Hypericin as a marker for determination of tissue viability after radiofrequency ablation in a murine liver tumor model.
ABSTRACT In this proof-of-principle study, the necrosis avid agent hypericin was investigated as a potential indicator for early therapeutic response following radiofrequency ablation (RFA) of murine liver tumors. Eight mice bearing intrahepatic RIF-1 tumors were intravenously injected with hypericin 1 h before or 24 h after RFA treatment. Mice were euthanized 24 h after hypericin injection and excised livers were investigated by means of fluoromacroscopic and fluoromicroscopic examinations in combination with conventional histomorphology. Significant differences in hypericin fluorescence were found in necrosis, viable tumor and normal liver tissue in a decreasing order: in necrosis, mean fluorescence densities were about 5 times higher than in viable tumor and approximately 12 times higher than in normal liver (p<0.05). Mean fluorescence densities were not significantly different when hypericin was injected 24 h after or 1 h before RFA treatment (p>0.05). As a conclusion, hypericin features the property to specifically enhance the imaging contrast between necrotic and viable tissues and to non-specifically distinguish viable tumor from normal liver. The results suggest that hypericin offers significant potential in the early assessment of response following necrosis-inducing antineoplastic treatments such as RFA.
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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. · 6.20 Impact Factor
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ABSTRACT: Abstract Hypericin (Hyp) is newly recognized as a necrosis avid agent, but its poor solubility imposes a great hindrance in clinical application. The aim of this paper was to explore sodium cholate (NaCh) as a potential solvent for Hyp and assess the targetability of (131)I-Hyp in rat necrosis models. Hyp solubility in NaCh solutions was evaluated by equilibrium solubility measurement. Biodistribution of (131)I-Hyp in NaCh solutions and mixed organic solvents was investigated in rat models of liver and muscle necrosis examined with MRI and SPECT/CT in vivo. In addition, pharmacokinetics of (131)I-Hyp in NaCh solutions was studied in healthy rats. Results showed NaCh could improve Hyp solubility and (131)I-Hyp incubated in NaCh solutions/rat plasma was stable up to 120 h. On SPECT/CT images at 24 h post injection, liver infarction location appeared as hot spots. Liver necrosis-to-liver ratios were 12.2, 10.0, 9.6 and 8.2 in 60, 15, 2 mmol/L of NaCh solutions and organic solvents, and muscle necrosis-to-liver ratios were 11.1, 10.1, 7.7 and 7.4, respectively. Pharmacokinetics study revealed t1/2z (11.93, 8.96 h, p > 0.05) and AUC (0-∞) (421.21, 553.34 MBq/L h, p < 0.05) of (131)I-Hyp in 2, 60 mmol/L of NaCh solutions, respectively. In conclusion, NaCh was an effective cosolvent, and the necrosis avidity of NaCh-dissolved (131)I-Hyp/Hyp was demonstrated.Journal of Drug Targeting 12/2013; · 2.77 Impact Factor
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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; · 2.77 Impact Factor