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Cona M.M.,University of Sfax | Cona M.M.,Molecular Small Animal Imaging Center | Koole M.,University Hospitals Group | Feng Y.,University of Sfax | And 7 more authors.
International Journal of Oncology | Year: 2014

Iodine-131-labeled monoiodohypericin ( 131I-Hyp) is a necrosis avid compound used as a complementary anticancer agent. Herein, the biodistribution in rats with re-perfused partial liver infarction (RPLI) was used to estimate its human internal radiation dosimetry. Iodine-123-labeled monoiodohypericin (123I-Hyp) as a safer surrogate for 131I-Hyp was prepared with iodogen as oxidant. Determination of radiochemical yield and purification was performed by high performance liquid chromatography (HPLC). To control aggregation, the formulation was macroscopically and microscopically examined. Biodistribution of 123I-Hyp was studied in RPLI rats (n=18) at 4, 24 and 48 h post-injection. Tissue gamma counting (TGC), autoradiography and histology were performed. Dosimetry of 131I-Hyp in hepatic necrosis and in normal human organs was estimated using biodistribution data of 123I-Hyp, the Organ Level Internal Dose Assessment/Exponential Modeling (OLINDA/EXM®), a sphere model and male and female phantoms. A radiochemical yield of 95% was achieved in labeling of 123I-Hyp with a radiochemical purity of 99% after HPLC purification. In the Hyp added formulation, no macroscopic but minimal microscopic aggregation was observed. By TGC, selective accumulation in hepatic infarction and low uptake in viable liver of 123I-Hyp/Hyp were detected, as confirmed by autoradiography and histology. Significantly higher doses of 131I-Hyp were delivered to necrotic (276-93,600 mGy/MBq) than to viable (4.2 mGy/MBq) liver (P<0.05). In normal organs, 123I-Hyp was eliminated within 24 h except for relatively high levels in the lungs and thyroid. Hepatobiliary elimination was a major pathway of 123I-Hyp causing high activity in the intestines. For both genders, dosimetry showed the longest residence time of 131I-Hyp in the remainder, followed by the lungs, intestines and thyroid. The highest absorbed radiation dose was seen in necrotic tissues and the shortest residence times and lowest absorbed radiation dose were found in the brain. 131I-Hyp selectively delivers higher radiation dose to necrosis compared with the rest of the body. Among normal organs, thyroids, lungs and intestines receive considerable radiation dose, which deserves cautious attention in developing this anticancer approach.


Li J.,Biomedical science Group | Li J.,Molecular Small Animal Imaging Center | Oyen R.,Biomedical science Group | Verbruggen A.,Laboratory of Radiopharmacy | And 2 more authors.
Journal of Cancer | Year: 2013

Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely 131I-hypericin (131I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications. ©Ivyspring International Publisher.


Rangarajan J.R.,Catholic University of Leuven | Rangarajan J.R.,Molecular Small Animal Imaging Center | Van Kuyck K.,Catholic University of Leuven | Himmelreich U.,Biomedical NMR Unit | And 4 more authors.
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2011

Clinical and pre-clinical studies show that deep brain stimulation (DBS) of targeted brain regions by neurosurgical techniques ameliorate psychiatric disorder such as anorexia nervosa. Neurosurgical interventions in preclinical rodent brain are mostly accomplished manually with a 2D atlas. Considering both the large number of animals subjected to stereotactic surgical experiments and the associated imaging cost, feasibility of sophisticated pre-operative imaging based surgical path planning and/or robotic guidance is limited. Here, we spatially normalize vasculature information and assess the intra-strain variability in cerebral vasculature for a neurosurgery planning. By co-registering and subsequently building a probabilistic vasculature template in a standard space,1 we evaluate the risk of a user defined electrode trajectory damaging a blood vessel on its path. The use of such a method may not only be confined to DBS therapy in small animals, but also could be readily applicable to a wide range of stereotactic small animal surgeries like targeted injection of contrast agents and cell labeling applications.© 2011 SPIE.


Casteels C.,University Hospital Leuven | Casteels C.,Molecular Small Animal Imaging Center | Lauwers E.,Molecular Small Animal Imaging Center | Lauwers E.,Catholic University of Leuven | And 7 more authors.
Brain Research | Year: 2010

Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [18F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [18F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [18F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p < 0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p = 0.001 and p < 0.0003, respectively). The number of TH+ neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p = 1.10-6). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p = 4.10-6). In vivo [18F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex. © 2009 Elsevier B.V. All rights reserved.


Li J.-J.,Biomedical science Group | Li J.-J.,Molecular Small Animal Imaging Center | Cona M.M.,Biomedical science Group | Cona M.M.,Molecular Small Animal Imaging Center | And 11 more authors.
Acta Pharmacologica Sinica | Year: 2012

Aim: Hypericin (Hyp) and its radio-derivatives have been investigated in animal models with ischemic heart diseases and malignancies for diagnostic and therapeutic purposes. Before radioiodinated Hyp (123I-Hyp or 131I-Hyp) can be considered as a clinically useful drug, vigorous evaluations on its chemotoxicity are necessary. In the present study, we examined the toxicity of a single dose of non-radioactive 127I-Hyp in normal mice for 24 h and 14 d.Methods:Studies were performed on 132 normal mice. 127I-Hyp at a clinically relevant dose of 0.1 mg/kg body weight and a 100-times higher dose of 10 mg/kg was intravenously injected into 40 mice. The safety aspects of clinical manifestations, serological biochemistry, and histopathology were assessed. In another 72 mice, 127I-Hyp was administered intravenously at assumed values to bracket the value of LD 50. The rest 20 mice were used in the control groups.Results:At 24 h and 14 d following the injection of 127I-Hyp at either 0.1 or 10 mg/kg, all mice tolerated well without mortality or any observable treatment-related symptoms. No significant differences were found in blood biochemical parameters between the test and control groups. All organs presented normal appearances upon histopathological inspection. The value of LD 50 of 127I-Hyp in mice through intravenous injection was 20.26 mg/kg, with the 95% confidence interval between 18.90 and 21.55 mg/kg.Conclusion:The current study reveals a broad safety range of 127I-Hyp, which not only supports the use of 123 I-Hyp or 131I-Hyp in the necrosis targeting theragnostic strategy, but also serves as a valuable reference for exploring other possible applications for iodinated Hyp. © 2012 CPS and SIMM All rights reserved.

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