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Extracellular vesicles (EVs) are natural and diverse lipid bilayer‐enclosed particles originating from various cellular components and containing an abundance of cargoes. Due to their unique properties, EVs have gained considerable interest as therapeutic agents for a variety of diseases, including central nervous system (CNS) disorders. Their therapeutic value depends on cell origin but can be further enhanced by enrichment of cargo when used as drug carriers. Therefore, there has been significant effort directed toward introducing them to clinical practice. However, it is essential to avoid the failures we have seen with whole‐cell therapy, in particular for the treatment of the CNS. Successful launching of clinical studies is contingent upon the understanding of the biodistribution of EVs, including their uptake and clearance from organs and specific homing into the region of interest. A multitude of noninvasive imaging methods has been explored in vitro to investigate the spatio‐temporal dynamics of EVs administered in vivo. However, only a few studies have been performed to track the delivery of EVs, especially delivery to the brain, which is the most therapeutically challenging organ. We focus here on the use of advanced imaging techniques as an essential tool to facilitate the acceleration of clinical translation of EV‐based therapeutics, especially in the CNS arena. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseDiagnostic Tools > in vivo Nanodiagnostics and Imaging [ABSTRACT FROM AUTHOR]

Rapidly ageing populations are beset by tissue wear and damage. Stem cell-based regenerative medicine is considered a solution. Years of research point to two important aspects: (1) the use of cellular imaging to achieve sufficient precision of therapeutic intervention, and the fact that (2) many therapeutic actions are executed through extracellular vesicles (EV), released by stem cells. Therefore, there is an urgent need to interrogate cellular labels in the context of EV release. We studied clinically applicable cellular labels: superparamagnetic iron oxide nanoparticles (SPION), and radionuclide detectable by two main imaging modalities: MRI and PET. We have demonstrated effective stem cell labeling using both labels. Then, we obtained EVs from cell cultures and tested for the presence of cellular labels. We did not find either magnetic or radioactive labels in EVs. Therefore, we report that stem cells do not lose labels in released EVs, which indicates the reliability of stem cell magnetic and radioactive labeling, and that there is no interference of labels with EV content. In conclusion, we observed that direct cellular labeling seems to be an attractive approach to monitoring stem cell delivery, and that, importantly, labels neither locate in EVs nor affect their basic properties. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are natural and diverse lipid bilayer-enclosed particles originating from various cellular components and containing an abundance of cargoes. Due to their unique properties, EVs have gained considerable interest as therapeutic agents for a variety of diseases, including central nervous system (CNS) disorders. Their therapeutic value depends on cell origin but can be further enhanced by enrichment of cargo when used as drug carriers. Therefore, there has been significant effort directed toward introducing them to clinical practice. However, it is essential to avoid the failures we have seen with whole-cell therapy, in particular for the treatment of the CNS. Successful launching of clinical studies is contingent upon the understanding of the biodistribution of EVs, including their uptake and clearance from organs and specific homing into the region of interest. A multitude of noninvasive imaging methods has been explored in vitro to investigate the spatio-temporal dynamics of EVs administered in vivo. However, only a few studies have been performed to track the delivery of EVs, especially delivery to the brain, which is the most therapeutically challenging organ. We focus here on the use of advanced imaging techniques as an essential tool to facilitate the acceleration of clinical translation of EV-based therapeutics, especially in the CNS arena. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging., (© 2020 Wiley Periodicals LLC.)

The healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19 F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF-BAPTA as a fluorinated Zn-binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10-fold difference in contrast following glucose-stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

While carbon dots (C-dots) have been extensively investigated pertaining to their fluorescent, phosphorescent, electrochemiluminescent, optoelectronic, and catalytic features, their inherent chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) properties are unknown. By virtue of their hydrophilicity and abundant exchangeable protons of hydroxyl, amine, and amide anchored on the surface, we report here that C-dots can be adapted as effective diamagnetic CEST (diaCEST) MRI contrast agents. As a proof-of-concept demonstration, human glioma cells were labeled with liposomes with or without encapsulated C-dots and implanted in mouse brain. In vivo CEST MRI was able to clearly differentiate labeled cells from non-labeled cells. The present findings may encourage new applications of C-dots for in vivo imaging in deep tissues, which is currently not possible using conventional fluorescent (near-infrared) C-dots., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Glioblastoma multiforme (GBM) is the most aggressive and common type of brain cancer. Five-year survival rates are below 12%, even with the most aggressive trimodal therapies. Poor blood-brain barrier (BBB) permeability of therapeutics is a major obstacle to efficacy. Intravenous administration of bevacizumab is the standard treatment for GBM. It has been recently demonstrated that a single intraarterial infusion of bevacizumab provides superior therapeutic outcomes in patients with recurrent GBM. Further GBM treatment benefits can be achieved through opening of the BBB before intraarterial infusion of bevacizumab. However, a rationale for intraarterial delivery and BBB opening when delivering antibodies is lacking. A method facilitating quantification of intraarterial delivery of bevacizumab is needed for more effective and personalized GBM treatment. Here, we demonstrate such a method using PET imaging of radiolabeled bevacizumab. Methods: Bevacizumab was conjugated with deferoxamine and subsequently radiolabeled with 89 Zr. 89 Zr-bevacizumab deferoxamine ( 89 Zr-BVDFO) was prepared with a specific radioactivity of 81.4 ± 7.4 MBq/mg (2.2 ± 0.2 μCi/mg). Brain uptake of 89 Zr-BVDFO on carotid artery and tail vein infusion with an intact BBB or with BBB opening with mannitol was initially monitored by dynamic PET, followed by whole-body PET/CT at 1 and 24 h after infusion. Th ex vivo biodistribution of 89 Zr-BVDFO was also determined. Results: Intraarterial administration of 89 Zr-BVDFO resulted in gradual accumulation of radioactivity in the ipsilateral hemisphere, with 9.16 ± 2.13 percentage injected dose/cm 3 at the end of infusion. There was negligible signal observed in the contralateral hemisphere. BBB opening with mannitol before intraarterial infusion of 89 Zr-BVDFO resulted in faster and higher uptake in the ipsilateral hemisphere (23.58 ± 4.46 percentage injected dose/cm 3 ) and negligible uptake in the contralateral hemisphere. In contrast, intravenous infusion of 89 Zr-BVDFO and subsequent BBB opening did not lead to uptake of radiotracer in the brain. The ex vivo biodistribution results validated the PET/CT studies. Conclusion: Our findings demonstrate that intraarterial delivery of bevacizumab into the brain across an osmotically opened BBB is effective, in contrast to the intravenous route., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To investigate the biocompatibility of type I collagen scaffold with rat bone marrow mesenchymal stem cell (BMSCs) and its role on proliferation and differentiation of BMSCs so as to explore the feasibility of collagen scaffold as neural tissue engineering scaffold., Methods: Type I collagen was used fabricate collagen scaffold. BMSCs were isolated by density gradient centrifugation. The 5th passage cells were used to prepare the collagen scaffold-BMSCs complex. The morphology of collagen scaffold and BMSCs was observed by scanning electron microscope (SEM) and HE staining. The cell proliferation was measured by MTT assay at 1, 3, 5, and 7 days after culture in vitro . After cultured on collagen scaffold for 24 hours, the growth and adhesion of green fluorescent protein positive (GFP + ) BMSCs were observed by confocal microscopy and live cell imaging., Results: The confocal microscopy and live cell imaging results showed that GFP + BMSCs uniformly distributed in the collagen scaffold; cells were fusiform shaped, and cell process or junctions between the cells formed in some cells, indicating good cell growth in the collagen scaffold. Collagen scoffold had porous fiber structure under SEM; BMSCs could adhered to the scaffold, with good cell morphology. The absorbance ( A ) value of BMSCs on collagen scaffold at 5 and 7 days after culture was significantly higher than that of purely-cultured BMSCs ( t =4.472, P =0.011; t =4.819, P =0.009). HE staining showed that collagen scaffold presented a homogeneous, light-pink filament like structure under light microscope. BMSCs on the collagen scaffold distributed uniformly at 24 hours; cell displayed various forms, and some cells extended multiple processes at 7 days, showing neuron-like cell morphology., Conclusion: Gelatinous collagen scaffold is easy to prepare and has superior biocompatibility. It is a promising scaffold for neural tissue engineering.