Currently, there is increasing interest in human bone marrow stromal cells (hBMSCs) as regeneration therapy against cerebral stroke. The aim of the present study was to evaluate the feasibility and validity of hBMSC cultures with allogeneic platelet lysates (PLs). Platelet concentrates (PC) were harvested from healthy volunteers and made into single donor-derived PL (sPL). The PL mixtures (mPL) were made from three different sPL. Some growth factors and platelet cell surface antigens were detected by enzyme-linked immunosorbent assay (ELISA). The hBMSCs cultured with 10% PL were analyzed for their proliferative potential, surface markers, and karyotypes. The cells were incubated with superparamagnetic iron oxide (SPIO) agents and injected into a pig brain. MRI and histological analysis were performed. Consequently, nine lots of sPL and three mPL were prepared. ELISA analysis showed that PL contained adequate growth factors and a particle of platelet surface antigens. Cell proliferation capacity of PLs was equivalent to or higher than that of fetal calf serum (FCS). No contradiction in cell surface markers and no chromosomal aberrations were found. The MRI detected the distribution of SPIO-labeled hBMSCs in the pig brain. In summary, the hBMSCs cultured with allogeneic PL are suitable for cell therapy against stroke.

Background 211At is one of the ideal nuclides for targeted radionuclide therapies (TRTs). Meta-[211At]astatobenzylguanidine (211At-MABG) has been proposed for the treatment of pheochromocytoma. To effectively use these radiopharmaceuticals, dosimetry must be performed. It is important to determine the absorbed doses of free 211At and 211At-MABG to determine the organs that may be at risk when using TRTs. The aim of this study was to estimate human dosimetry from preclinical biodistribution of free 211At and 211At-MABG in various organs in normal mice. Methods Male C57BL/6 N mice were administered 0.13 MBq of free 211At or 0.20 MBq of 211At-MABG by tail-vein injection. The mice were sacrificed at 5 min, and at 1, 3, 6, and 24 h after the injection (n = 5 for each group). The percentage of injected activity per mass in organs and blood (%IA/g) was determined. The human absorbed doses of free 211At and 211At-MABG were calculated using the Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) version 2.0 and IDAC-Dose 2.1. Results High uptake of free 211At was observed in the lungs, spleen, salivary glands, stomach, and thyroid. The absorbed doses of free 211At in the thyroid and several tissues were higher than those of 211At-MABG. The absorbed doses of 211At-MABG in the adrenal glands, heart wall, and liver were higher than those of free 211At. Conclusions The absorbed doses of 211At-MABG in organs expressing the norepinephrine transporter were higher than those of free 211At. In addition, the biodistribution of free 211At was different from that of 211At-MABG. The absorbed dose of free 211At may help predict the organs potentially at risk during TRTs using 211At-MABG due to deastatination.

BackgroundThe potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET.The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO.ResultsRats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group.ConclusionsThe present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

Recently, both basic and clinical studies demonstrated that bone marrow stromal cell (BMSC) transplantation therapy can promote functional recovery of patients with CNS disorders. A non-invasive method for cell tracking using MRI and superparamagnetic iron oxide (SPIO)-based labeling agents has been applied to elucidate the behavior of transplanted cells. However, the long-term safety of SPIO-labeled BMSCs still remains unclear. The aim of this study was to investigate the short-, middle- and long-term safety of the SPIO-labeled allogeneic BMSC transplantation. For this purpose, BMSCs were isolated from transgenic rats expressing green fluorescent protein (GFP) and were labeled with SPIO. The Na/K ATPase pump inhibitor ouabain or vehicle was stereotactically injected into the right striatum of wild-type rats to induce a lacunar lesion (n = 22). Seven days after the insult, either BMSCs or SPIO solution were stereotactically injected into the left striatum. A 7.0-Tesla MRI was performed to serially monitor the behavior of BMSCs in the host brain. The animals were sacrificed after 7 days (n = 7), 6 weeks (n = 6) or 10 months (n = 9) after the transplantation. MRI demonstrated that BMSCs migrated to the damage area through the corpus callosum. Histological analysis showed that activated microglia were present around the bolus of donor cells 7 days after the allogeneic cell transplantation, although an immunosuppressive drug was administered. The SPIO-labeled BMSCs resided and started to proliferate around the route of the cell transplantation. Within 6 weeks, large numbers of SPIO-labeled BMSCs reached the lacunar infarction area from the transplantation region through the corpus callosum. Some SPIO nanoparticles were phagocytized by microglia. After 10 months, the number of SPIO-positive cells was lower compared with the 7-day and 6-week groups. There was no tumorigenesis or severe injury observed in any of the animals. These findings suggest that BMSCs are safe after cell transplantation for the treatment of stroke.

Background Eribulin, an inhibitor of microtubule dynamics, shows antitumor potency against a variety of solid cancers through its antivascular activity and remodeling of tumor vasculature. 18 F-Fluoromisonidazole ( 18 F-FMISO) is the most widely used PET probe for imaging tumor hypoxia. In this study, we utilized 18 F-FMISO to clarify the effects of eribulin on the tumor hypoxic condition in comparison with histological findings. Material and methods Mice bearing a human cancer cell xenograft were intraperitoneally administered a single dose of eribulin (0.3 or 1.0 mg/kg) or saline. Three days after the treatment, mice were injected with 18 F-FMISO and pimonidazole (hypoxia marker for immunohistochemistry), and intertumoral 18 F-FMISO accumulation levels and histological characteristics were determined. PET/CT was performed pre- and post-treatment with eribulin (0.3 mg/kg, i.p.). Results The 18 F-FMISO accumulation levels and percent pimonidazole-positive hypoxic area were significantly lower, whereas the number of microvessels was higher in the tumors treated with eribulin. The PET/CT confirmed that 18 F-FMISO distribution in the tumor was decreased after the eribulin treatment. Conclusions Using 18 F-FMISO, we demonstrated the elimination of the tumor hypoxic condition by eribulin treatment, concomitantly with the increase in microvessel density. These findings indicate that PET imaging using 18 F-FMISO may provide the possibility to detect the early treatment response in clinical patients undergoing eribulin treatment.

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to explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the 211 At-labeled anti-C-X-C chemokine receptor type 4 monoclonal antibody ( 211 At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of 211 At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using 211 At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.Targeted α-particle therapy (TAT) has great potential for the treatment of cancer based on the specific delivery of a high radiation dose from α-particles emitting radionuclides to tumors while minimizing systemic toxic effects, and it may lead to additional treatment options for many types of advanced or refractory cancer 1 . The high level of radiobiological effectiveness of α-particles, in comparison with β-particles emissions, requires fewer radiation tracks to induce cell death. The short path length of α-particles radiation confines its cytotoxic effect to the target tissue and the surrounding tumor microenvironment while limiting toxic effects to non-neoplastic tissues.Following the successful clinical TAT with 223 Ra dichloride for the treatment of metastatic castration-resistant prostate cancer with bone metastases and the clinical experience with 213 Bi-and 225 Ac-labeled compounds 2-4 , there has been an increased interest in new applications of TAT for many tumor types. Among the α-particles-emitting radionuclides for TAT, 211 At can be produced using a cyclotron with an α-particle beam, and its separation and purification from the target has been established after decades of continuous research. After a branch decay with a half-life of 7.21 h, 211 At completely emits α-particles with 100% probability. A few clinical applications of 211 At for the treatment of malignant neoplasms have been reported 5,6 .The failure of medical and radiological anti-cancer therapies is partially attributable to the heterogeneity of cancer. One of the mechanisms explaining cancer heterogeneity is the existence of cancer stem cells (CSCs) 7 . CSCs exhibit self-renewal activity and long-term proliferating capability 8 . The concept of neoplastic stem cells may explain the failure of various therapies to achieve long-lasting responses in patients 9 , because CSCs are suggested as a potential source of resistance to different types of anti-neoplastic drug. Anti-neoplastic drugs are considered to act on mature neoplastic cells rather than on CSCs in many neoplastic tissues. This is partially owing to th...