Hongying Bao
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, 215123, China
| | - Yuyang Xia
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Xinyu Ning
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Xiaoyun Liu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Han Fu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Zhongjin Chen
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Jie Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
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20
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Homing and Tracking of Iron Oxide Labelled Mesenchymal Stem Cells After Infusion in Traumatic Brain Injury Mice: a Longitudinal In Vivo MRI Study. Stem Cell Rev Rep 2019; 14:888-900. [PMID: 29911289 DOI: 10.1007/s12015-018-9828-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Stem cells transplantation has emerged as a promising alternative therapeutic due to its potency at injury site. The need to monitor and non-invasively track the infused stem cells is a significant challenge in the development of regenerative medicine. Thus, in vivo tracking to monitor infused stem cells is especially vital. In this manuscript, we have described an effective in vitro labelling method of MSCs, a serial in vivo tracking of implanted stem cells at traumatic brain injury (TBI) site through 7 T magnetic resonance imaging (MRI). Proper homing of infused MSCs was carried out at different time points using histological analysis and Prussian blue staining. Longitudinal in vivo tracking of infused MSCs were performed up to 21 days in different groups through MRI using relaxometry technique. Results demonstrated that MSCs incubated with iron oxide-poly-L-lysine complex (IO-PLL) at a ratio of 50:1.5 μg/ml and a time period of 6 h was optimised to increase labelling efficiency. T2*-weighted images and relaxation study demonstrated a significant signal loss and effective decrease in transverse relaxation time on day-3 at injury site after systemic transplantation, revealed maximum number of stem cells homing to the lesion area. MRI results further correlate with histological and Prussian blue staining in different time periods. Decrease in negative signal and increase in relaxation times were observed after day-14, may indicate damage tissue replacement with healthy tissue. MSCs tracking with synthesized negative contrast agent represent a great advantage during both in vitro and in vivo analysis. The proposed absolute bias correction based relaxometry analysis could be extrapolated for stem cell tracking and therapies in various neurodegenerative diseases.
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Ngen EJ, Benham Azad B, Boinapally S, Lisok A, Brummet M, Jacob D, Pomper MG, Banerjee SR. MRI Assessment of Prostate-Specific Membrane Antigen (PSMA) Targeting by a PSMA-Targeted Magnetic Nanoparticle: Potential for Image-Guided Therapy. Mol Pharm 2019; 16:2060-2068. [DOI: 10.1021/acs.molpharmaceut.9b00036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Ethel J. Ngen
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Babak Benham Azad
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Srikanth Boinapally
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Ala Lisok
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Mary Brummet
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Desmond Jacob
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Martin G. Pomper
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
| | - Sangeeta R. Banerjee
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
- The F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland 21205, United States
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22
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Qin X, Han D, Wu JC. Molecular imaging of cardiac regenerative medicine. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2019. [DOI: 10.1016/j.cobme.2019.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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23
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Yin C, Wen G, Liu C, Yang B, Lin S, Huang J, Zhao P, Wong SHD, Zhang K, Chen X, Li G, Jiang X, Huang J, Pu K, Wang L, Bian L. Organic Semiconducting Polymer Nanoparticles for Photoacoustic Labeling and Tracking of Stem Cells in the Second Near-Infrared Window. ACS NANO 2018; 12:12201-12211. [PMID: 30433761 DOI: 10.1021/acsnano.8b05906] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Photoacoustic (PA) imaging and tracking of stem cells plays an important role in the real-time assessment of cell-based therapies. Nevertheless, the limitations of conventional inorganic PA contrast agents and the narrow range of the excitation wavelength in the first near-infrared (NIR-I) window hamper the applications of PA imaging in living subjects. Herein, we report the design and synthesis of a second near-infrared (NIR-II) absorptive organic semiconducting polymer (OSP)-based nanoprobe (OSPN+) for PA imaging and tracking of stem cells. Comparison studies in biological tissue show that NIR-II light excited PA imaging of the OSPN+ has significantly higher signal-to-noise ratio than NIR-I light excited PA imaging, thereby demonstrating the superiority of the OSPN+ for deep tissue imaging. With good biocompatibility, appropriate size, and optimized surface property, the OSPN+ shows enhanced cellular uptake for highly efficient PA labeling of stem cells. In vivo investigations reveal significant NIR-II PA contrast enhancement of the transplanted OSPN+-labeled human mesenchymal stem cells by 40.6- and 21.7-fold in subcutaneous and brain imaging, respectively, compared with unlabeled cases. Our work demonstrates a class of OSP-based nanomaterials for NIR-II PA stem cell imaging to facilitate a better understanding and evaluation of stem cell-based therapies.
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Affiliation(s)
- Chao Yin
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Guohua Wen
- Department of Biomedical Engineering , City University of Hong Kong , 83 Tat Chee Avenue , Kowloon , Hong Kong , China
| | - Chao Liu
- Department of Biomedical Engineering , City University of Hong Kong , 83 Tat Chee Avenue , Kowloon , Hong Kong , China
| | - Boguang Yang
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Sien Lin
- Department of Orthopaedics and Traumatology, Faculty of Medicine , The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin , Hong Kong China
- Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences , The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin , Hong Kong , China
- Department of Pharmacology, Guangdong Key Laboratory for Research and Development of Natural Drugs , Guangdong Medical University , Zhanjiang , Guangdong 510000 , China
| | - Jiawei Huang
- School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong , China
| | - Pengchao Zhao
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Siu Hong Dexter Wong
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Kunyu Zhang
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Xiaoyu Chen
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine , The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin , Hong Kong China
- Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences , The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin , Hong Kong , China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal Systems , The Chinese University of Hong Kong Shenzhen Research Institute , Shenzhen 518172 , China
| | - Xiaohua Jiang
- School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong , China
| | - Jianping Huang
- Department of Orthopaedics and Traumatology, Faculty of Medicine , The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin , Hong Kong China
| | - Kanyi Pu
- School of Chemical and Biomedical Engineering , Nanyang Technological University , 70 Nanyang Drive , 637457 Singapore
| | - Lidai Wang
- Department of Biomedical Engineering , City University of Hong Kong , 83 Tat Chee Avenue , Kowloon , Hong Kong , China
- City University of Hong Kong Shenzhen Research Institute , Yuexing Yi Dao, Nanshan District, Shenzhen , Guangdong 518057 , China
| | - Liming Bian
- Department of Biomedical Engineering , The Chinese University of Hong Kong , Shatin , New Territories, Hong Kong , China
- Shenzhen Research Institute , The Chinese University of Hong Kong , Shenzhen 518172 , China
- China Orthopedic Regenerative Medicine Group (CORMed) , Hangzhou , Zhejiang 310058 , China
- Translational Research Centre of Regenerative Medicine and 3D Printing Technologies of Guangzhou Medical University , The Third Affiliated Hospital of Guangzhou Medical University , Guangzhou , P.R. China , 510150
- Centre for Novel Biomaterials , Chinese University of Hong Kong , Shatin , Hong Kong SAR, P.R. China , 100097
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Gabrielson K, Maronpot R, Monette S, Mlynarczyk C, Ramot Y, Nyska A, Sysa-Shah P. In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources. ILAR J 2018; 59:80-98. [PMID: 30541081 PMCID: PMC6645176 DOI: 10.1093/ilar/ily010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 07/18/2018] [Indexed: 12/13/2022] Open
Abstract
Preclinical noninvasive imaging can be an indispensable tool for studying animal models of disease. In vivo imaging to assess anatomical, functional, and molecular features requires verification by a comparison to the macroscopic and microscopic morphological features, since all noninvasive in vivo imaging methods have much lower resolution than standard histopathology. Comprehensive pathological evaluation of the animal model is underutilized; yet, many institutions have veterinary or human pathologists with necessary comparative pathology expertise. By performing a rigorous comparison to gross or histopathology for image interpretation, these trained individuals can assist scientists with the development of the animal model, experimental design, and evaluation of the in vivo imaging data. These imaging and pathology corroboration studies undoubtedly increase scientific rigor and reproducibility in descriptive and hypothesis-driven research. A review of case examples including ultrasound, nuclear, optical, and MRI is provided to illustrate how a wide range of imaging modalities data can be confirmed by gross or microscopic pathology. This image confirmation and authentication will improve characterization of the model and may contribute to decreasing costs and number of animals used and to more rapid translation from preclinical animal model to the clinic.
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Affiliation(s)
- Kathleen Gabrielson
- Departments of Molecular and Comparative Pathology and Pathology School of Medicine, Environmental Health Engineering Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | | | - Sébastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, New York
| | - Coraline Mlynarczyk
- Department of Medicine, Division of Hematology & Medical Oncology and the Meyer Cancer Center, Weill Cornell Medicine, New York, New York
| | - Yuval Ramot
- Department of Dermatology, Hadassah—Hebrew University Medical Center, Kiryat Hadassah, Jerusalem, Israel
| | - Abraham Nyska
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel and Toxicologic Pathology, Timrat, Israel
| | - Polina Sysa-Shah
- Department of Radiology, Miller Research Building Molecular Imaging Service Center, Johns Hopkins University, Baltimore, Maryland
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25
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MRI-guided intrathecal transplantation of hydrogel-embedded glial progenitors in large animals. Sci Rep 2018; 8:16490. [PMID: 30405160 PMCID: PMC6220305 DOI: 10.1038/s41598-018-34723-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/19/2018] [Indexed: 12/13/2022] Open
Abstract
Disseminated diseases of the central nervous system such as amyotrophic lateral sclerosis (ALS) require that therapeutic agents are delivered and distributed broadly. Intrathecal route is attractive in that respect, but to date there was no methodology available allowing for optimization of this technique to assure safety and efficacy in a clinically relevant setting. Here, we report on interventional, MRI-guided approach for delivery of hydrogel-embedded glial progenitor cells facilitating cell placement over extended surface of the spinal cord in pigs and in naturally occurring ALS-like disease in dogs. Glial progenitors used as therapeutic agent were embedded in injectable hyaluronic acid-based hydrogel to support their survival and prevent sedimentation or removal. Intrathecal space was reached through lumbar puncture and the catheter was advanced under X-ray guidance to the cervical part of the spine. Animals were then transferred to MRI suite for MRI-guided injection. Interventional and follow-up MRI as well as histopathology demonstrated successful and predictable placement of embedded cells and safety of the procedure.
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26
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Santelli J, Lechevallier S, Baaziz H, Vincent M, Martinez C, Mauricot R, Parini A, Verelst M, Cussac D. Multimodal gadolinium oxysulfide nanoparticles: a versatile contrast agent for mesenchymal stem cell labeling. NANOSCALE 2018; 10:16775-16786. [PMID: 30156241 DOI: 10.1039/c8nr03263g] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Despite a clear development of innovative therapies based on stem cell manipulation, the availability of new tools to better understand and follow stem cell behavior and improve their biomedical applications is not adequate. Indeed, an ideal tracking device must have good ability to label stem cells as well as complete neutrality relative to their biology. Furthermore, preclinical studies imply in vitro and in vivo approaches that often require several kinds of labeling and/or detection procedures. Consequently, the multimodality concept presented in this work may present a solution to this problem as it has the potential to combine complementary imaging techniques. Spherical europium-doped gadolinium oxysulfide (Gd2O2S:Eu3+) nanoparticles are presented as a candidate as they are detectable by (1) magnetic resonance (MRI), (2) X-ray and (3) photoluminescence imaging. Whole body in vivo distribution, elimination and toxicity evaluation revealed a high tolerance of nanoparticles with a long-lasting MRI signal and slow hepatobiliary and renal clearance. In vitro labeling of a wide variety of cells unveils the nanoparticle potential for efficient and universal cell tracking. Emphasis on mesenchymal stromal cells (MSCs) leads to the definition of optimal conditions for labeling and tracking in the context of cell therapy: concentrations below 50 μg mL-1 and diameters between 170 and 300 nm. Viability, proliferation, migration and differentiation towards mesodermal lineages are preserved under these conditions, and cell labeling appears to be persistent and without any leakage. Ex vivo detection of as few as five thousand Gd2O2S:Eu3+-labeled MSCs by MRI combined with in vitro examination with fluorescence microscopy highlights the feasibility of cell tracking in cell therapy using this new nanoplatform.
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Affiliation(s)
- Julien Santelli
- CEMES-CNRS, Université de Toulouse, CNRS 29, rue Jeanne Marvig, BP 94347, 31055 Toulouse Cedex 4, France.
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27
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Thapa B, Diaz-Diestra D, Santiago-Medina C, Kumar N, Tu K, Beltran-Huarac J, Jadwisienczak WM, Weiner BR, Morell G. T 1- and T 2-weighted Magnetic Resonance Dual Contrast by Single Core Truncated Cubic Iron Oxide Nanoparticles with Abrupt Cellular Internalization and Immune Evasion. ACS APPLIED BIO MATERIALS 2018; 1:79-89. [PMID: 30094416 PMCID: PMC6077774 DOI: 10.1021/acsabm.8b00016] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 06/15/2018] [Indexed: 11/28/2022]
Abstract
![]()
Conventional T1- or T2-weighted single mode
contrast-enhanced magnetic resonance imaging (MRI) may produce false
results. Thereby, there is a need to develop dual contrast agents,
T1- and T2-weighted, for more accurate MRI imaging.
The dual contrast agents should possess high magnetic resonance (MR)
relaxivities, targeted tumor linking, and minimum recognition by the
immune system. We have developed nitrodopamine-PEG grafted single
core truncated cubic iron oxide nanoparticles (ND-PEG-tNCIOs) capable
of producing marked dual contrasts in MRI with enhanced longitudinal
and transverse relaxivities of 32 ± 1.29 and 791 ± 38.39
mM–1 s–1, respectively. Furthermore,
the ND-PEG-tNCIOs show excellent colloidal stability in physiological
buffers and higher cellular internalization in cancerous cells than
in phagocytic cells, indicating the immune evasive capability of the
nanoparticles. These findings indicate that tNCIOs are strong candidates
for dual contrast MRI imaging, which is vital for noninvasive real-time
detection of nascent cancer cells in vivo and for monitoring stem
cells transplants.
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Affiliation(s)
- Bibek Thapa
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Physics, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
| | - Daysi Diaz-Diestra
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
| | - Carlene Santiago-Medina
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
| | - Nitu Kumar
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States
| | - Kaixiong Tu
- Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
| | - Juan Beltran-Huarac
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Environmental Health, Harvard University, Boston, Massachusetts 02115-5810, United States
| | - Wojciech M Jadwisienczak
- School of Electrical Engineering and Computer Science, Ohio University, Athens, Ohio 45701-2769, United States
| | - Brad R Weiner
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
| | - Gerardo Morell
- Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926-2614, United States.,Department of Physics, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00925-2537, United States
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28
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Stem Cell Tracing Through MR Molecular Imaging. Tissue Eng Regen Med 2018; 15:249-261. [PMID: 30603551 DOI: 10.1007/s13770-017-0112-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/09/2017] [Accepted: 12/27/2017] [Indexed: 01/12/2023] Open
Abstract
Stem cell therapy opens a new window in medicine to overcome several diseases that remain incurable. It appears such diseases as cardiovascular disorders, brain injury, multiple sclerosis, urinary system diseases, cartilage lesions and diabetes are curable with stem cell transplantation. However, some questions related to stem cell therapy have remained unanswered. Stem cell imaging allows approval of appropriated strategies such as selection of the type and dose of stem cell, and also mode of cell delivery before being tested in clinical trials. MRI as a non-invasive imaging modality provides proper conditions for this aim. So far, different contrast agents such as superparamagnetic or paramagnetic nanoparticles, ultrasmall superparamagnetic nanoparticles, fluorine, gadolinium and some types of reporter genes have been used for imaging of stem cells. The core subject of these studies is to investigate the survival and differentiation of stem cells, contrast agent's toxicity and long term following of transplanted cells. The promising results of in vivo and some clinical trial studies may raise hope for clinical stem cells imaging with MRI.
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29
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Chen G, Lin S, Huang D, Zhang Y, Li C, Wang M, Wang Q. Revealing the Fate of Transplanted Stem Cells In Vivo with a Novel Optical Imaging Strategy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14. [PMID: 29171718 DOI: 10.1002/smll.201702679] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 09/30/2017] [Indexed: 05/17/2023]
Abstract
Stem-cell-based regenerative medicine holds great promise in clinical practices. However, the fate of stem cells after transplantation, including the distribution, viability, and the cell clearance, is not fully understood, which is critical to understand the process and the underlying mechanism of regeneration for better therapeutic effects. Herein, we develop a dual-labeling strategy to in situ visualize the fate of transplanted stem cells in vivo by combining the exogenous near-infrared fluorescence imaging in the second window (NIR-II) and endogenous red bioluminescence imaging (BLI). The NIR-II fluorescence of Ag2 S quantum dots is employed to dynamically monitor the trafficking and distribution of all transplanted stem cells in vivo due to its deep tissue penetration and high spatiotemporal resolution, while BLI of red-emitting firefly luciferase (RfLuc) identifies the living stem cells after transplantation in vivo because only the living stem cells express RfLuc. This facile strategy allows for in situ visualization of the dynamic trafficking of stem cells in vivo and the quantitative evaluation of cell translocation and viability with high temporal and spatial resolution, and thus reports the fate of transplanted stem cells and how the living stem cells help, regeneration, for an instance, of a mouse with acute liver failure.
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Affiliation(s)
- Guangcun Chen
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Suying Lin
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Dehua Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Yejun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- Suzhou NIR-Optics Technology Co., Ltd., Suzhou, 215124, China
| | - Chunyan Li
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Mao Wang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Qiangbin Wang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, CAS Center for Excellence in Brain Science, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- College of Materials Sciences and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
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30
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Scarfe L, Brillant N, Kumar JD, Ali N, Alrumayh A, Amali M, Barbellion S, Jones V, Niemeijer M, Potdevin S, Roussignol G, Vaganov A, Barbaric I, Barrow M, Burton NC, Connell J, Dazzi F, Edsbagge J, French NS, Holder J, Hutchinson C, Jones DR, Kalber T, Lovatt C, Lythgoe MF, Patel S, Patrick PS, Piner J, Reinhardt J, Ricci E, Sidaway J, Stacey GN, Starkey Lewis PJ, Sullivan G, Taylor A, Wilm B, Poptani H, Murray P, Goldring CEP, Park BK. Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies. NPJ Regen Med 2017; 2:28. [PMID: 29302362 PMCID: PMC5677988 DOI: 10.1038/s41536-017-0029-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/30/2017] [Accepted: 07/24/2017] [Indexed: 02/08/2023] Open
Abstract
Regenerative medicine therapies hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. Most progress in this field to date has been achieved with cell-based regenerative medicine therapies, with over a thousand clinical trials performed up to 2015. However, lack of adequate safety and efficacy data is currently limiting wider uptake of these therapies. To facilitate clinical translation, non-invasive in vivo imaging technologies that enable careful evaluation and characterisation of the administered cells and their effects on host tissues are critically required to evaluate their safety and efficacy in relevant preclinical models. This article reviews the most common imaging technologies available and how they can be applied to regenerative medicine research. We cover details of how each technology works, which cell labels are most appropriate for different applications, and the value of multi-modal imaging approaches to gain a comprehensive understanding of the responses to cell therapy in vivo.
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Affiliation(s)
- Lauren Scarfe
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Nathalie Brillant
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
- Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - J. Dinesh Kumar
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
| | - Noura Ali
- College of Health Science, University of Duhok, Duhok, Iraq
| | - Ahmed Alrumayh
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Mohammed Amali
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Stephane Barbellion
- Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Vendula Jones
- GlaxoSmithKline, David Jack Centre for Research and Development, Ware, UK
| | - Marije Niemeijer
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Sophie Potdevin
- SANOFI Research and Development, Disposition, Safety and Animal Research, Alfortville, France
| | - Gautier Roussignol
- SANOFI Research and Development, Disposition, Safety and Animal Research, Alfortville, France
| | - Anatoly Vaganov
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Ivana Barbaric
- Department of Biomedical Science, University of Sheffield, Sheffield, UK
| | - Michael Barrow
- Department of Chemistry, University of Liverpool, Liverpool, UK
| | | | - John Connell
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | - Francesco Dazzi
- Department of Haemato-Oncology, King’s College London, London, UK
| | | | - Neil S. French
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Julie Holder
- Roslin Cells, University of Cambridge, Cambridge, UK
| | - Claire Hutchinson
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
- Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - David R. Jones
- Medicines and Healthcare Products Regulatory Agency, London, UK
| | - Tammy Kalber
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | - Cerys Lovatt
- GlaxoSmithKline, David Jack Centre for Research and Development, Ware, UK
| | - Mark F. Lythgoe
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | - Sara Patel
- ReNeuron Ltd, Pencoed Business Park, Pencoed, Bridgend, UK
| | - P. Stephen Patrick
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | - Jacqueline Piner
- GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
| | | | - Emanuelle Ricci
- Institute of Veterinary Science, University of Liverpool, Liverpool, UK
| | | | - Glyn N. Stacey
- UK Stem Cell Bank, Division of Advanced Therapies, National Institute for Biological Standards Control, Medicines and Healthcare Products Regulatory Agency, London, UK
| | - Philip J. Starkey Lewis
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Gareth Sullivan
- Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Norwegian Center for Stem Cell Research, Blindern, Oslo, Norway
- Institute of Immunology, Oslo University Hospital-Rikshospitalet, Nydalen, Oslo, Norway
- Hybrid Technology Hub—Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway
| | - Arthur Taylor
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Bettina Wilm
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Harish Poptani
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Patricia Murray
- Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Chris E. P. Goldring
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
- Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - B. Kevin Park
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
- Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
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31
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Zhang Y, Zhang H, Ding L, Zhang H, Zhang P, Jiang H, Tan B, Deng Z. MRI reveals slow clearance of dead cell transplants in mouse forelimb muscles. Mol Med Rep 2017; 16:4068-4074. [PMID: 28765924 PMCID: PMC5646989 DOI: 10.3892/mmr.2017.7100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 07/07/2017] [Indexed: 12/23/2022] Open
Abstract
A small molecule tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd‑DOTA)4‑TPP agent is used to label human mesenchymal stem cells (hMSCs) via electroporation (EP). The present study assessed the cytotoxicity of cell labeling, in addition to its effect on cell differentiation potential. There were no significant adverse effects on cell viability or differentiation induced by either EP or cellular uptake of (Gd‑DOTA)4‑TPP. Labeled live and dead hMSCs were transplanted into mouse forelimb muscles. T2‑weighted magnetic resonance imaging (MRI) was used to track the in vivo fate of the cell transplants. The labeling and imaging strategy allowed long term tracking of the cell transplants and unambiguous distinguishing of the cell transplants from their surrounding tissues. Cell migration was observed for live hMSCs injected into subcutaneous tissues, however not for either live or dead hMSCS injected into limb muscles. A slow clearance process occurred of the dead cell transplants in the limb muscular tissue. The MRI results therefore reveal that the fate and physiological activities of cell transplants depend on the nature of their host tissue.
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Affiliation(s)
- Yanhui Zhang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Hongyan Zhang
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
- Institute of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, P.R. China
| | - Lijun Ding
- Center for Reproductive Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Hailu Zhang
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Pengli Zhang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Haizhen Jiang
- College of Sciences, Shanghai University, Shanghai 200444, P.R. China
| | - Bo Tan
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
| | - Zongwu Deng
- CAS Key Laboratory of Nano-Bio Interface and Division of Nanobionics Research, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P.R. China
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32
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Differential of live and dead cells by magnetic resonance imaging. Med Chem Res 2017. [DOI: 10.1007/s00044-017-1899-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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33
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Ngen EJ, Kato Y, Artemov D. Direct Cell Labeling to Image Transplanted Stem Cells in Real Time Using a Dual-Contrast MRI Technique. ACTA ACUST UNITED AC 2017; 42:5A.10.1-5A.10.19. [PMID: 28806856 DOI: 10.1002/cpsc.33] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Exogenous direct cell labeling with superparamagnetic iron oxide nanoparticles (SPIONs) is currently the most employed cell-labeling technique for tracking transplanted cells using magnetic resonance imaging (MRI). Although SPION-based cell labeling is effective for monitoring cell delivery and migration, monitoring cell survival is still a challenge. This unit describes an MRI technique that permits detection of the delivery, migration, and death of transplanted cells. This dual-contrast technique involves labeling cells with two different classes of MRI contrast agents, possessing different diffusion coefficients: SPIONs (T2 /T2* contrast agents, with lower diffusion coefficients) and gadolinium chelates (T1 contrast agents, with higher diffusion coefficients). In live cells, where both agents are in close proximity, the T2 /T2* contrast predominates and the T1 contrast is quenched. In dead cells, where the cell membrane is breached, gadolinium chelates diffuse from the SPIONs and generate a signature T1 contrast enhancement in the vicinity of dead cells. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- Ethel J Ngen
- In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yoshinori Kato
- In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Current address: Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan
| | - Dmitri Artemov
- In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
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34
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van Rijt S, Habibovic P. Enhancing regenerative approaches with nanoparticles. J R Soc Interface 2017; 14:20170093. [PMID: 28404870 PMCID: PMC5414913 DOI: 10.1098/rsif.2017.0093] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 03/27/2017] [Indexed: 12/13/2022] Open
Abstract
In this review, we discuss recent developments in the field of nanoparticles and their use in tissue regeneration approaches. Owing to their unique chemical properties and flexibility in design, nanoparticles can be used as drug delivery systems, to create novel features within materials or as bioimaging agents, or indeed these properties can be combined to create smart multifunctional structures. This review aims to provide an overview of this research field where the focus will be on nanoparticle-based strategies to stimulate bone regeneration; however, the same principles can be applied for other tissue and organ regeneration strategies. In the first section, nanoparticle-based methods for the delivery of drugs, growth factors and genetic material to promote tissue regeneration are discussed. The second section deals with the addition of nanoparticles to materials to create nanocomposites. Such materials can improve several material properties, including mechanical stability, biocompatibility and biological activity. The third section will deal with the emergence of a relatively new field of research using nanoparticles in advanced cell imaging and stem cell tracking approaches. As the development of nanoparticles continues, incorporation of this technology in the field of regenerative medicine will ultimately lead to new tools that can diagnose, track and stimulate the growth of new tissues and organs.
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Affiliation(s)
- Sabine van Rijt
- MERLN Institute for Technology-inspired Regenerative Medicine, Maastricht University, The Netherlands
| | - Pamela Habibovic
- MERLN Institute for Technology-inspired Regenerative Medicine, Maastricht University, The Netherlands
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35
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Li CX, Zhang X. Whole body MRI of the non-human primate using a clinical 3T scanner: initial experiences. Quant Imaging Med Surg 2017; 7:267-275. [PMID: 28516052 PMCID: PMC5418147 DOI: 10.21037/qims.2017.04.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 04/07/2017] [Indexed: 12/12/2022]
Abstract
With the advent of parallel imaging MRI techniques, whole-body MRI is being increasingly used in clinical diagnosis. However, its application in preclinical research using large animals remains very limited. In the present study, the whole-body MRI techniques for adult macaque monkeys were explored using a conventional clinic 3T scanner. The T1, T2 anatomical images, and MR angiography of adult macaque whole bodies were illustrated. The preliminary results suggest whole-body MRI can be a robust tool to examine multiple organs of non-human primate (NHP) models from head to toe non-invasively and simultaneously using a conventional clinical setting. As NHPs are intensely used in biomedical research such as HIV/AIDS and vaccine discovery, whole body MRI techniques can have a wide range of applications in translational research using NHPs.
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Affiliation(s)
- Chun-Xia Li
- Yerkes Imaging Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA
| | - Xiaodong Zhang
- Yerkes Imaging Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA
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36
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Jasmin, de Souza GT, Louzada RA, Rosado-de-Castro PH, Mendez-Otero R, Campos de Carvalho AC. Tracking stem cells with superparamagnetic iron oxide nanoparticles: perspectives and considerations. Int J Nanomedicine 2017; 12:779-793. [PMID: 28182122 PMCID: PMC5279820 DOI: 10.2147/ijn.s126530] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Superparamagnetic iron oxide nanoparticles (SPIONs) have been used for diagnoses in biomedical applications, due to their unique properties and their apparent safety for humans. In general, SPIONs do not seem to produce cell damage, although their long-term in vivo effects continue to be investigated. The possibility of efficiently labeling cells with these magnetic nanoparticles has stimulated their use to noninvasively track cells by magnetic resonance imaging after transplantation. SPIONs are attracting increasing attention and are one of the preferred methods for cell labeling and tracking in preclinical and clinical studies. For clinical protocol approval of magnetic-labeled cell tracking, it is essential to expand our knowledge of the time course of SPIONs after cell incorporation and transplantation. This review focuses on the recent advances in tracking SPION-labeled stem cells, analyzing the possibilities and limitations of their use, not only focusing on myocardial infarction but also discussing other models.
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Affiliation(s)
- Jasmin
- NUMPEX-Bio, Federal University of Rio de Janeiro, Duque de Caxias, RJ
| | - Gustavo Torres de Souza
- Laboratory of Animal Reproduction, Embrapa Dairy Cattle, Juiz de Fora, MG
- Laboratory of Genetics, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Ruy Andrade Louzada
- Institute Gustave-Roussy of Oncology, Paris-Sud University, Villejuif, France
| | | | - Rosalia Mendez-Otero
- Institute Carlos Chagas Filho of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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37
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Advances in Monitoring Cell-Based Therapies with Magnetic Resonance Imaging: Future Perspectives. Int J Mol Sci 2017; 18:ijms18010198. [PMID: 28106829 PMCID: PMC5297829 DOI: 10.3390/ijms18010198] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/05/2017] [Accepted: 01/10/2017] [Indexed: 01/07/2023] Open
Abstract
Cell-based therapies are currently being developed for applications in both regenerative medicine and in oncology. Preclinical, translational, and clinical research on cell-based therapies will benefit tremendously from novel imaging approaches that enable the effective monitoring of the delivery, survival, migration, biodistribution, and integration of transplanted cells. Magnetic resonance imaging (MRI) offers several advantages over other imaging modalities for elucidating the fate of transplanted cells both preclinically and clinically. These advantages include the ability to image transplanted cells longitudinally at high spatial resolution without exposure to ionizing radiation, and the possibility to co-register anatomical structures with molecular processes and functional changes. However, since cellular MRI is still in its infancy, it currently faces a number of challenges, which provide avenues for future research and development. In this review, we describe the basic principle of cell-tracking with MRI; explain the different approaches currently used to monitor cell-based therapies; describe currently available MRI contrast generation mechanisms and strategies for monitoring transplanted cells; discuss some of the challenges in tracking transplanted cells; and suggest future research directions.
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38
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Current Perspective of Stem Cell Therapy in Neurodegenerative and Metabolic Diseases. Mol Neurobiol 2016; 54:7276-7296. [PMID: 27815831 DOI: 10.1007/s12035-016-0217-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 10/12/2016] [Indexed: 12/11/2022]
Abstract
Neurodegenerative diseases have been an unsolved riddle for quite a while; to date, there are no proper and effective curative treatments and only palliative and symptomatic treatments are available to treat these illnesses. The absence of therapeutic treatments for neurodegenerative ailments has huge economic hit and strain on the society. Pharmacotherapies and various surgical procedures like deep brain stimulation are being given to the patient, but they are only effective for the symptoms and not for the diseases. This paper reviews the recent studies and development of stem cell therapy for neurodegenerative disorders. Stem cell-based treatment is a promising new way to deal with neurodegenerative diseases. Stem cell transplantation can advance useful recuperation by delivering trophic elements that impel survival and recovery of host neurons in animal models and patients with neurodegenerative maladies. Several mechanisms, for example, substitution of lost cells, cell combination, release of neurotrophic factor, proliferation of endogenous stem cell, and transdifferentiation, may clarify positive remedial results. With the current advancements in the stem cell therapies, a new hope for the cure has come out since they have potential to be a cure for the same. This review compiles stem cell therapy recent conceptions in neurodegenerative and neurometabolic diseases and updates in this field. Graphical Absract ᅟ.
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39
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Ngen EJ, Bar-Shir A, Jablonska A, Liu G, Song X, Ansari R, Bulte JWM, Janowski M, Pearl M, Walczak P, Gilad AA. Imaging the DNA Alkylator Melphalan by CEST MRI: An Advanced Approach to Theranostics. Mol Pharm 2016; 13:3043-53. [PMID: 27398883 DOI: 10.1021/acs.molpharmaceut.6b00130] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Brain tumors are among the most lethal types of tumors. Therapeutic response variability and failure in patients have been attributed to several factors, including inadequate drug delivery to tumors due to the blood-brain barrier (BBB). Consequently, drug delivery strategies are being developed for the local and targeted delivery of drugs to brain tumors. These drug delivery strategies could benefit from new approaches to monitor the delivery of drugs to tumors. Here, we evaluated the feasibility of imaging 4-[bis(2-chloroethyl)amino]-l-phenylalanine (melphalan), a clinically used DNA alkylating agent, using chemical exchange saturation transfer magnetic resonance imaging (CEST MRI), for theranostic applications. We evaluated the physicochemical parameters that affect melphalan's CEST contrast and demonstrated the feasibility of imaging the unmodified drug by saturating its exchangeable amine protons. Melphalan generated a CEST signal despite its reactivity in an aqueous milieu. The maximum CEST signal was observed at pH 6.2. This CEST contrast trend was then used to monitor therapeutic responses to melphalan in vitro. Upon cell death, the decrease in cellular pH from ∼7.4 to ∼6.4 caused an amplification of the melphalan CEST signal. This is contrary to what has been reported for other CEST contrast agents used for imaging cell death, where a decrease in the cellular pH following cell death results in a decrease in the CEST signal. Ultimately, this method could be used to noninvasively monitor melphalan delivery to brain tumors and also to validate therapeutic responses to melphalan clinically.
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Affiliation(s)
- Ethel J Ngen
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States
| | - Amnon Bar-Shir
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States
| | - Anna Jablonska
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States
| | - Guanshu Liu
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States
| | - Xiaolei Song
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States
| | | | - Jeff W M Bulte
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States
| | - Miroslaw Janowski
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,NeuroRepair Department, Mossakowski Medical Research Centre, PAS , 02106 Warsaw, Poland.,Department of Neurosurgery, Mossakowski Medical Research Centre, PAS , 02106 Warsaw, Poland
| | - Monica Pearl
- Division of Interventional Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Department of Radiology, Children's National Medical Center , Washington, D.C. 20010, United States
| | - Piotr Walczak
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury , Olsztyn, Poland
| | - Assaf A Gilad
- Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.,F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States
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40
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Hapuarachchige S, Kato Y, Ngen EJ, Smith B, Delannoy M, Artemov D. Non-Temperature Induced Effects of Magnetized Iron Oxide Nanoparticles in Alternating Magnetic Field in Cancer Cells. PLoS One 2016; 11:e0156294. [PMID: 27244470 PMCID: PMC4887104 DOI: 10.1371/journal.pone.0156294] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 05/12/2016] [Indexed: 01/08/2023] Open
Abstract
This paper reports the damaging effects of magnetic iron-oxide nanoparticles (MNP) on magnetically labeled cancer cells when subjected to oscillating gradients in a strong external magnetic field. Human breast cancer MDA-MB-231 cells were labeled with MNP, placed in the high magnetic field, and subjected to oscillating gradients generated by an imaging gradient system of a 9.4T preclinical MRI system. Changes in cell morphology and a decrease in cell viability were detected in cells treated with oscillating gradients. The cytotoxicity was determined qualitatively and quantitatively by microscopic imaging and cell viability assays. An approximately 26.6% reduction in cell viability was detected in magnetically labeled cells subjected to the combined effect of a static magnetic field and oscillating gradients. No reduction in cell viability was observed in unlabeled cells subjected to gradients, or in MNP-labeled cells in the static magnetic field. As no increase in local temperature was observed, the cell damage was not a result of hyperthermia. Currently, we consider the coherent motion of internalized and aggregated nanoparticles that produce mechanical moments as a potential mechanism of cell destruction. The formation and dynamics of the intracellular aggregates of nanoparticles were visualized by optical and transmission electron microscopy (TEM). The images revealed a rapid formation of elongated MNP aggregates in the cells, which were aligned with the external magnetic field. This strategy provides a new way to eradicate a specific population of MNP-labeled cells, potentially with magnetic resonance imaging guidance using standard MRI equipment, with minimal side effects for the host.
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Affiliation(s)
- Sudath Hapuarachchige
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
| | - Yoshinori Kato
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, United States of America
| | - Ethel J. Ngen
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
| | - Barbara Smith
- Cell Biology Imaging Facility, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
| | - Michael Delannoy
- Cell Biology Imaging Facility, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
| | - Dmitri Artemov
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, United States of America
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, United States of America
- * E-mail:
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41
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Loai S, Haedicke I, Mirzaei Z, Simmons CA, Zhang XA, Cheng HL. Positive-contrast cellular MRI of embryonic stem cells for tissue regeneration using a highly efficientT1MRI contrast agent. J Magn Reson Imaging 2016; 44:1456-1463. [DOI: 10.1002/jmri.25299] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 04/20/2016] [Accepted: 04/21/2016] [Indexed: 01/15/2023] Open
Affiliation(s)
- Sadi Loai
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON Canada
- Translational Biology and Engineering Program; Ted Rogers Centre for Heart Research; Toronto ON Canada
- Department of Chemical Engineering and Bioengineering; McMaster University; Hamilton ON Canada
| | - Inga Haedicke
- Department of Physical and Environmental Sciences; University of Toronto Scarborough; Toronto ON Canada
- Department of Chemistry; University of Toronto; Toronto ON Canada
| | - Zahra Mirzaei
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON Canada
- Translational Biology and Engineering Program; Ted Rogers Centre for Heart Research; Toronto ON Canada
| | - Craig A. Simmons
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON Canada
- Translational Biology and Engineering Program; Ted Rogers Centre for Heart Research; Toronto ON Canada
- Department of Mechanical and Industrial Engineering; University of Toronto; Toronto ON Canada
| | - Xiao-an Zhang
- Department of Physical and Environmental Sciences; University of Toronto Scarborough; Toronto ON Canada
- Department of Chemistry; University of Toronto; Toronto ON Canada
| | - Hai Ling Cheng
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto ON Canada
- Translational Biology and Engineering Program; Ted Rogers Centre for Heart Research; Toronto ON Canada
- The Edward S. Rogers Sr. Department of Electrical and Computer Engineering; University of Toronto Toronto; ON Canada
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42
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Ngen EJ, Wang L, Gandhi N, Kato Y, Armour M, Zhu W, Wong J, Gabrielson KL, Artemov D. A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies. J Neurooncol 2016; 128:225-33. [PMID: 27021492 DOI: 10.1007/s11060-016-2111-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 03/22/2016] [Indexed: 01/15/2023]
Abstract
Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.
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Affiliation(s)
- Ethel J Ngen
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building 217, Baltimore, MD, 21205, USA
| | - Lee Wang
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building 217, Baltimore, MD, 21205, USA
| | - Nishant Gandhi
- Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yoshinori Kato
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building 217, Baltimore, MD, 21205, USA
| | - Michael Armour
- Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wenlian Zhu
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building 217, Baltimore, MD, 21205, USA
| | - John Wong
- Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kathleen L Gabrielson
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dmitri Artemov
- Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Traylor Building 217, Baltimore, MD, 21205, USA.
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