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Marlein Miranda Cona,
Yuanbo Feng,
Yue Li,
Feng Chen,
Kathleen Vunckx,
Lin Zhou,
Katrien Van Slambrouck,
Ahmadreza Rezaei,
Olivier Gheysens,
Johan Nuyts,
Alfons Verbruggen,
Raymond Oyen, Yicheng Ni
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ABSTRACT: Identification of myocardial infarction (MI) by imaging is critical for clinical management of ischemic heart disease. Iodine-123-labeled-hypericin (I-Hyp) is a new potent infarct avid agent. We sought to compare target selectivity and organ distribution between I-Hyp and the myocardial perfusion agent, technetium-99m-labeled-hexakis [2-methoxyisobutylisonitril] (Tc-Sestamibi) in rabbits with acute MI. Hypericin was radiolabeled with iodine-123 using Iodogen as oxidant, and Tc-Sestamibi was prepared from a commercial kit and radioactive sodium pertechnetate. Rabbits (n=6) with 24h-old MI received intravenously I-Hyp and, 9h later Tc-Sestamibi. They were studied by dual-isotope simultaneous acquisition-micro single photon emission computed tomography/computed tomography (DISA-µSPECT/CT), tissue-gamma counting (TGC), autoradiography and histology. After purification, I-Hyp was obtained with radiochemical purity (RCP) around 99%. DISA-µSPECT/CT images showed I-Hyp retention in infarcted but not normal myocardium. By TGC, accumulation values reached 1.175 ± 0.096 %ID/g and 0.028 ± 0.007%ID/g in infarcts and normal myocardium with high tracer concentration in liver, intestines and gallbladder. Tc-Sestamibi was prepared with RCP over 95%. DISA-µSPECT/CT showed no accumulation in MI and high initial radioactivity levels in normal myocardium that were rapidly cleared as confirmed by TGC (0.011 ± 0.003%ID/g). Liver and intestines were clearly visualized. By TGC, gallbladder and kidneys show moderate Tc-Sestamibi uptake. The selectivity of I-Hyp for infarcts and Tc-Sestamibi for normal myocardium was confirmed. I-Hyp distribution in rabbits is characterized by hepatobiliary excretion. Tc-Sestamibi undergoes hepatorenal elimination.
Journal of cardiovascular pharmacology 05/2013; · 2.83 Impact Factor
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Ming Kong,
Jian Zhang,
Cuihua Jiang,
Xiao Jiang,
Yue Li,
Meng Gao,
Nan Yao,
Dejian Huang,
Xiaoning Wang,
Zhijun Fang,
Wei Liu,
Ziping Sun, Yicheng Ni
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ABSTRACT: Abstract Cancers are often with spontaneous or therapeutic necrosis that could be utilized as a generic target for developing new treatments. The purpose of this study was to investigate the biodistribution and pharmacokinetics of radioiodinated hypericin (Hyp), a naturally occurring compound, after intravenous (i.v.) injection in a rat model of liver and muscle necrosis (n = 42), and evaluate its necrosis affinity. Hyp was labeled with (131)I with labeling efficiency >99%. After incubating in solution/rat plasma for 8 days, radiochemical purity of (131)I-Hyp remained 98.1 and 97.1%, respectively, indicating good in vitro stability. SPECT-CT images at 24 h after i.v. injection of (131)I-Hyp in rats with induced liver and muscle necrosis showed obvious tracer absorption in necrotic tissues. Biodistribution studies revealed that the percentage of the injected dose per gram of tissue (%ID/g) evolved from 1.9 %ID/g at 6 h, through a maximum 3.0 %ID/g at 12 h, to 1.0 %ID/g at 192 h in necrotic liver. Pharmacokinetics studies revealed that the terminal elimination half-life, total body clearance and area under the curve of (131)I-Hyp were 32.7 h, 9.2 L/h/kg and 1.6 MBq/L*h, respectively. These results demonstrated that (131)I-Hyp features a long blood circulation in animals and persistent retention in necrotic tissues. Therefore, (131)I-labeled Hyp could be a broad-spectrum anti-tumor agent with a cost much cheaper relative to the biological agents such as monoclonal antibodies.
Journal of Drug Targeting 04/2013; · 2.70 Impact Factor
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ABSTRACT: The aim of the present study was to develop a (68)Ga labeled bis-DOTA derivative of benzylidene-bis-indole and compare the in vivo stability and biodistribution with that of the previously reported bis-DTPA derivate for in vivo imaging of necrosis using PET. Uptake of the tracer was evaluated in a mouse model of Fas-mediated hepatic apoptosis in correlation with histochemical stainings. The novel (68)Ga labeled tracer showed an improved in vivo stability and could therefore be used for selective non-invasive imaging of necrotic cell death using PET.
Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor
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ABSTRACT: Differently located tumors of the same origin may exhibit diverse responses to the same therapeutics. To test this hypothesis, we compared the responses of rodent hepatic and subcutaneous engrafts of rhabdomyosarcoma-1 (R1) to a vascular disrupting agent Combretastatin A4 phosphate (CA4P).
Twelve WAG/Rij rats, each bearing three R1 implanted in the right and left hepatic lobes and subcutaneously in the thoracic region, received CA4P intravenously at 5 mg/kg (n = 6) or solvent (n = 6). Therapeutic responses were compared interindividually and intraindividually among tumors of different sites till 48 hours after injection using in vivo MRI, postmortem digital microangiography, and histopathology.
MRI revealed that the subcutaneous tumors (STs) significantly increased in volume than hepatic tumors (HTs) 48 hours after CA4P (P < .05). Relative to vehicle controls and treated group at baseline, necrosis ratio, apparent diffusion coefficient, and enhancement ratio changed slightly with the STs but significantly with HTs (P < .05) after CA4P treatment. Vessel density derived from microangiography was significantly lower in STs compared to HTs without CA4P treatment. CA4P treatment resulted in decreased vessel density in HTs, while it did not affect vessel density in STs. MRI and microangiography outcomes were supported by histopathologic findings.
MRI and microangiography allowed quantitative comparison of therapeutic responses to CA4P in rats with multifocal tumors. The discovered diverse effects of the same drug on tumors of the same origin but different locations emphasize the presence of cancer heterogeneity and the importance of individualization of drug delivery.
Translational oncology 02/2013; 6(1):42-50. · 3.40 Impact Factor
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Marlein Miranda Cona,
Junjie Li,
Feng Chen,
Yuanbo Feng,
Yeranddy Aguiar Alpizar,
Florent Vanstapel,
Karel Talavera Pérez,
Peter de Witte,
Alfons Verbruggen,
Ziping Sun,
Raymond Oyen, Yicheng Ni
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ABSTRACT: Abstract 1. Iodogen (tetrachloro-diphenyl glycoluril) dissolved in DMSO (dimethyl sulphoxide) appears indispensable in radioiodination of hypericin for a new anticancer strategy. We studied the safety of intravenously administered iodogen/DMSO in mice (n = 132). 2. Median lethal dose (LD(50)) of iodogen/DMSO was determined with doses of 40.0, 50.0, 55.0, 60.0, 65.0 and 70.0 mg/kg. Next, toxicity of iodogen/DMSO at 30.0 mg/kg was evaluated using saline and DMSO as controls. Changes in behaviour, body weight and serum biochemistry were evaluated. Histopathology of lungs, heart, liver and kidney was performed. 3. LD(50) values of iodogen/DMSO were 59.5 mg/kg (95% confidence limits (CI): 54.1-65.4 mg/kg) and 61.0 mg/kg (95%CI: 56.2-66.2 mg/kg) for female and male mice, respectively. Similar to that of control groups, no animal deaths were encountered after iodogen/DMSO administration at 30.0 mg/kg. Body weights over 24 h were not altered in all groups, but significantly higher in iodogen/DMSO and DMSO groups (p < 0.05) 14 d post-injection. Blood urea nitrogen and alkaline phosphatase increased (p < 0.05) in iodogen/DMSO group without clinical symptoms. No pathologies were found by gross and microscopic inspection. 4. A single dose of iodogen/DMSO up to 30.0 mg/kg, over 3000 times the dose in potential human applications, appears safe, with an LD(50) doubling that dose in mice.
Xenobiotica 01/2013; · 1.79 Impact Factor
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Junjie Li,
Marlein Miranda Cona,
Feng Chen,
Yuanbo Feng,
Lin Zhou,
Guozhi Zhang,
Johan Nuyts,
Peter de Witte,
Jian Zhang,
Jie Yu,
Raymond Oyen,
Alfons Verbruggen, Yicheng Ni
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ABSTRACT: Based on the soil-to-seeds principle, we explored the small-molecular sequential dual-targeting theranostic strategy (SMSDTTS) for prolonged survival and imaging detectability in a xenograft tumor model.
Thirty severe combined immunodeficiency (SCID) mice bearing bilateral radiation-induced fibrosarcoma-1 (RIF-1) subcutaneously were divided into group A of SMSDTTS with sequential intravenous injections of combretastatin A4 phosphate (CA4P) and (131)I-iodohypericin ((131)I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of (131)I-Hyp; and group C of vehicle control (10 mice per group). Tumoricidal events were monitored by in vivo magnetic resonance imaging (MRI) and planar gamma scintiscan, and validated by ex vivo autoradiography and histopathology. Besides, 9 mice received sequential intravenous injections of CA4P and (131)I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h.
Gamma counting revealed fast clearance of (131)I-Hyp from normal organs but intense accumulation in necrotic tumor over 120 h. After only one treatment, significantly prolonged survival (p<0.001) was found in group A compared to group B and C with median survival of 33, 22, and 21 days respectively. Tumor volume on day 15 was 2.0 ± 0.89, 5.66 ± 1.66, and 5.02 ± 1.0 cm(3) with tumor doubling time 7.8 ± 2.8, 4.4 ± 0.67, and 4.5 ± 0.5 days respectively. SMSDTTS treated tumors were visualized as hot spots on gamma scintiscans, and necrosis over tumor ratio remained consistently high on MRI, autoradiography and histology.
The synergistic antitumor effects, multifocal targetability, simultaneous theranostic property, and good tolerance of the SMSDTTS were evident in this experiment, which warrants further development for preclinical and clinical applications.
Theranostics. 01/2013; 3(2):127-37.
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ABSTRACT: 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 (131)I-hypericin ((131)I-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.
Journal of Cancer. 01/2013; 4(2):133-45.
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ABSTRACT: The objective of this study was to determine the possibility of creating a novel animal model of abdominal aortic aneurysm (AAA) in rabbits by the periarterial application of papain.
Twelve New Zealand white rabbits were randomized into two groups: (1) the papain group, which received 2mg of papain (n=8) and (2) the control group, which received physiologic saline solution (n=4). A 1-cm aortic segment proximal to the bifurcation was isolated, and its adventitia was incubated with papain for 20 minutes. The rabbits underwent intravenous digital subtraction angiography (IVDSA) 5 and 21 days after the operation. The animals were then humanely killed for histomorphometric and immunohistochemical studies.
All animals in the papain group developed AAA, with an average aneurysm diameter of 4.0±0.6 and 4.1±0.4mm on days 5 and 21, respectively. No aneurysms were seen in the control group. On day 5, the papain-incubated aortas exhibited thinned and disorganized aortic walls, with decreased smooth muscle cells (SMCs) and fragmented and almost nonexistent elastic lamella. Media thickening, intimal hyperplasia, and smooth muscle cell regeneration were obvious on day 21. Immunostaining of matrix metalloproteinase (MMP)-9 and RAM11 showed strong expression in the papain group. On the contrary, the control group did not present histologic alterations and showed almost no expression of MMP-9 and RAM11.
A novel in vivo rabbit model of AAA can be induced through periarterial application of papain for 20 minutes. This model is similar to an elastase-induced aneurysm model and could be useful to clarify AAA pathogenesis and endovascular treatment intervention.
Journal of vascular and interventional radiology: JVIR 11/2012; 23(11):1529-36. · 1.81 Impact Factor
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ABSTRACT: Purpose: The aim of this study was to develop an electrode system with simple needle electrodes which would allow a reliable and predictable ablation zone with radiofrequency ablation (RFA). Materials and methods: In the first step, four parallel electrodes (active length 3 cm, diameter 1.8 mm) were inserted in ex vivo bovine liver. A power of 50 W was applied between two pairs of electrodes for 10 min or until current shut-off due to impedance rise. In the second step, the influence of changing inter-electrode distance on coagulation size and geometry was measured. In the third step, a finite element method (FEM) analysis of the experiment was performed to better understand the experimental findings. Results: A bipolar four-electrode system with templates adjusting the inter-electrode distance was successfully developed for ex vivo experiments. A complete and reliable coagulation zone of a 3 × 2 × 2-cm block was obtained most efficiently with an inter-electrode distance of 2 cm in 5.12 ± 0.71 min. Above 2 cm, coagulation was incomplete due to a too low electric field, as demonstrated by the FEM analysis. Conclusions: The optimal inter-electrode distance of the present bipolar four-electrode system was 2 cm, allowing a reliable and predictable ablation zone in ex vivo liver. The FEM analysis correctly simulated and explained the findings in ex vivo liver. The experimental set-up may serve as a platform to gain more insight and to optimise the application of RFA by means of four or more simple needle electrodes.
International Journal of Hyperthermia 09/2012; 28(7):686-97. · 1.92 Impact Factor
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ABSTRACT: Objectives: To establish an animal model of proximal descending thoracic aortic aneurysm for the study of branched stent grafts.Materials and Methods: Eleven mongrel dogs underwent the surgical procedure during which an autologous pericardial patch was sewn onto a longitudinal incision in the anterolateral wall of the thoracic aorta near the left subclavian artery to create an artificial thoracic aortic aneurysm.Results: All eleven animals survived the surgical procedure. One animal died from rupture at the surgical site during the first week after surgery. The distance between the artificial aneurysm and the left subclavian artery was 8.29 ± 0.91 mm. The average diameter of the artificial aneurysms did not significantly change over the 4-month follow-up period.Conclusion: A canine model for proximal descending thoracic aortic aneurysm can be achieved using a safe and convenient method. The model can be used in the study of new branched stent graft applied to the aortic arch.
Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 08/2012;
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ABSTRACT: Background:Radiofrequency ablation (RFA) has emerged as a potential alternative for surgery in clinical oncology. This animal experiment was conducted to evaluate the feasibility of RFA in the treatment of renal tumor.Methods:Eighteen rabbits with renal implantation of VX2 tumors were divided into two groups. Group A (n = 12) was treated with RFA by using a cooled-tip RF system at 30 W for 80 to 180 seconds. Group B (n = 6) received a sham operation. The therapeutic efficacy was evaluated by survival rate, magnetic resonance imaging (MRI), and histology.Results:All animals in group B died within 3 months after tumor implantation. Total tumor eradication was achieved in 10 of 12 rabbits (83.3%) in group A, of which 5 rabbits survived longer than 6 months (absolute eradication) and another 5 rabbits were found free of viable tumor when killed (relative eradication). Two rabbits experienced local tumor relapse, lung metastasis, or both. Six-month survival rate of RFA-treated rabbits was significantly higher (P < .01) than that of control rabbits. The typical MRI appearances of the acute RFA lesion consisted of five characteristic concentric zones, which corresponded to central needle track (zone A), tumor coagulation (zone B), renal tissue coagulation (zone C), peripheral hemorrhage (zone D), and inflammatory layer (zone E) on histology.Conclusions:RFA may become a promising therapy for the treatment of renal tumor. MRI is a useful modality for assessment of renal tumor ablation.
Annals of Surgical Oncology 04/2012; 8(8):651-657. · 4.17 Impact Factor
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Marlein Miranda Cona,
Matthias Bauwens,
Yichao Zheng,
Walter Coudyzer,
Junjie Li,
Yuanbo Feng,
Huaijun Wang,
Feng Chen,
Alfons Verbruggen,
Raymond Oyen, Yicheng Ni
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ABSTRACT: Multiple uses of automatic contrast injection systems may impose septic risks on patients. The purpose of this experiment was to verify whether a newly developed replaceable patient-delivery system may allow multiple uses of the system but without such risks.
Twelve patient-delivery systems were tested according to a multiple-use approach using an automatic contrast injection system consisting of dual syringes and one filling and injecting set. Two protocols with normal saline only (n = 6) or contrast media plus normal saline (n = 6) loaded in the injection system were performed. Each patient-delivery system was connected through an infusion catheter to the ear vein of a rabbit that was intravenously preinjected with a diffusible radiotracer (99m)Tc-dimercaptopropionyl-human serum albumin. Aliquots were sampled from the filling and injecting set, patient line, and animal blood for radioactive analysis after the replacement of each patient-delivery system.
For the protocol performed using only normal saline, radioactivity was found in the blood circulation of the rabbit (1655903 ± 593221 CPM) and in the patient line (52894 ± 33080 CPM), but, virtually, in none of samples from the filling and injecting set (8 ± 3 CPM), relative to the background (7 ± 3 CPM) (P = 0.726). Similarly, experimental results attained using contrast plus saline show radioactivity in the blood circulation of the rabbit (1119107 ± 183174 CPM) as well as in the patient line (32991 ± 20232 CPM) but in none of samples from the filling and injecting set (6 ± 6 CPM), relative to the background (6 ± 4 CPM) (P = 0.955).
The tested patient-delivery system proves convenient and safe. It allows multiple uses of the contrast injection system and avoids the risk of cross contamination.
Investigative radiology 02/2012; 47(4):247-51. · 4.85 Impact Factor
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ABSTRACT: Translational oncology aims to translate laboratory research into new anticancer therapies. Contrary to conventional surgery, chemotherapy, and radiotherapy, targeted anticancer therapy (TAT) refers to systemic administration of drugs with particular mechanisms that specifically act on well-defined targets or biologic pathways that, when activated or inactivated, may cause regression or destruction of the malignant process, meanwhile with minimized adverse effects on healthy tissues. In this article, we intend to first give a brief review on various known TAT approaches that are deemed promising for clinical applications in the current trend of personalized medicine, and then we will introduce our newly developed approach namely small molecular sequential dual targeting theragnostic strategy as a generalized class of TAT for the management of most solid malignancies, which, after optimization, is expected to help improve overall cancer treatability and curability.
Targeted Oncology 02/2012; 7(1):69-85. · 3.61 Impact Factor
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Clinical neurology and neurosurgery 01/2012; 114(6):717-20. · 1.30 Impact Factor
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ABSTRACT: It is estimated that 30–80% of solid tumor mass represents necrotic tissue that consists out of a significant number of dead and dying cells. The fact that these necrotic zones are restricted to dysplastic and malignant tissue and are rarely present in normal tissue makes necrosis an interesting target both for cancer diagnosis and therapy. In this study, the avidity of hypericin, [123I]iodohypericin and [131I]iodohypericin to tumor necrosis was explored for both diagnosis and therapy of experimental malignancies. The intratumoral distribution in RIF-1 tumors was investigated by means of fluorescence microscopy (hypericin) and autoradiography ([123I]iodohypericin). Results show high uptake of the tracers in necrosis at 24 hr, lasting for up to 72 hr p.i. Ratios of activity of [123I]iodohypericin in necrotic tissue over viable tumor reached up to 19.63 ± 4.66, correlating with 9.20% ID/g in necrosis. Nude mice bearing RIF-1 tumors that received three injections of 300 μCi over a 3-week treatment period showed stabilization in tumor growth for 5 days, as measured by caliper and micro-positron emission tomography using [18F]fluorodeoxyglucose. Based on these results, we suggest the potentials of radiolabeled hypericin (1) in diagnostic aspects including prognosis or staging assessment of bulky necrotic cancers, monitoring of treatments and therapeutic follow-up; and (2) in cancer treatment based on tumor necrosis. In conclusion, we showed that hypericin radiolabeled with iodine is a necrosis avid tracer that can be used both as a tumor diagnostic and therapeutic.
International Journal of Cancer 01/2012; 131(2):E129 - E137. · 5.44 Impact Factor
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Feng Chen,
Yingmei Feng,
Kaier Zheng,
Frederik De Keyzer,
Junjie Li,
Yuanbo Feng,
Marlein Miranda Cona,
Huaijun Wang,
Yansheng Jiang,
Jie Yu,
Guy Marchal,
Catherine Verfaillie,
Bart De Geest,
Raymond Oyen, Yicheng Ni
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ABSTRACT: A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.
PLoS ONE 01/2012; 7(7):e41140. · 4.09 Impact Factor
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Junjie Li,
Marlein Miranda Cona,
Feng Chen,
Yuanbo Feng,
Lin Zhou,
Jie Yu,
Johan Nuyts,
Peter de Witte,
Jian Zhang,
Uwe Himmelreich,
Alfons Verbruggen, Yicheng Ni
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ABSTRACT: The present animal experiments were conducted to evaluate radioiodinated Hypericin (Hyp) for its regional distribution as well as theranostic potentials.
Rat models of reperfused liver infarction (RLI) and hepatic rhabdomyosarcoma (R1) were surgically induced. R1 models received Combretastatin A4 phosphate (CA4P) intravenously at 10 mg/kg 24 h prior to radioiodinated Hyp. Three groups of 6 rats each containing 3 RLI and 3 R1 models received iv injections of (123)I-Hyp at 37, 74, and 185 MBq/kg respectively and followed by 0.1 ml of 1% Evans blue solution were sacrificed at 4, 24 and 48 hour post injection immediately after in vivo examination of MRI and planar gamma scintigraphy. Besides, two groups of 6 R1 models that received either 300 MBq/kg of (131)I-Hyp or vehicle intravenously were examined using MRI to compare tumor growth for 12 days. Autoradiography, gamma counting, and histopathology were performed for postmortem verifications and quantification.
Necrosis as seen in vivo on contrast-enhanced MRI corresponded well with the hot spots on planar scintigraphy. Autoradiography and gamma counting revealed intense accumulation of (123)I-Hyp in necrotic liver (3.94 ± 1.60, 5.38 ± 1.04, and 6.03 ± 2.09 %ID/g ± SD) and necrotic tumor (4.27 ± 0.76, 5.57 ± 0.76, and 5.68 ± 1.33 %ID/g ± SD) relative to normal liver (1.76 ± 0.54, 0.41 ± 0.18, and 0.16 ± 0.07 %ID/g ± SD), with a high necrosis-to-liver ratio of 2.3, 14.0, and 37.0 at 4, 24 and 48 h respectively. Tumor volumes in R1 models that received (131)I-Hyp and vehicle changed from 0.45 ± 0.09, and 0.47 ± 0.12 cm(3) (p > 0.05) on day 0 to1.32 ± 0.76 and 3.63 ± 0.72 cm(3 )(p < 0.001) on day 12, with the corresponding necrosis ratios from 73 ± 12 %, and 76 ± 17 % to 47 ± 18% and 17 ± 13 % (p < 0.01), and with the tumor DT of 7.3 ± 1.0 and 4.2 ± 0.7 days, respectively.
Radioiodinated Hyp as a necrosis avid tracer appears promising for non-invasive imaging diagnosis of necrosis-related pathologies. Its prominent targetability to necrosis allows targeted radiotherapy for malignancies on top of a prior necrosis-inducing treatment.
Theranostics. 01/2012; 2(10):1010-9.
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ABSTRACT: As an alternative to directly targeting of necrotic tissue using hypericin, we synthesized a conjugate of hypericin to biotin for use in a pretargeting approach. With this conjugate, we explored the possibility of a two-step pretargeting strategy using (123)I-labeled avidin as effector molecule directed against necrotic RIF-1 tumors. Hypericin was conjugated to biotin-ethylenediamine in a straightforward coupling method using n-hydroxysuccinimide and dicyclohexylcarbodiimide. The necrosis avidity of the conjugate was first confirmed in necrotic liver tissue by means of fluorescence microscopy. Using autoradiography imaging and whole body-biodistribution, the accumulation of (123)I-avidin in necrotic tumor tissue was evaluated 24 h after administration and 48 h after pretargeting with hypericin-biotin. Analysis of autoradiography images show a higher accumulation of (123)I-avidin in pretargeted compared to nontargeted tissue. However, absolute accumulation of (123)I-avidin in necrotic tumors was low as shown by biodistribution experiments. Direct injection of hypericin-biotin or biotin-fluorescein did not substantially improve (123)I-avidin accumulation after pretargeting, pointing towards a poor penetration of avidin in necrotic tissue. Our results show the feasibility of a pretargeting technique using a small molecule as targeting agent. However, for a more efficient accumulation of the effector molecule in necrotic tissue, other pretargeting strategies need to be investigated.
Investigational New Drugs 12/2011; · 3.36 Impact Factor
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ABSTRACT: It is estimated that 30-80% of solid tumor mass represents necrotic tissue that consists out of a significant number of dead and dying cells. The fact that these necrotic zones are restricted to dysplastic and malignant tissue and are rarely present in normal tissue makes necrosis an interesting target both for cancer diagnosis and therapy. In this study, the avidity of hypericin, [(123) I]iodohypericin and [(131) I]iodohypericin to tumor necrosis was explored for both diagnosis and therapy of experimental malignancies. The intratumoral distribution in RIF-1 tumors was investigated by means of fluorescence microscopy (hypericin) and autoradiography ([(123) I]iodohypericin). Results show high uptake of the tracers in necrosis at 24 hr, lasting for up to 72 hr p.i. Ratios of activity of [(123) I]iodohypericin in necrotic tissue over viable tumor reached up to 19.63 ± 4.66, correlating with 9.20% ID/g in necrosis. Nude mice bearing RIF-1 tumors that received three injections of 300 μCi over a 3-week treatment period showed stabilization in tumor growth for 5 days, as measured by caliper and micro-positron emission tomography using [(18) F]fluorodeoxyglucose. Based on these results, we suggest the potentials of radiolabeled hypericin (1) in diagnostic aspects including prognosis or staging assessment of bulky necrotic cancers, monitoring of treatments and therapeutic follow-up; and (2) in cancer treatment based on tumor necrosis. In conclusion, we showed that hypericin radiolabeled with iodine is a necrosis avid tracer that can be used both as a tumor diagnostic and therapeutic.
International Journal of Cancer 10/2011; 131(2):E129-37. · 5.44 Impact Factor
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ABSTRACT: Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted radiotherapy (STR) is a radiotherapeutic modality based on systemic administration of radioactive agents for selectively delivering high doses of energy to destroy cancer cells. For this purpose, diverse tumour-target specific agents including monoclonal antibodies (MoAb), MoAb fragments and peptides have been tested and some of them have already got FDA approval for clinical use. However, MoAbs and their tailored analogues have shown non-homogeneous tumour distribution, limited diffusion, insufficient intratumoral accumulation and retention, unwanted uptake in normal tissues and scarcity of identified cancer antigens for generating new MoAbs. Similarly, peptides have also exhibited retention in normal organs, lacks of favourable membrane permeability or drug cell internalization and short-term residence in cancer cells. Recently, a new category of target-specific agent with strong affinity for necrosis has emerged as an excellent option for developing targeted radiotherapeutic agents to be used after necrosis-inducing treatments (NITs). The combination of their high, specific and long-term accumulation and retention at necrotic sites with the crossfire effect of ionizing particle-emitters allows irradiating adjacent residual viable tumour cells during a prolonged period of time. It may considerably enhance the therapeutic response and open a new horizon for improved cancer treatability or curability.
Investigational New Drugs 10/2011; 30(5):2050-65. · 3.36 Impact Factor
