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Robertson N, Sempere L, Kenyon E, Mallet C, Smith K, Hix J, Halim A, Fan J, Moore A. Omniparticle Contrast Agent for Multimodal Imaging: Synthesis and Characterization in an Animal Model. Mol Imaging Biol 2023; 25:401-412. [PMID: 36071300 PMCID: PMC9989039 DOI: 10.1007/s11307-022-01770-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 10/14/2022]
Abstract
PURPOSE Individual imaging modalities have certain advantages, but each suffers from drawbacks that other modalities may overcome. The goal of this study was to create a novel contrast agent suitable for various imaging modalities that after a single administration can bridge and strengthen the collaboration between the research fields as well as enrich the information obtained from any one modality. PROCEDURES The contrast agent platform is based on dextran-coated iron oxide nanoparticles (for MRI and MPI) and synthesized using a modified co-precipitation method, followed by a series of conjugation steps with a fluorophore (for fluorescence and photoacoustic imaging), thyroxine (for CT imaging), and chelators for radioisotope labeling (for PET imaging). The fully conjugated agent was then tested in vitro in cell uptake, viability, and phantom studies and in vivo in a model of intraductal injection and in a tumor model. RESULTS The agent was synthesized, characterized, and tested in vitro where it showed the ability to produce a signal on MRI/MPI/FL/PA/CT and PET images. Studies in cells showed the expected concentration-dependent uptake of the agent without noticeable toxicity. In vivo studies demonstrated localization of the agent to the ductal tree in mice after intraductal injection with different degrees of resolution, with CT being the best for this particular application. In a model of injected labeled tumor cells, the agent produced a signal with all modalities and showed persistence in tumor cells confirmed by histology. CONCLUSIONS A fully functional omniparticle contrast agent was synthesized and tested in vitro and in vivo in two animal models. Results shown here point to the generation of a potent signal in all modalities tested without detrimental toxicity. Future use of this agent includes its exploration in various models of human disease including image-guided diagnostic and therapeutic applications.
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Affiliation(s)
- Neil Robertson
- Precision Health Program, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
| | - Lorenzo Sempere
- Precision Health Program, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
| | - Elizabeth Kenyon
- Precision Health Program, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
| | - Christiane Mallet
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 775 Woodlot Drive, East Lansing, MI, 48824, USA
| | - Kylie Smith
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 775 Woodlot Drive, East Lansing, MI, 48824, USA
- Department of Biomedical Engineering, College of Engineering, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
| | - Jeremy Hix
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 775 Woodlot Drive, East Lansing, MI, 48824, USA
| | - Alan Halim
- Precision Health Program, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
| | - Jinda Fan
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA
- Institute for Quantitative Health Science and Engineering, Michigan State University, 775 Woodlot Drive, East Lansing, MI, 48824, USA
- Department of Biomedical Engineering, College of Engineering, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA
| | - Anna Moore
- Precision Health Program, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, 766 Service Road, East Lansing, MI, 48824, USA.
- Department of Chemistry, College of Natural Sciences, Michigan State University, 578 S Shaw Lane, East Lansing, MI, 48824, USA.
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Puskar A, Saadah B, Rauf A, Kasperek SR, Umair M. A primer on contrast agents for magnetic resonance imaging of post‐procedural and follow‐up imaging of islet cell transplant. NANO SELECT 2023. [DOI: 10.1002/nano.202200147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
Affiliation(s)
- Anessa Puskar
- Carle Illinois College of Medicine Urbana‐Champaign Urbana Illinois USA
| | - Bara Saadah
- Carle Illinois College of Medicine Urbana‐Champaign Urbana Illinois USA
| | - Asad Rauf
- Carle Illinois College of Medicine Urbana‐Champaign Urbana Illinois USA
| | | | - Muhammad Umair
- Department of Radiology Johns Hopkins Baltimore Maryland USA
- Department of Biomedical Engineering University of Illinois Urbana‐Champaign Urbana Illinois USA
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3
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Sun A, Kenyon E, Gudi M, Li W, Aguirre A, Wang P. In Vivo Bioluminescence for the Detection of the Fate of Pancreatic Islet Organoids Post-transplantation. Methods Mol Biol 2023; 2592:195-206. [PMID: 36507995 DOI: 10.1007/978-1-0716-2807-2_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic islet transplantation is a promising cell replacement treatment for patients afflicted with type 1 diabetes (T1D), which is an autoimmune disease resulting in the destruction of insulin-producing islet β-cells. However, the shortage of donor pancreatic islets significantly hampers the widespread application of this strategy as routine therapy. Pluripotent stem cell-derived insulin-producing islet organoids constitute a promising alternative β-cell source for T1D patients. Early after transplantation, it is critical to know the fate of transplanted islet organoids, but determining their survival remains a significant technical challenge. Bioluminescence imaging (BLI) is an optical molecular imaging technique that detects the survival of living cells using light emitted from luciferase-expressing bioreporter cells. Through BLI, the post-transplantation fate of islet organoids can be evaluated over time in a noninvasive fashion with minimal intervention, thus making BLI an ideal tool to determine the success of the transplant and improving cell replacement therapy approaches for T1D.
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Affiliation(s)
- Aixia Sun
- Precision Health Program, Michigan State University, East Lansing, MI, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Elizabeth Kenyon
- Precision Health Program, Michigan State University, East Lansing, MI, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Mithil Gudi
- Precision Health Program, Michigan State University, East Lansing, MI, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Wen Li
- Institute for Quantitative Health Science and Engineering (IQ), East Lansing, MI, USA
- Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI, USA
| | - Aitor Aguirre
- Institute for Quantitative Health Science and Engineering (IQ), East Lansing, MI, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
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4
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Yamada K, Eisenson DL, Chen X, Ji L, Santillan MR, Moore A. Vascularized Islet Transplantation as Composite Islet-Kidney Grafts with Nanoparticle-Labeled Islets in Large Animal Preclinical Transplant Models. Methods Mol Biol 2023; 2592:233-249. [PMID: 36507998 PMCID: PMC11462519 DOI: 10.1007/978-1-0716-2807-2_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although there are many patients with diabetes and end-stage renal failure (DM/ESRD) who would benefit from a transplantation strategy that addresses both their ESRD and its underlying cause, current methods of islet and kidney transplantation using live donors have had only limited success. The first major obstacle is that the number of islets obtained from a live donor partial pancreatectomy is generally insufficient to cure diabetes in recipients, as large numbers of intraportally administered islets are lost due to ischemia before they are engrafted and vascularized in the recipient liver. To overcome this hurdle, we have developed a strategy to transplant islets as a vascularized graft. Autologous prevascularization of donor islets under the donor's own renal capsule prior to transplantation preserves islets and thus achieves normal glycemic control in diabetic recipients in our preclinical transplant models with a limited donor pancreas resection. In addition, from an immunological perspective, the innate tolerogenic qualities of the kidney provide immunoprotection for the engrafted, vascularized islets when they are transplanted as part of the composite islet-kidney (I-K) grafts. This "Trojan Horse" approach of transplanting a composite I-K eliminates the lengthy time which is otherwise required for vascularization of intraportally administered free islets, minimizing loss of islets to ischemic damage and facilitating the induction of tolerance. We have also recently developed a strategy to further minimize the required size of resected donor pancreas to prepare composite I-K graft using a novel, synthesized, small interfering RNA (siRNA)-nanoparticle probe. In this chapter, we introduce our living donor transplantation strategy to cure diabetic nephropathy using composite I-K graft.
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Affiliation(s)
- Kazuhiko Yamada
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Daniel L Eisenson
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xiaojuan Chen
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Lei Ji
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Michelle R Santillan
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
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5
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Nigam S, Moore A, Wang P. miRNA Theranostic Nanoparticles Promote Pancreatic Beta Cell Proliferation in Type 1 Diabetes Model. Methods Mol Biol 2023; 2592:207-218. [PMID: 36507996 DOI: 10.1007/978-1-0716-2807-2_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder which affects the insulin-producing beta cells in the pancreas. A variety of strategies, namely, insulin replacement therapy, engineered vaccines, immunomodulators, etc., have been explored to correct this condition. Recent studies have attributed the development of T1D to the anomalous expression of microRNAs in the pancreatic islets. Here, we describe the protocol for the development of a theranostic approach to modify the expression of aberrant miRNAs. The MRI-based nanodrug consists of superparamagnetic iron oxide nanoparticles conjugated to microRNA-targeting oligonucleotides that can promote proliferation of pancreatic beta cells in a mouse model of T1D. This theranostic approach can successfully serve as a potential therapeutic approach for the targeted treatment of T1D with minimal side effects.
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Affiliation(s)
- Saumya Nigam
- Precision Health Program, Michigan State University, East Lansing, MI, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
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6
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Synthesis of siRNA-Conjugated Dextran-Coated Iron Oxide Nanoparticles for Islet Protection During Transplantation and Noninvasive Imaging. Methods Mol Biol 2022; 2592:163-174. [PMID: 36507992 DOI: 10.1007/978-1-0716-2807-2_11] [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: 12/15/2022]
Abstract
Pancreatic islet transplantation (Tx) has a lifesaving potential for type 1 diabetes (T1D) patients. Islet damage during and after transplantation is one of the major reasons hampering its wide clinical application. Inability to monitor transplanted islets also severely limits our understanding of mechanisms regarding declining graft function after transplantation. Our team has proposed to use magnetic nanoparticles conjugated to siRNA (MN-siRNA) to label islets prior to transplantation with two goals in mind: to protect them from damage by silencing harmful genes and to monitor them after transplantation using noninvasive magnetic resonance imaging (MRI). This manuscript provides a step-by-step protocol for the synthesis and characterization of MN-siRNA probes.
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7
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Friedrich RP, Cicha I, Alexiou C. Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering. NANOMATERIALS 2021; 11:nano11092337. [PMID: 34578651 PMCID: PMC8466586 DOI: 10.3390/nano11092337] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022]
Abstract
In recent years, many promising nanotechnological approaches to biomedical research have been developed in order to increase implementation of regenerative medicine and tissue engineering in clinical practice. In the meantime, the use of nanomaterials for the regeneration of diseased or injured tissues is considered advantageous in most areas of medicine. In particular, for the treatment of cardiovascular, osteochondral and neurological defects, but also for the recovery of functions of other organs such as kidney, liver, pancreas, bladder, urethra and for wound healing, nanomaterials are increasingly being developed that serve as scaffolds, mimic the extracellular matrix and promote adhesion or differentiation of cells. This review focuses on the latest developments in regenerative medicine, in which iron oxide nanoparticles (IONPs) play a crucial role for tissue engineering and cell therapy. IONPs are not only enabling the use of non-invasive observation methods to monitor the therapy, but can also accelerate and enhance regeneration, either thanks to their inherent magnetic properties or by functionalization with bioactive or therapeutic compounds, such as drugs, enzymes and growth factors. In addition, the presence of magnetic fields can direct IONP-labeled cells specifically to the site of action or induce cell differentiation into a specific cell type through mechanotransduction.
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8
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Sun A, Hayat H, Liu S, Tull E, Bishop JO, Dwan BF, Gudi M, Talebloo N, Dizon JR, Li W, Gaudet J, Alessio A, Aguirre A, Wang P. 3D in vivo Magnetic Particle Imaging of Human Stem Cell-Derived Islet Organoid Transplantation Using a Machine Learning Algorithm. Front Cell Dev Biol 2021; 9:704483. [PMID: 34458264 PMCID: PMC8397508 DOI: 10.3389/fcell.2021.704483] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/15/2021] [Indexed: 12/17/2022] Open
Abstract
Stem cell-derived islet organoids constitute a promising treatment of type 1 diabetes. A major hurdle in the field is the lack of appropriate in vivo method to determine graft outcome. Here, we investigate the feasibility of in vivo tracking of transplanted stem cell-derived islet organoids using magnetic particle imaging (MPI) in a mouse model. Human induced pluripotent stem cells-L1 were differentiated to islet organoids and labeled with superparamagnetic iron oxide nanoparticles. The phantoms comprising of different numbers of labeled islet organoids were imaged using an MPI system. Labeled islet organoids were transplanted into NOD/scid mice under the left kidney capsule and were then scanned using 3D MPI at 1, 7, and 28 days post transplantation. Quantitative assessment of the islet organoids was performed using the K-means++ algorithm analysis of 3D MPI. The left kidney was collected and processed for immunofluorescence staining of C-peptide and dextran. Islet organoids expressed islet cell markers including insulin and glucagon. Image analysis of labeled islet organoids phantoms revealed a direct linear correlation between the iron content and the number of islet organoids. The K-means++ algorithm showed that during the course of the study the signal from labeled islet organoids under the left kidney capsule decreased. Immunofluorescence staining of the kidney sections showed the presence of islet organoid grafts as confirmed by double staining for dextran and C-peptide. This study demonstrates that MPI with machine learning algorithm analysis can monitor islet organoids grafts labeled with super-paramagnetic iron oxide nanoparticles and provide quantitative information of their presence in vivo.
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Affiliation(s)
- Aixia Sun
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Hasaan Hayat
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States
| | - Sihai Liu
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
- Department of Orthopedics, Beijing Charity Hospital, Capital Medical University, Beijing, China
| | - Eliah Tull
- Medgar Evers College, City University of New York, Brooklyn, NY, United States
| | - Jack Owen Bishop
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Neuroscience, College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Bennett Francis Dwan
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Mithil Gudi
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States
| | - Nazanin Talebloo
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - James Raynard Dizon
- Department of Radiology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Wen Li
- Department of Electrical and Computer Engineering, College of Engineering, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States
| | - Jeffery Gaudet
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States
- Magnetic Insight Inc., Alameda, CA, United States
| | - Adam Alessio
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States
- Department of Computational Mathematics, Science and Engineering, College of Engineering, Michigan State University, East Lansing, MI, United States
| | - Aitor Aguirre
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
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Hayat H, Nukala A, Nyamira A, Fan J, Wang P. A concise review: the synergy between artificial intelligence and biomedical nanomaterials that empowers nanomedicine. Biomed Mater 2021; 16:052001. [PMID: 34280907 DOI: 10.1088/1748-605x/ac15b2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/19/2021] [Indexed: 12/17/2022]
Abstract
Nanomedicine has recently experienced unprecedented growth and development. However, the complexity of operations at the nanoscale introduces a layer of difficulty in the clinical translation of nanodrugs and biomedical nanotechnology. This problem is further exacerbated when engineering and optimizing nanomaterials for biomedical purposes. To navigate this issue, artificial intelligence (AI) algorithms have been applied for data analysis and inference, allowing for a more applicable understanding of the complex interaction amongst the abundant variables in a system involving the synthesis or use of nanomedicine. Here, we report on the current relationship and implications of nanomedicine and AI. Particularly, we explore AI as a tool for enabling nanomedicine in the context of nanodrug screening and development, brain-machine interfaces and nanotoxicology. We also report on the current state and future direction of nanomedicine and AI in cancer, diabetes, and neurological disorder therapy.
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Affiliation(s)
- Hasaan Hayat
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States of America
| | - Arijit Nukala
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America
| | - Anthony Nyamira
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States of America
| | - Jinda Fan
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States of America
| | - Ping Wang
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States of America
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10
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Shende P, Trivedi R. Nanotheranostics in epilepsy: A perspective for multimodal diagnosis and strategic management. NANO SELECT 2021. [DOI: 10.1002/nano.202000141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS Vile Parle (W) Mumbai India
| | - Riddhi Trivedi
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS Vile Parle (W) Mumbai India
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Szunerits S, Melinte S, Barras A, Pagneux Q, Voronova A, Abderrahmani A, Boukherroub R. The impact of chemical engineering and technological advances on managing diabetes: present and future concepts. Chem Soc Rev 2021; 50:2102-2146. [PMID: 33325917 DOI: 10.1039/c9cs00886a] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Monitoring blood glucose levels for diabetic patients is critical to achieve tight glycaemic control. As none of the current antidiabetic treatments restore lost functional β-cell mass in diabetic patients, insulin injections and the use of insulin pumps are most widely used in the management of glycaemia. The use of advanced and intelligent chemical engineering, together with the incorporation of micro- and nanotechnological-based processes have lately revolutionized diabetic management. The start of this concept goes back to 1974 with the description of an electrode that repeatedly measures the level of blood glucose and triggers insulin release from an infusion pump to enter the blood stream from a small reservoir upon need. Next to the insulin pumps, other drug delivery routes, including nasal, transdermal and buccal, are currently investigated. These processes necessitate competences from chemists, engineers-alike and innovative views of pharmacologists and diabetologists. Engineered micro and nanostructures hold a unique potential when it comes to drug delivery applications required for the treatment of diabetic patients. As the technical aspects of chemistry, biology and informatics on medicine are expanding fast, time has come to step back and to evaluate the impact of technology-driven chemistry on diabetics and how the bridges from research laboratories to market products are established. In this review, the large variety of therapeutic approaches proposed in the last five years for diabetic patients are discussed in an applied context. A survey of the state of the art of closed-loop insulin delivery strategies in response to blood glucose level fluctuation is provided together with insights into the emerging key technologies for diagnosis and drug development. Chemical engineering strategies centered on preserving and regenerating functional pancreatic β-cell mass are evoked in addition as they represent a permanent solution for diabetic patients.
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Affiliation(s)
- Sabine Szunerits
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
| | - Sorin Melinte
- Institute of Information and Communication Technologies, Electronics and Applied Mathematics, Université catholique de Louvain, 1348 Louvain-la-Neuve, Belgium
| | - Alexandre Barras
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
| | - Quentin Pagneux
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
| | - Anna Voronova
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
| | - Rabah Boukherroub
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520-IEMN, F-59000 Lille, France.
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12
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Pomposelli T, Schuetz C, Wang P, Yamada K. A Strategy to Simultaneously Cure Type 1 Diabetes and Diabetic Nephropathy by Transplant of Composite Islet-Kidney Grafts. Front Endocrinol (Lausanne) 2021; 12:632605. [PMID: 34054721 PMCID: PMC8153710 DOI: 10.3389/fendo.2021.632605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 04/16/2021] [Indexed: 11/13/2022] Open
Abstract
In recent years islet cell transplant has proven itself to be a viable clinical option for a select group of diabetic patients. Graft loss after transplant however continues to hinder the long-term success of the procedure. Transplanting the islets as a pre-vascularized composite islet-kidney graft has emerged as a relevant solution. Much groundbreaking research has been done utilizing this model in conjunction with strategies aimed towards islet cell survival and prolongation of function in the host. Transplanting the islet cells as a prevascularized graft under the capsule of the donor kidney as a composite islet-kidney graft has been shown to provide long term durable blood glucose control in large animal studies by limiting graft apoptosis as well as providing a physical barrier against the host immune response. While promising, this technique is limited by long term immunosuppression requirements of the host with its well-known adverse sequelae. Research into tolerance inducing strategies of the host to the allogeneic and xenogeneic islet-kidney graft has shown much promise in the avoidance of long-term immunosuppression. In addition, utilizing xenogeneic tissue grafts could provide a near-limitless supply of organs. The islet-kidney model could provide a durable and long-term cure for diabetes. Here we summarize the most recent data, as well as groundbreaking strategies to avoid long term immunosuppression and promote graft acceptance.
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Affiliation(s)
- Thomas Pomposelli
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, United States
| | - Christian Schuetz
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI, United States
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Kazuhiko Yamada
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, United States
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13
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Hayat H, Sun A, Hayat H, Liu S, Talebloo N, Pinger C, Bishop JO, Gudi M, Dwan BF, Ma X, Zhao Y, Moore A, Wang P. Artificial Intelligence Analysis of Magnetic Particle Imaging for Islet Transplantation in a Mouse Model. Mol Imaging Biol 2021; 23:18-29. [PMID: 32833112 PMCID: PMC7785569 DOI: 10.1007/s11307-020-01533-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Current approaches to quantification of magnetic particle imaging (MPI) for cell-based therapy are thwarted by the lack of reliable, standardized methods of segmenting the signal from background in images. This calls for the development of artificial intelligence (AI) systems for MPI analysis. PROCEDURES We utilize a canonical algorithm in the domain of unsupervised machine learning, known as K-means++, to segment the regions of interest (ROI) of images and perform iron quantification analysis using a standard curve model. We generated in vitro, in vivo, and ex vivo data using islets and mouse models and applied the AI algorithm to gain insight into segmentation and iron prediction on these MPI data. In vitro models included imaging the VivoTrax-labeled islets in varying numbers. In vivo mouse models were generated through transplantation of increasing numbers of the labeled islets under the kidney capsule of mice. Ex vivo data were obtained from the MPI images of excised kidney grafts. RESULTS The K-means++ algorithms segmented the ROI of in vitro phantoms with minimal noise. A linear correlation between the islet numbers and the increasing prediction of total iron value (TIV) in the islets was observed. Segmentation results of the ROI of the in vivo MPI scans showed that with increasing number of transplanted islets, the signal intensity increased with linear trend. Upon segmenting the ROI of ex vivo data, a linear trend was observed in which increasing intensity of the ROI yielded increasing TIV of the islets. Through statistical evaluation of the algorithm performance via intraclass correlation coefficient validation, we observed excellent performance of K-means++-based model on segmentation and quantification analysis of MPI data. CONCLUSIONS We have demonstrated the ability of the K-means++-based model to provide a standardized method of segmentation and quantification of MPI scans in an islet transplantation mouse model.
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Affiliation(s)
- Hasaan Hayat
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Aixia Sun
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Hanaan Hayat
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Sihai Liu
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Orthopedics, Beijing Charity Hospital, Capital Medical University, Beijing, China
| | - Nazanin Talebloo
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Cody Pinger
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Jack Owen Bishop
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Neuroscience, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Mithil Gudi
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Bennett Francis Dwan
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Xiaohong Ma
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Zhao
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anna Moore
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Ping Wang
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
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14
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Pomposelli T, Wang P, Takeuchi K, Miyake K, Ariyoshi Y, Watanabe H, Chen X, Shimizu A, Robertson N, Yamada K, Moore A. Protection of Pancreatic Islets Using Theranostic Silencing Nanoparticles in a Baboon Model of Islet Transplantation. Diabetes 2020; 69:2414-2422. [PMID: 32855170 PMCID: PMC7576559 DOI: 10.2337/db20-0517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/24/2020] [Indexed: 12/15/2022]
Abstract
The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation, and other factors continues to limit Tx efficacy. In this project, we demonstrate a novel approach aimed at protecting islets before Tx in nonhuman primates (NHPs) (baboons) by silencing a gene (caspase-3) responsible for induction of apoptosis. This was done using siRNA (siCas-3) conjugated to magnetic nanoparticles (MNs). In addition to serving as carriers for siCas-3, these nanoparticles also act as reporters for MRI, so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the antiapoptotic effect of MN-siCas-3 on islets in culture, resulting in minimal islet loss. For in vivo studies, donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted with even a marginal number of labeled islets compared with controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaveric or living donors.
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Affiliation(s)
- Thomas Pomposelli
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
| | - Kazuhiro Takeuchi
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Katsunori Miyake
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Yuichi Ariyoshi
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Hironosuke Watanabe
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Xiaojuan Chen
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Akira Shimizu
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Neil Robertson
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
| | - Kazuhiko Yamada
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
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15
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Current Progress and Perspective: Clinical Imaging of Islet Transplantation. Life (Basel) 2020; 10:life10090213. [PMID: 32961769 PMCID: PMC7555367 DOI: 10.3390/life10090213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 12/13/2022] Open
Abstract
Islet transplantation has great potential as a cure for type 1 diabetes. At present; the lack of a clinically validated non-invasive imaging method to track islet grafts limits the success of this treatment. Some major clinical imaging modalities and various molecular probes, which have been studied for non-invasive monitoring of transplanted islets, could potentially fulfill the goal of understanding pathophysiology of the functional status and viability of the islet grafts. In this current review, we summarize the recent clinical studies of a variety of imaging modalities and molecular probes for non-invasive imaging of transplanted beta cell mass. This review also includes discussions on in vivo detection of endogenous beta cell mass using clinical imaging modalities and various molecular probes, which will be useful for longitudinally detecting the status of islet transplantation in Type 1 diabetic patients. For the conclusion and perspectives, we highlight the applications of multimodality and novel imaging methods in islet transplantation.
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16
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Wang P, Liu Q, Zhao H, Bishop JO, Zhou G, Olson LK, Moore A. miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model. Sci Rep 2020; 10:5302. [PMID: 32210316 PMCID: PMC7093482 DOI: 10.1038/s41598-020-62269-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 03/06/2020] [Indexed: 11/30/2022] Open
Abstract
Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, βTC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulin-producing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.
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Affiliation(s)
- Ping Wang
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan, 48823, USA.
| | - Qiong Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Fudan University, Shanghai, 200032, China
| | - Hongwei Zhao
- Shanxi Medical University, Taiyuan, Shanxi, 030001, China
- Department of Gynecologic Oncology, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi, 030013, China
| | - Jack Owen Bishop
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan, 48823, USA
- Department of Neuroscience, College of Natural Science, Michigan State University, East Lansing, Michigan, 48824, USA
| | - Guoli Zhou
- Biomedical Research Informatics Core, Clinical & Translational Sciences Institute, Michigan State University, East Lansing, Michigan, 48824, USA
| | - L Karl Olson
- Department of Physiology, College of Natural Science, Michigan State University, East Lansing, Michigan, 48824, USA
| | - Anna Moore
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan, 48823, USA.
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17
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Zheng L, Wang Y, Yang B, Zhang B, Wu Y. Islet Transplantation Imaging in vivo. Diabetes Metab Syndr Obes 2020; 13:3301-3311. [PMID: 33061492 PMCID: PMC7520574 DOI: 10.2147/dmso.s263253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 07/29/2020] [Indexed: 12/31/2022] Open
Abstract
Although islet transplantation plays an effective and powerful role in the treatment of diabetes, a large amount of islet grafts are lost at an early stage due to instant blood-mediated inflammatory reactions, immune rejection, and β-cell toxicity resulting from immunosuppressive agents. Timely intervention based on the viability and function of the transplanted islets at an early stage is crucial. Various islet transplantation imaging techniques are available for monitoring the conditions of post-transplanted islets. Due to the development of various imaging modalities and the continuous study of contrast agents, non-invasive islet transplantation imaging in vivo has made great progress. The tracing and functional evaluation of transplanted islets in vivo have thus become possible. However, most studies on contrast agent and imaging modalities are limited to animal experiments, and long-term toxicity and stability need further evaluation. Accordingly, the clinical application of the current achievements still requires a large amount of effort. In this review, we discuss the contrast agents for MRI, SPECT/PET, BLI/FI, US, MPI, PAI, and multimodal imaging. We further summarize the advantages and limitations of various molecular imaging methods.
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Affiliation(s)
- Lei Zheng
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Yinghao Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Bin Yang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Bo Zhang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Correspondence: Bo Zhang; Yulian Wu Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China Tel/Fax +86 571 87783563 Email ;
| | - Yulian Wu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
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18
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Dwan BF, Moore A, Wang P. Nucleic acid-based theranostics in type 1 diabetes. Transl Res 2019; 214:50-61. [PMID: 31491371 DOI: 10.1016/j.trsl.2019.08.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 08/01/2019] [Accepted: 08/17/2019] [Indexed: 12/12/2022]
Abstract
Application of RNAi interference for type 1 diabetes (T1D) therapy bears tremendous potential. This review will discuss vehicles for oligonucleotide delivery, imaging modalities used for delivery monitoring, therapeutic targets, and different theranostic strategies that can be applied for T1D treatment.
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Affiliation(s)
- Bennett Francis Dwan
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan; College of Natural Science, Michigan State University, East Lansing, Michigan
| | - Anna Moore
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan
| | - Ping Wang
- Precision Health Program, Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, Michigan.
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19
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Avcıbaşı U, Ateş B, Ünak P, Gümüşer FG, Gülcemal S, Ol KK, Akgöl S, Tekin V. A novel radiolabeled graft polymer: Investigation of the radiopharmaceutical potential using Albino Wistar rats. Appl Radiat Isot 2019; 154:108872. [PMID: 31470192 DOI: 10.1016/j.apradiso.2019.108872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/31/2019] [Accepted: 08/21/2019] [Indexed: 12/23/2022]
Abstract
Fe3O4 magnetic graft-Lys-poly(HEMA) was synthesized, labeled with 99mTc for the first time and its radiopharmaceutical potential was investigated using animal models in this study. Quality control procedures were carried out using thin layer radiochromatography. The labeling yield of radiolabeled polymer was found to be about 100%. Then, stability and lipophilicity were determined. The lipophilicity of 99mTc labeled Fe3O4 graft-Lys-poly(HEMA) was found to be 3.77. The serum stability experiments demonstrated that approximately 100% of radiolabeled polymer existed as an intact complex in the rat serum within 240 min. Biodistribution of radiolabeled magnetic graft-Lys-poly(HEMA) was performed on female Albino Wistar rats by scintigraphy and biodistribution studies. High uptake was seen in the stomach, the pancreas, brain, ovarian, intestines and the breast.
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Affiliation(s)
- Uğur Avcıbaşı
- Department of Chemistry, Manisa Celal Bayar University, Faculty of Art and Science, 45140, Manisa, Turkey.
| | - Buket Ateş
- Department of Chemistry, Manisa Celal Bayar University, Faculty of Art and Science, 45140, Manisa, Turkey
| | - Perihan Ünak
- Institute of Nuclear Sciences, Ege University, Department of Nuclear Applications, 35100, İzmir, Turkey
| | - Fikriye Gül Gümüşer
- Department of Nuclear Medicine, Manisa Celal Bayar University, School of Medicine, 45030, Manisa, Turkey
| | - Süleyman Gülcemal
- Department of Chemistry, Ege University, Faculty of Science, 35100, Izmir, Turkey
| | - Kevser Kusat Ol
- Turkish Health of Ministry, Turkish Medicines and Medical Devices Agency, Ankara, Turkey
| | - Sinan Akgöl
- Department of Biochemistry, Faculty of Science, Ege University, 35100, İzmir, Turkey
| | - Volkan Tekin
- Institute of Nuclear Sciences, Ege University, Department of Nuclear Applications, 35100, İzmir, Turkey
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20
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Cruz-Acuña M, Halman JR, Afonin KA, Dobson J, Rinaldi C. Magnetic nanoparticles loaded with functional RNA nanoparticles. NANOSCALE 2018; 10:17761-17770. [PMID: 30215080 DOI: 10.1039/c8nr04254c] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
RNA is now widely acknowledged not only as a multifunctional biopolymer but also as a dynamic material for constructing nanostructures with various biological functions. Programmable RNA nanoparticles (NPs) allow precise control over their formulation and activation of multiple functionalities, with the potential to self-assemble in biological systems. These attributes make them attractive for drug delivery and therapeutic applications. In the present study, we demonstrate the ability of iron oxide magnetic nanoparticles (MNPs) to deliver different types of RNA NPs functionalized with dicer substrate RNAs inside human cells. Our results show that use of functionalized RNA NPs result in statistically higher transfection efficiency compared to the use of RNA duplexes. Furthermore, we show that the nucleic acids in the MNP/RNA NP complexes are protected from nuclease degradation and that they can achieve knockdown of target protein expression, which is amplified by magnetic stimulus. The current work represents the very first report indicating that iron oxide nanoparticles may efficiently protect and deliver programmable RNA NPs to human cells.
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Affiliation(s)
- Melissa Cruz-Acuña
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Biomedical Sciences Building JG-56, P.O. Box 116131, Gainesville, Florida 32611, USA.
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21
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Wang P, Goodwill PW, Pandit P, Gaudet J, Ross A, Wang J, Yu E, Hensley DW, Doyle TC, Contag CH, Conolly S, Moore A. Magnetic particle imaging of islet transplantation in the liver and under the kidney capsule in mouse models. Quant Imaging Med Surg 2018; 8:114-122. [PMID: 29675353 DOI: 10.21037/qims.2018.02.06] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background Islet transplantation (Tx) represents the most promising therapy to restore normoglycemia in type 1 diabetes (T1D) patients to date. As significant islet loss has been observed after the procedure, there is an urgent need for developing strategies for monitoring transplanted islet grafts. In this report we describe for the first time the application of magnetic particle imaging (MPI) for monitoring transplanted islets in the liver and under the kidney capsule in experimental animals. Methods Pancreatic islets isolated from Papio hamadryas were labeled with superparamagnetic iron oxides (SPIOs) and used for either islet phantoms or Tx in the liver or under the kidney capsule of NOD scid mice. MPI was used to image and quantify islet phantoms and islet transplanted experimental animals post-mortem at 1 and 14 days after Tx. Magnetic resonance imaging (MRI) was used to confirm the presence of labeled islets in the liver and under the kidney capsule 1 day after Tx. Results MPI of labeled islet phantoms confirmed linear correlation between the number of islets and the MPI signal (R2=0.988). Post-mortem MPI performed on day 1 after Tx showed high signal contrast in the liver and under the kidney capsule. Quantitation of the signal supports islet loss over time, which is normally observed 2 weeks after Tx. No MPI signal was observed in control animals. In vivo MRI confirmed the presence of labeled islets/islet clusters in liver parenchyma and under the kidney capsule one day after Tx. Conclusions Here we demonstrate that MPI can be used for quantitative detection of labeled pancreatic islets in the liver and under the kidney capsule of experimental animals. We believe that MPI, a modality with no depth attenuation and zero background tissue signal could be a suitable method for imaging transplanted islet grafts.
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Affiliation(s)
- Ping Wang
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Precision Health Program, Department of Radiology, Michigan State University, East Lansing, MI, USA
| | - Patrick W Goodwill
- Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA.,Magnetic Insight, Inc., Alameda, CA, USA
| | | | | | - Alana Ross
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Junfeng Wang
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Elaine Yu
- Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA
| | - Daniel W Hensley
- Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA
| | - Timothy C Doyle
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Christopher H Contag
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.,Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Steven Conolly
- Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA
| | - Anna Moore
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Precision Health Program, Department of Radiology, Michigan State University, East Lansing, MI, USA
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22
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Duong C, Yoshida S, Chen C, Barisone G, Diaz E, Li Y, Beckett L, Chung J, Antony R, Nolta J, Nitin N, Satake N. Novel targeted therapy for neuroblastoma: silencing the MXD3 gene using siRNA. Pediatr Res 2017; 82:527-535. [PMID: 28419087 PMCID: PMC5766270 DOI: 10.1038/pr.2017.74] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 02/03/2017] [Accepted: 02/26/2017] [Indexed: 12/13/2022]
Abstract
BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real-time reverse transcription PCR, and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single-agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide-common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, on combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionThese results indicate that MXD3 is a potential new target and that the use of MXD3 siRNA nanocomplexes is a novel therapeutic approach for neuroblastoma.
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Affiliation(s)
- Connie Duong
- Department of Pediatrics, University of California, Davis, California,Stem Cell Program, University of California, Davis, California
| | - Sakiko Yoshida
- Department of Pediatrics, University of California, Davis, California,Stem Cell Program, University of California, Davis, California,Department of Pediatrics, Niigata University, Japan
| | - Cathy Chen
- Department of Pediatrics, University of California, Davis, California,Stem Cell Program, University of California, Davis, California
| | - Gustavo Barisone
- Department of Pharmacology, University of California, Davis, California,Department of Internal Medicine, University of California, Davis, California
| | - Elva Diaz
- Department of Pharmacology, University of California, Davis, California
| | - Yueju Li
- Department of Public Health Sciences, University of California, Davis, California
| | - Laurel Beckett
- Department of Public Health Sciences, University of California, Davis, California
| | - Jong Chung
- Department of Pediatrics, University of California, Davis, California
| | - Reuben Antony
- Department of Pediatrics, University of California, Davis, California
| | - Jan Nolta
- Stem Cell Program, University of California, Davis, California
| | - Nitin Nitin
- Department of Biological & Agricultural Engineering, University of California, Davis, California
| | - Noriko Satake
- Department of Pediatrics, University of California, Davis, California,Stem Cell Program, University of California, Davis, California,Corresponding author: Noriko Satake, Department of Pediatrics, 2516 Stockton Blvd., Sacramento, CA 95817, Phone: 916-734-2781, FAX: 916-451-3014,
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Ito K, Ookawara S, Ishibashi K, Morishita Y. Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus. NANO REVIEWS & EXPERIMENTS 2017; 8:1341758. [PMID: 30410709 PMCID: PMC6167029 DOI: 10.1080/20022727.2017.1341758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/05/2017] [Indexed: 11/09/2022]
Abstract
Gene therapy that targets the pancreas and intestines with delivery systems using nano-sized carriers such as viral and non-viral vectors could improve the control of blood glucose levels, resulting in an improved prognosis for patients with diabetes mellitus. Allogenic pancreatic islet cell transplantations using such delivery systems have been developed as therapeutic options for diabetes mellitus. This review focuses on transgenes and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus.
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Affiliation(s)
- Kiyonori Ito
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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24
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Paredes-Juarez GA, de Vos P, Bulte JWM. Recent progress in the use and tracking of transplanted islets as a personalized treatment for type 1 diabetes. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017; 2:57-67. [PMID: 29276781 PMCID: PMC5737787 DOI: 10.1080/23808993.2017.1302305] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the pancreas produces insufficient amounts of insulin. T1DM patients require exogenous sources of insulin to maintain euglycemia. Transplantation of naked or microencapsulated pancreatic islets represents an alternative paradigm to obtain an autonomous regulation of blood glucose levels in a controlled and personalized fashion. However, once transplanted, the fate of these personalized cellular therapeutics is largely unknown, justifying the development of non-invasive tracking techniques. AREAS COVERED In vivo imaging of naked pancreatic islet transplantation, monitoring of microencapsulated islet transplantation, visualizing pancreatic inflammation, imaging of molecular-genetic therapeutics, imaging of beta cell function. EXPERT COMMENTARY There are still several hurdles to overcome before (microencapsulated) islet cell transplantation will become a mainstay therapy. Non-invasive imaging methods that can track graft volume, graft rejection, graft function (insulin secretion) microcapsule engraftment, microcapsule rupture, and pancreatic inflammation are currently being developed to design the best experimental transplantation paradigms.
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Affiliation(s)
- Genaro A Paredes-Juarez
- Russell H. Morgan Department of Radiology, Division of Magnetic Resonance Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Paul de Vos
- University Medical Center Groningen (UMCG), Department of Pathology and Medical Biology, Section Immunoendocrinology. Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Jeff W M Bulte
- Russell H. Morgan Department of Radiology, Division of Magnetic Resonance Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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25
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Wang P, Moore A. In Vivo Magnetic Resonance Imaging of Small Interfering RNA Nanodelivery to Pancreatic Islets. Methods Mol Biol 2016; 1372:25-36. [PMID: 26530912 DOI: 10.1007/978-1-4939-3148-4_2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Pancreatic islet transplantation is a promising therapeutic approach for type 1 diabetes.However, recent advances in islet transplantation are limited by significant graft loss after transplantation. Multiple immunological and nonimmunological factors contribute to this loss. Novel therapies that could target the core reasons for the islet graft loss are desperately needed. Small interfering RNA can be used to inhibit the expression of virtually any gene with single-nucleotide specificity including genes responsible for islet damage. Applying adequate delivery of siRNA molecules to pancreatic islets prior to transplantation holds a great potential for improving the survival of islet grafts. Noninvasive imaging provides means for monitoring the survival of transplanted islets in real time. Here, we summarize the approach that has been developed to deliver siRNA to pancreatic islets in conjunction with tracking of the graft outcome by in vivo magnetic resonance imaging (MRI). We synthesize a nano-sized theranostic agent consisting of magnetic nanoparticles (MN), a reporter for MRI, labeled with Cy5.5 dye for near-infrared fluorescence (NIRF) imaging, and conjugated to siRNA molecule targeting genes that are harmful to islet grafts. Pre-labeling of islets by MN-Cy5.5-siRNA allowed us to monitor the survival of transplanted islet grafts by MRI and NIRF imaging and resulted in efficient silencing of the target genes in vivo. This novel approach combines a therapeutic effect provided by RNA interference technology with in vivo MR imaging and is expected to significantly improve the outcome of islet transplantation in patients with type 1 diabetes.
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Affiliation(s)
- Ping Wang
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Building 75, 13th Street, Charlestown, MA, 02129, USA
- , Boston, USA
| | - Anna Moore
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Building 75, 13th Street, Charlestown, MA, 02129, USA.
- , Boston, USA.
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26
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Controlling RNA Expression in Cancer Using Iron Oxide Nanoparticles Detectable by MRI and In Vivo Optical Imaging. Methods Mol Biol 2016; 1372:163-79. [PMID: 26530923 DOI: 10.1007/978-1-4939-3148-4_13] [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] [Indexed: 02/04/2023]
Abstract
Herein, we describe a protocol for the preparation of iron oxide nanoparticle-based contrast agents and drug delivery vehicles for noninvasive cancer imaging and therapy. In the first part of the chapter we describe the details of the contrast agent synthesis, functionalization, and characterization. In the second part we describe the methods for tumor imaging using the synthesized particles with noninvasive T2-weighted magnetic resonance imaging (MRI) and in vivo near infrared optical imaging.
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27
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Kim JY. Current Prospects of RNA Interference-based Therapy in Organ Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2015. [DOI: 10.4285/jkstn.2015.29.3.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Jae Young Kim
- Department of Life Science, Gachon University, Seongnam, Korea
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28
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Yoo B, Ifediba MA, Ghosh S, Medarova Z, Moore A. Combination treatment with theranostic nanoparticles for glioblastoma sensitization to TMZ. Mol Imaging Biol 2015; 16:680-9. [PMID: 24696184 DOI: 10.1007/s11307-014-0734-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE Tumor resistance to chemotherapeutic drugs is one of the major obstacles in the treatment of glioblastoma multiforme (GBM). In this study, we attempted to modulate tumor response to chemotherapy by combination treatment that included experimental (small interference RNA (siRNA), chlorotoxin) and conventional (temozolomide, TMZ) therapeutics. PROCEDURES siRNA therapy was used to silence O(6)-methylguanine methyltransferase (MGMT), a key factor in brain tumor resistance to TMZ. For targeting of tumor cells, we used chlorotoxin (CTX), a peptide with antitumoral properties. siRNA and CTX were conjugated to iron oxide nanoparticles (NP) that served as the drug carrier and allowed the means to monitor the changes in tumor volume by magnetic resonance imaging (MRI). RESULTS Theranostic nanoparticles (termed CTX-NP-siMGMT) were internalized by T98G glioblastoma cells in vitro leading to enhancement of TMZ toxicity. Combination treatment of mice bearing orthotopic tumors with CTX-NP-siMGMT and TMZ led to significant retardation of tumor growth, which was monitored by MRI. CONCLUSIONS While our results demonstrate that siRNA delivery by targeted nanoparticles resulted in modulating tumor response to chemotherapy in GBM, they also point to a significant contribution of CTX to tumor cell death.
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Affiliation(s)
- Byunghee Yoo
- Molecular Imaging Laboratory, MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Building 75, 13th Street, Charlestown, MA, 02129, USA
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29
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Barsanti C, Lenzarini F, Kusmic C. Diagnostic and prognostic utility of non-invasive imaging in diabetes management. World J Diabetes 2015; 6:792-806. [PMID: 26131322 PMCID: PMC4478576 DOI: 10.4239/wjd.v6.i6.792] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/23/2014] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
Medical imaging technologies are acquiring an increasing relevance to assist clinicians in diagnosis and to guide management and therapeutic treatment of patients, thanks to their non invasive and high resolution properties. Computed tomography, magnetic resonance imaging, and ultrasonography are the most used imaging modalities to provide detailed morphological reconstructions of tissues and organs. In addition, the use of contrast dyes or radionuclide-labeled tracers permits to get functional and quantitative information about tissue physiology and metabolism in normal and disease state. In recent years, the development of multimodal and hydrid imaging techniques is coming to be the new frontier of medical imaging for the possibility to overcome limitations of single modalities and to obtain physiological and pathophysiological measurements within an accurate anatomical framework. Moreover, the employment of molecular probes, such as ligands or antibodies, allows a selective in vivo targeting of biomolecules involved in specific cellular processes, so expanding the potentialities of imaging techniques for clinical and research applications. This review is aimed to give a survey of characteristics of main diagnostic non-invasive imaging techniques. Current clinical appliances and future perspectives of imaging in the diagnostic and prognostic assessment of diabetic complications affecting different organ systems will be particularly addressed.
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30
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Serra P, Santamaria P. Nanoparticle-based autoimmune disease therapy. Clin Immunol 2015; 160:3-13. [PMID: 25704658 DOI: 10.1016/j.clim.2015.02.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 02/09/2015] [Accepted: 02/10/2015] [Indexed: 01/10/2023]
Abstract
The goal of immunotherapy against autoimmunity is to block pathogenic inflammation without impairing immunity against infections and tumours. Regulatory T-cells (Tregs) play a central role in maintaining immune homeostasis, and autoimmune inflammation is frequently associated with decreased numbers and/or function of these T-cells. Therapies harnessing Tregs to treat autoimmune inflammation remain under-developed with caveats ranging from the lack of antigenic and disease specificity to the potential phenotypic and functional instability of in vitro-expanded Treg cells in vivo. Here, we review nanotechnology-based approaches designed to promote immune tolerance through various mechanisms, ranging from systemic or local suppression of antigen-presenting cells and deletion of antigen-specific T-cells, to the systemic expansion of antigen- and disease-specific Treg cells in vivo.
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Affiliation(s)
- Pau Serra
- Institut D'Investigacions Biomediques August Pi i Sunyer, Barcelona 08036, Spain.
| | - Pere Santamaria
- Institut D'Investigacions Biomediques August Pi i Sunyer, Barcelona 08036, Spain; Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cummings School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
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31
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Balcioglu M, Rana M, Robertson N, Yigit MV. DNA-length-dependent quenching of fluorescently labeled iron oxide nanoparticles with gold, graphene oxide and MoS2 nanostructures. ACS APPLIED MATERIALS & INTERFACES 2014; 6:12100-12110. [PMID: 25014711 DOI: 10.1021/am503553h] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
We controlled the fluorescence emission of a fluorescently labeled iron oxide nanoparticle using three different nanomaterials with ultraefficient quenching capabilities. The control over the fluorescence emission was investigated via spacing introduced by the surface-functionalized single-stranded DNA molecules. DNA molecules were conjugated on different templates, either on the surface of the fluorescently labeled iron oxide nanoparticles or gold and nanographene oxide. The efficiency of the quenching was determined and compared with various fluorescently labeled iron oxide nanoparticle and nanoquencher combinations using DNA molecules with three different lengths. We have found that the template for DNA conjugation plays significant role on quenching the fluorescence emission of the fluorescently labeled iron oxide nanoparticles. We have observed that the size of the DNA controls the quenching efficiency when conjugated only on the fluorescently labeled iron oxide nanoparticles by setting a spacer between the surfaces and resulting change in the hydrodynamic size. The quenching efficiency with 12mer, 23mer and 36mer oligonucleotides decreased to 56%, 54% and 53% with gold nanoparticles, 58%, 38% and 32% with nanographene oxide, 46%, 38% and 35% with MoS2, respectively. On the other hand, the presence, not the size, of the DNA molecules on the other surfaces quenched the fluorescence significantly with different degrees. To understand the effect of the mobility of the DNA molecules on the nanoparticle surface, DNA molecules were attached to the surface with two different approaches. Covalently immobilized oligonucleotides decreased the quenching efficiency of nanographene oxide and gold nanoparticles to ∼22% and ∼21%, respectively, whereas noncovalently adsorbed oligonucleotides decreased it to ∼25% and ∼55%, respectively. As a result, we have found that each nanoquencher has a powerful quenching capability against a fluorescent nanoparticle, which can be tuned with surface functionalized DNA molecules.
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Affiliation(s)
- Mustafa Balcioglu
- Department of Chemistry and RNA Institute, University at Albany , SUNY, 1400 Washington Avenue, Albany, New York 12222, United States
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32
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Wang P, Yoo B, Yang J, Zhang X, Ross A, Pantazopoulos P, Dai G, Moore A. GLP-1R-targeting magnetic nanoparticles for pancreatic islet imaging. Diabetes 2014; 63:1465-74. [PMID: 24458362 PMCID: PMC4178324 DOI: 10.2337/db13-1543] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 01/19/2014] [Indexed: 12/19/2022]
Abstract
Noninvasive assessment of pancreatic β-cell mass would tremendously aid in managing type 1 diabetes (T1D). Toward this goal, we synthesized an exendin-4 conjugated magnetic iron oxide-based nanoparticle probe targeting glucagon-like peptide 1 receptor (GLP-1R), which is highly expressed on the surface of pancreatic β-cells. In vitro studies in βTC-6, the β-cell line, showed specific accumulation of the targeted probe (termed MN-Ex10-Cy5.5) compared with nontargeted (termed MN-Cy5.5). In vivo magnetic resonance imaging showed a significant transverse relaxation time (T2) shortening in the pancreata of mice injected with the MN-Ex10-Cy5.5 probe compared with control animals injected with the nontargeted probe at 7.5 and 24 h after injection. Furthermore, ΔT2 of the pancreata of prediabetic NOD mice was significantly higher than that of diabetic NOD mice after the injection of MN-Ex10-Cy5.5, indicating the decrease of probe accumulation in these animals due to β-cell loss. Of note, ΔT2 of prediabetic and diabetic NOD mice injected with MN-Cy5.5 was not significantly changed, reflecting the nonspecific mode of accumulation of nontargeted probe. We believe our results point to the potential for using this agent for monitoring the disease development and response of T1D to therapy.
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Affiliation(s)
- Ping Wang
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Byunghee Yoo
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Jingsheng Yang
- Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Xueli Zhang
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Center for Drug Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Alana Ross
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Pamela Pantazopoulos
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Guangping Dai
- Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Anna Moore
- Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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33
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Nayak TR, Krasteva LK, Cai W. Multimodality imaging of RNA interference. Curr Med Chem 2014; 20:3664-75. [PMID: 23745567 DOI: 10.2174/0929867311320290012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 03/13/2013] [Accepted: 03/13/2013] [Indexed: 12/16/2022]
Abstract
The discovery of small interfering RNAs (siRNAs) and their potential to knock down virtually any gene of interest has ushered in a new era of RNA interference (RNAi). Clinical use of RNAi faces severe limitations due to inefficiency delivery of siRNA or short hairpin RNA (shRNA). Many molecular imaging techniques have been adopted in RNAi-related research for evaluation of siRNA/shRNA delivery, biodistribution, pharmacokinetics, and the therapeutic effect. In this review article, we summarize the current status of in vivo imaging of RNAi. The molecular imaging techniques that have been employed include bioluminescence/fluorescence imaging, magnetic resonance imaging/ spectroscopy, positron emission tomography, single-photon emission computed tomography, and various combinations of these techniques. Further development of non-invasive imaging strategies for RNAi, not only focusing on the delivery of siRNA/shRNA but also the therapeutic efficacy, is critical for future clinical translation. Rigorous validation will be needed to confirm that biodistribution of the carrier is correlated with that of siRNA/shRNA, since imaging only detects the label (e.g. radioisotopes) but not the gene or carrier themselves. It is also essential to develop multimodality imaging approaches for realizing the full potential of therapeutic RNAi, as no single imaging modality may be sufficient to simultaneously monitor both the gene delivery and silencing effect of RNAi.
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Affiliation(s)
- T R Nayak
- Department of Radiology, University of Wisconsin - Madison, Madison, WI 53705-2275, USA
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34
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Wang P, Moore A. Theranostic MRI: the future for Type 1 diabetes management? ACTA ACUST UNITED AC 2014. [DOI: 10.2217/iim.13.67] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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35
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Clemente-Casares X, Santamaria P. Nanomedicine in autoimmunity. Immunol Lett 2014; 158:167-74. [PMID: 24406504 DOI: 10.1016/j.imlet.2013.12.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 12/09/2013] [Accepted: 12/20/2013] [Indexed: 11/15/2022]
Abstract
The application of nanotechnology to the diagnosis and therapy of human diseases is already a reality and is causing a real revolution in how we design new therapies and vaccines. In this review we focus on the applications of nanotechnology in the field of autoimmunity. First, we review scenarios in which iron oxide nanoparticles have been used in the diagnosis of autoimmune diseases, mostly through magnetic resonance imaging (MRI), both in animal models and patients. Second, we discuss the potential of nanoparticles as an immunotherapeutic platform for autoimmune diseases, for now exclusively in pre-clinical models. Finally, we discuss the potential of this field to generate the 'perfect drug' with the capacity to report on its therapeutic efficacy in real time, that is, the birth of theranostics in autoimmunity.
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Affiliation(s)
- Xavier Clemente-Casares
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Pere Santamaria
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Institut D'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
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36
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Sakata N, Yoshimatsu G, Tsuchiya H, Aoki T, Mizuma M, Motoi F, Katayose Y, Kodama T, Egawa S, Unno M. Imaging of transplanted islets by positron emission tomography, magnetic resonance imaging, and ultrasonography. Islets 2013; 5:179-87. [PMID: 24231367 PMCID: PMC4010569 DOI: 10.4161/isl.26980] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
While islet transplantation is considered a useful therapeutic option for severe diabetes mellitus (DM), the outcome of this treatment remains unsatisfactory. This is largely due to the damage and loss of islets in the early transplant stage. Thus, it is important to monitor the condition of the transplanted islets, so that a treatment can be selected to rescue the islets from damage if needed. Recently, numerous trials have been performed to investigate the efficacy of different imaging modalities for visualizing transplanted islets. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are the most commonly used imaging modalities for this purpose. Some groups, including ours, have also tried to visualize transplanted islets by ultrasonography (US). In this review article, we discuss the recent progress in islet imaging.
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Affiliation(s)
- Naoaki Sakata
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
- Correspondence to: Naoaki Sakata,
| | - Gumpei Yoshimatsu
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Haruyuki Tsuchiya
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Takeshi Aoki
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Masamichi Mizuma
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Fuyuhiko Motoi
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Yu Katayose
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
- Division of Integrated Surgery and Oncology; Tohoku University Graduate School of Medicine; Sendai, Japan
| | - Tetsuya Kodama
- Department of Biomedical Engineering; Graduate School of Biomedical Engineering; Tohoku University; Sendai, Japan
| | - Shinichi Egawa
- Division of International Cooperation for Disaster Medicine; International Research Institute of Disaster Science; Tohoku University; Sendai, Japan
| | - Michiaki Unno
- Division of Hepato-Biliary-Pancreatic Surgery; Department of Surgery; Tohoku University Graduate School of Medicine; Sendai, Japan
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37
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Balcioglu M, Rana M, Yigit MV. Doxorubicin loading on graphene oxide, iron oxide and gold nanoparticle hybrid. J Mater Chem B 2013; 1:6187-6193. [DOI: 10.1039/c3tb20992j] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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38
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Wang YXJ, Xuan S, Port M, Idee JM. Recent advances in superparamagnetic iron oxide nanoparticles for cellular imaging and targeted therapy research. Curr Pharm Des 2013; 19:6575-93. [PMID: 23621536 PMCID: PMC4082310 DOI: 10.2174/1381612811319370003] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 04/22/2013] [Indexed: 12/15/2022]
Abstract
Advances of nanotechnology have led to the development of nanomaterials with both potential diagnostic and therapeutic applications. Among them, superparamagnetic iron oxide (SPIO) nanoparticles have received particular attention. Over the past decade, various SPIOs with unique physicochemical and biological properties have been designed by modifying the particle structure, size and coating. This article reviews the recent advances in preparing SPIOs with novel properties, the way these physicochemical properties of SPIOs influence their interaction with cells, and the development of SPIOs in liver and lymph nodes magnetic resonance imaging (MRI) contrast. Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which offers higher intra-cellular concentration. When SPIOs are used as carrier vehicle, additional advantages can be achieved including magnetic targeting and hyperthermia options, as well as monitoring with MRI. Other potential applications of SPIO include magnetofection and gene delivery, targeted retention of labeled stem cells, sentinel lymph nodes mapping, and magnetic force targeting and cell orientation for tissue engineering.
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Affiliation(s)
- Yi-Xiang J Wang
- Department of Imaging and Interventional Radiology, The Chinese university of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
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39
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Wang P, Moore A. Theranostic magnetic resonance imaging of type 1 diabetes and pancreatic islet transplantation. Quant Imaging Med Surg 2012; 2:151-62. [PMID: 23256077 DOI: 10.3978/j.issn.2223-4292.2012.08.04] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 08/27/2012] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes mellitus results in impaired insulin production by pancreatic islets due to autoimmunity. Islet transplantation has recently emerged as a promising treatment for this disease. To visualize and monitor endogenous and transplanted islets, non-invasive strategies are currently being developed. These include strategies for in vivo magnetic resonance imaging of microvascular changes during diabetes development, tracking the recruitment of diabetogenic T cells to the pancreas, and imaging of endogenous and transplanted islet mass. The combination of MR imaging agents with therapy is a novel state-of-the-art theranostic approach that has a tremendous potential for type 1 diabetes management. Though still in its infancy, theranostic MR imaging has shown certain encouraging progress. Here we provide an overview of the latest accomplishments in this area as it applies to changes in islet vasculature during diabetes development, monitoring autoimmune attack mediated by T cells, and imaging of transplanted islets. Future challenges and opportunities in the area of theranostic MRI are discussed as well.
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Affiliation(s)
- Ping Wang
- Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA
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Wang P, Yigit MV, Ran C, Ross A, Wei L, Dai G, Medarova Z, Moore A. A theranostic small interfering RNA nanoprobe protects pancreatic islet grafts from adoptively transferred immune rejection. Diabetes 2012; 61:3247-54. [PMID: 22923469 PMCID: PMC3501867 DOI: 10.2337/db12-0441] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Islet transplantation has recently emerged as an acceptable clinical modality for restoring normoglycemia in patients with type 1 diabetes mellitus (T1DM). The long-term survival and function of islet grafts is compromised by immune rejection-related factors. Downregulation of factors that mediate immune rejection using RNA interference holds promise for improving islet graft resistance to damaging factors after transplantation. Here, we used a dual-purpose therapy/imaging small interfering (si)RNA magnetic nanoparticle (MN) probe that targets β(2) microglobulin (B2M), a key component of the major histocompatibility class I complex (MHC I). In addition to serving as a siRNA carrier, this MN-siB2M probe enables monitoring of graft persistence noninvasively using magnetic resonance imaging (MRI). Human islets labeled with these MNs before transplantation into B2M (null) NOD/scid mice showed significantly improved preservation of graft volume starting at 2 weeks, as determined by longitudinal MRI in an adoptive transfer model (P < 0.05). Furthermore, animals transplanted with MN-siB2M-labeled islets demonstrated a significant delay of up to 23.8 ± 4.8 days in diabetes onset after the adoptive transfer of T cells relative to 6.5 ± 4.5 days in controls. This study demonstrated that our approach could protect pancreatic islet grafts from immune rejection and could potentially be applied to allotransplantation and prevention of the autoimmune recurrence of T1DM in islet transplantation or endogenous islets.
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Affiliation(s)
- Ping Wang
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Mehmet V. Yigit
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Chongzhao Ran
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Alana Ross
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Lingling Wei
- Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Guangping Dai
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Zdravka Medarova
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
| | - Anna Moore
- From the Molecular Imaging Laboratory, (MGH)/(MIT)/(HMS) Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the
- Corresponding author: Anna Moore,
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Yigit MV, Medarova Z. In vivo and ex vivo applications of gold nanoparticles for biomedical SERS imagingi. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2012; 2:232-241. [PMID: 23133814 PMCID: PMC3477733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 03/10/2012] [Indexed: 06/01/2023]
Abstract
Surface enhanced Raman scattering (SERS) is a signal-increasing phenomenon that occurs whenever Raman scattering on a metal surface is enhanced many orders of magnitude. Recently SERS has received considerable attention due to its ultrasensitive multiplex imaging capability with strong photostability. It provides rich molecular information on any Raman molecule adsorbed to rough metal surfaces. The signal enhancement is so remarkable that identification of a single molecule is possible. SERS has become a genuine molecular imaging technique. Gold nanoparticles, encoded with Raman reporters, provide a SERS signal and have been used as imaging probes, often referred to as SERS nanoparticles. They have been used for molecular imaging in vivo, ex vivo and in vitro. Detection of picomolar concentrations of target molecules has been achieved by functionalizing the nanoparticles with target recognition ligands. This review focuses on recent achievements in utilizing SERS nanoparticles for in vivo molecular imaging. In the near future, SERS technology may allow detection of disease markers at the single cell level.
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Affiliation(s)
- Mehmet V Yigit
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School Charlestown, MA 02129
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Magnetic nanoparticles for cancer diagnosis and therapy. Pharm Res 2012; 29:1180-8. [PMID: 22274558 DOI: 10.1007/s11095-012-0679-7] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 01/06/2012] [Indexed: 01/07/2023]
Abstract
Nanotechnology is evolving as a new field that has a potentially high research and clinical impact. Medicine, in particular, could benefit from nanotechnology, due to emerging applications for noninvasive imaging and therapy. One important nanotechnological platform that has shown promise includes the so-called iron oxide nanoparticles. With specific relevance to cancer therapy, iron oxide nanoparticle-based therapy represents an important alternative to conventional chemotherapy, radiation, or surgery. Iron oxide nanoparticles are usually composed of three main components: an iron core, a polymer coating, and functional moieties. The biodegradable iron core can be designed to be superparamagnetic. This is particularly important, if the nanoparticles are to be used as a contrast agent for noninvasive magnetic resonance imaging (MRI). Surrounding the iron core is generally a polymer coating, which not only serves as a protective layer but also is a very important component for transforming nanoparticles into biomedical nanotools for in vivo applications. Finally, different moieties attached to the coating serve as targeting macromolecules, therapeutics payloads, or additional imaging tags. Despite the development of several nanoparticles for biomedical applications, we believe that iron oxide nanoparticles are still the most promising platform that can transform nanotechnology into a conventional medical discipline.
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Chou FC, Huang SH, Sytwu HK. Genetically engineered islets and alternative sources of insulin-producing cells for treating autoimmune diabetes: quo vadis? Int J Endocrinol 2012; 2012:296485. [PMID: 22690214 PMCID: PMC3368364 DOI: 10.1155/2012/296485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 03/29/2012] [Indexed: 01/29/2023] Open
Abstract
Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.
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Affiliation(s)
- Feng-Cheng Chou
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
| | - Shing-Hwa Huang
- Department of General Surgery, Tri-Service General Hospital, Taipei 114, Taiwan
| | - Huey-Kang Sytwu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
- *Huey-Kang Sytwu:
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Chhabra P, Brayman KL. Current status of immunomodulatory and cellular therapies in preclinical and clinical islet transplantation. J Transplant 2011; 2011:637692. [PMID: 22046502 PMCID: PMC3199196 DOI: 10.1155/2011/637692] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 07/11/2011] [Indexed: 02/08/2023] Open
Abstract
Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells.
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Affiliation(s)
- Preeti Chhabra
- Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | - Kenneth L. Brayman
- Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
- Division of Transplantation, Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
- The Center for Cellular Transplantation and Therapeutics, University of Virginia, Charlottesville, VA 22908, USA
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Molecular imaging: a promising tool to monitor islet transplantation. J Transplant 2011; 2011:202915. [PMID: 22013504 PMCID: PMC3195545 DOI: 10.1155/2011/202915] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Accepted: 07/29/2011] [Indexed: 12/18/2022] Open
Abstract
Replacement of insulin production by pancreatic islet transplantation has great potential as a therapy for type 1 diabetes mellitus. At present, the lack of an effective approach to islet grafts assessment limits the success of this treatment. The development of molecular imaging techniques has the potential to fulfill the goal of real-time noninvasive monitoring of the functional status and viability of the islet grafts. We review the application of a variety of imaging modalities for detecting endogenous and transplanted beta-cell mass. The review also explores the various molecular imaging strategies for assessing islet delivery, the metabolic effects on the islet grafts as well as detection of immunorejection. Here, we highlight the use of combined imaging and therapeutic interventions in islet transplantation and the in vivo monitoring of stem cells differentiation into insulin-producing cells.
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