• Bioactivities
• Drug delivery system (DDS)
• Hypericin
• Photodynamic therapy (PDT)

• Humans
• Anthraquinones/pharmacology
• Anthracenes/therapeutic use
• Neoplasms/drug therapy
• Photochemotherapy

• biotin
• folate
• hypericin
• multifunctional micelles
• photodynamic therapy
• spermine

• Brain metastasis
• artificial intelligence
• blood-brain barrier
• imaging
• model
• nuclear medicine
• targeted therapy

• Coated-lipid
• Copolymer micelles
• Hypericin
• Lipid vesicles
• Photodynamic therapy
• Photophysical characterization
• Pluronic®

• Anthracenes
• Caco-2 Cells
• Humans
• Liposomes
• Micelles
• Nanostructures
• Perylene/analogs & derivatives
• Photochemotherapy
• Photosensitizing Agents/therapeutic use
• Polyethylenes
• Polypropylenes

• Rhein
• mechanism exploration
• molecular imaging
• monitoring of therapeutic efficacy
• necrosis avidity
• visualisation of myocardial necrosis

Hypericin (Hyp) had been explored as a tumor-seeking agent for years; however, more recent studies showed its necrosis-avidity rather than cancer-seeking property. To further look into this discrepancy, we conducted an in vitro study on Hyp retention in vital and dead cancerous HepG2 and normal LO2 cell lines by measuring the fluorescence intensity and concentration of Hyp in cells. To question the DNA binding theory for its necrosis-avidity, the subcellular distribution of Hyp was also investigated to explore the possible mechanisms of the necrosis avidity. The fluorescence intensity and concentration are significantly higher in dead cells than those in vital cells, and this difference did not differ between HepG2 and LO2 cell lines. Hyp was taken up in vital cells in the early phase and excreted within hours, whereas it was retained in dead cells for more than two days. Confocal microscopy showed that Hyp selectively accumulated in lysosomes rather than cell membrane or nuclei. Hyp showed a necrosis-avid property rather than cancer-targetability. The long-lasting retention of Hyp in dead cells may be associated with halted energy metabolism and/or binding with certain degraded cellular substrates. Necrosis-avidity of Hyp was confirmed, which may be associated with halted energy metabolism in dead LO2 or HepG2 cells.

• confocal microscopy and mechanism
• fluorescence
• hypericin
• liver cancer
• necrosis-avidity

• Exposed DNA
• Molecular imaging
• Myocardial infarction
• Necrosis avid agents
• Solid tumor
• Targeted therapy

To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology.

Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg (control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). In vivo MRI findings were verified by postmortem techniques.

On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h (P < 0.05), followed by further perfusion decrease at 12 h (P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) (P < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors.

This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents.​

• Hepatocellular carcinoma
• Combretastatin A4 phosphate
• Rhabdomyosarcoma
• Vascular-disrupting agent
• Magnetic resonance imaging
• Rats

• Angiography
• Animals
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/therapeutic use
• Carcinoma, Hepatocellular/blood supply
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Contrast Media/administration & dosage
• Diethylnitrosamine/toxicity
• Humans
• Liver/diagnostic imaging
• Liver/pathology
• Liver Neoplasms/blood supply
• Liver Neoplasms/chemically induced
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms, Experimental/chemically induced
• Liver Neoplasms, Experimental/diagnostic imaging
• Liver Neoplasms, Experimental/drug therapy
• Liver Neoplasms, Experimental/pathology
• Magnetic Resonance Imaging/methods
• Male
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/pathology
• Rats
• Rhabdomyosarcoma/blood supply
• Rhabdomyosarcoma/drug therapy
• Rhabdomyosarcoma/pathology
• Rhabdomyosarcoma/secondary
• Stilbenes/pharmacology
• Stilbenes/therapeutic use
• Treatment Outcome
• Tumor Microenvironment/drug effects
• Xenograft Model Antitumor Assays

Successful treatment of cancer patients requires balancing of the dose, timing, and type of therapeutic regimen. Detection of increased cell death may serve as a predictor of the eventual therapeutic success. Imaging of cell death may thus lead to early identification of treatment responders and nonresponders, and to “patient‐tailored therapy.” Cell death in organs and tissues of the human body can be visualized, using positron emission tomography or single‐photon emission computed tomography, although unsolved problems remain concerning target selection, tracer pharmacokinetics, target‐to‐nontarget ratio, and spatial and temporal resolution of the scans. Phosphatidylserine exposure by dying cells has been the most extensively studied imaging target. However, visualization of this process with radiolabeled Annexin A5 has not become routine in the clinical setting. Classification of death modes is no longer based only on cell morphology but also on biochemistry, and apoptosis is no longer found to be the preponderant mechanism of cell death after antitumor therapy, as was earlier believed. These conceptual changes have affected radiochemical efforts. Novel probes targeting changes in membrane permeability, cytoplasmic pH, mitochondrial membrane potential, or caspase activation have recently been explored. In this review, we discuss molecular changes in tumors which can be targeted to visualize cell death and we propose promising biomarkers for future exploration.

• apoptosis
• early treatment response
• necrosis
• positron emission tomography (PET)
• single photon emission computed tomography (SPECT)

• 131I-Sennoside A
• excretion
• necrosis-avid agent
• toxicity evaluation

• hypericin
• necrosis
• targeted radiotherapy
• vascular disrupting treatment

• St. John's wort
• anticancer activities
• drug resistance
• hypericin
• photodynamic diagnosis
• photodynamic therapy

• imaging
• resistance
• solutions
• vascular disrupting agents

• Angiogenesis Inhibitors
• Animals
• Drug Resistance, Neoplasm
• Humans
• Neoplasms/diagnostic imaging
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neovascularization, Pathologic/drug therapy

• 131I
• SPECT/CT
• cancer
• necrosis
• skyrin
• targeted radionuclide therapy

• Chemically induced primary malignancy
• carcinogen
• carcinogenesis
• magnetic resonance imaging (MRI)
• noninvasive imaging

• Biodistribution
• Hypericin (PubChem CID: 5281051)
• Necrosis avidity
• Radioiodinated Sennidin A
• Reperfused myocardial infarction
• SPECT
• Sennidin A (PubChem CID: 122839)

• anticancer therapy
• combretastatin A4-phosphate
• tubulin-binding agent
• vascular disrupting agent

• Autoradiography
• THPPMnCl
• biodistribution
• microscopic fluorescence imaging
• necrosis-targeting
• pharmacokinetics

• 131I-hypericin
• common bile duct drainage
• distribution
• duodenal drainage
• radioactivity
• solid tumor therapy

Residual cancer cells and subsequent tumor relapse is an obstacle for curative cancer treatment. Tumor necrosis therapy (TNT) has recently been developed to cause residual tumor regression or destruction. Here, we exploited the avidity of the sennidin A (SA) tracer and radioiodinated SA (¹³¹I-SA) to necrotic tumors in order to further empower TNT. We showed high uptake and prolonged retention of SA in necrotic tumors and a quick clearance in other non-targeted tissues including the liver. On SPECT-CT images, tumor mass appeared persistently as a hotspot. Based on the prominent targetability of ¹³¹I-SA to the tumor necrosis, we designed a combinational theragnostic modality. The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) was used to cause massive tumor necrosis, which formed the target of ¹³¹I-SA that subsequently killed the residual tumor cells by cross-fire irradiation of beta particles. Consequently, ¹³¹I-SA combined with CA4P significantly inhibited tumor growth, extended tumor doubling time and prolonged mean animal survival. In conclusion, ¹³¹I-SA in combination with necrosis inducing drugs/therapies may generate synergetic tumoricidal effects on solid malignancies by means of primary debulking and secondary cleansing process.

• Autoradiography
• SPECT/CT imaging
• biodistribution
• intra-tumoral administration
• necrosis-avid theranostic agent
• radioiodinated hypericin
• small-molecular tumor necrosis therapy

• Autoradiography
• SPECT imaging
• biodistribution
• necrosis targeting
• pharmacokinetics
• radioiodine
• sennoside B

• Rabbit
• cardiac imaging
• contrast
• histology
• myocardial infarction (MI)

Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin (¹²³I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid ¹²³I-Hyp and the commercially available ^99mTc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce costs and save resources. However, cross-contaminations with blood-borne pathogens of infectious diseases may occur. We developed a radioactive method for safety evaluation of a new replaceable patient-delivery system. By mimicking pathogens with a radiotracer, we assessed the feasibility of using the system repeatedly without septic risks. This overview is deemed to be interesting to those involved in the related fields for translational research.

• Translational medical research
• Cancer treatment
• OncoCiDia
• Vascular disrupting agent
• Hypericin
• Myocardial infarction
• Gallstone
• Transflux

• Evans blue
• MRI
• area at risk
• myocardial infarction
• rabbits

AIM: To develop a method for studying myocardial area at risk (AAR) in ischemic heart disease in correlation with cardiac magnetic resonance imaging (cMRI).

METHODS: Nine rabbits were anesthetized, intubated and subjected to occlusion and reperfusion of the left circumflex coronary artery (LCx) to induce myocardial infarction (MI). ECG-triggered cMRI with delayed enhancement was performed at 3.0 T. After euthanasia, the heart was excised with the LCx re-ligated. Bifunctional staining was performed by perfusing the aorta with a homemade red-iodized-oil (RIO) dye. The heart was then agar-embedded for ex vivo magnetic resonance imaging and sliced into 3 mm-sections. The AAR was defined by RIO-staining and digital radiography (DR). The perfusion density rate (PDR) was derived from DR for the AAR and normal myocardium. The MI was measured by in vivo delayed enhancement (iDE) and ex vivo delayed enhancement (eDE) cMRI. The AAR and MI were compared to validate the bifunctional straining for cardiac imaging research. Linear regression with Bland-Altman agreement, one way-ANOVA with Bonferroni’s multiple comparison, and paired t tests were applied for statistics.

RESULTS: All rabbits tolerated well the surgical procedure and subsequent cMRI sessions. The open-chest occlusion and close-chest reperfusion of the LCx, double suture method and bifunctional staining were successfully applied in all animals. The percentage MI volumes globally (n = 6) and by slice (n = 25) were 36.59% ± 13.68% and 32.88% ± 12.38% on iDE, and 35.41% ± 12.25% and 32.40% ± 12.34% on eDE. There were no significant differences for MI determination with excellent linear regression correspondence (r_global = 0.89; r_slice = 0.9) between iDE and eDE. The percentage AAR volumes globally (n = 6) and by slice (n = 25) were 44.82% ± 15.18% and 40.04% ± 13.64% with RIO-staining, and 44.74% ± 15.98% and 40.48% ± 13.26% by DR showing high correlation in linear regression analysis (r_global = 0.99; r_slice = 1.0). The mean differences of the two AAR measurements on Bland-Altman were almost zero, indicating RIO-staining and DR were essentially equivalent or inter-replaceable. The AAR was significantly larger than MI both globally and slice-by-slice (P < 0.01). After correction with the background and the blank heart without bifunctional staining (n = 3), the PDR for the AAR and normal myocardium was 32% ± 15% and 35.5% ± 35%, respectively, which is significantly different (P < 0.001), suggesting that blood perfusion to the AAR probably by collateral circulation was only less than 10% of that in the normal myocardium.

CONCLUSION: The myocardial area at risk in ischemic heart disease could be accurately determined postmortem by this novel bifunctional staining, which may substantially contribute to translational cardiac imaging research.

• Reperfused
• Acute myocardial infarction
• Rabbit model
• Cardiac magnetic resonance imaging
• Oil-red-o dye
• Iodized oil

• Animals
• Anthracenes
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/metabolism
• Antineoplastic Agents/pharmacology
• Chemistry, Pharmaceutical/methods
• Dimethyl Sulfoxide/chemistry
• Iodine Radioisotopes/chemistry
• Iodine Radioisotopes/metabolism
• Iodine Radioisotopes/pharmacology
• Liver/metabolism
• Male
• Necrosis
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Perylene/analogs & derivatives
• Perylene/chemistry
• Perylene/metabolism
• Perylene/pharmacology
• Polyethylene Glycols/chemistry
• Radiopharmaceuticals/chemistry
• Radiopharmaceuticals/metabolism
• Radiopharmaceuticals/pharmacology
• Rats
• Spleen/metabolism
• Tissue Distribution
• Water/chemistry

Objectives: 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.

Materials and Methods: 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 ¹³¹I-iodohypericin (¹³¹I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of ¹³¹I-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 ¹³¹I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h.

Results: Gamma counting revealed fast clearance of ¹³¹I-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 cm³ 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.

Conclusion: 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.

• necrosis targeting radiotherapy
• radiation-induced fibrosarcoma-1 (RIF-1)
• survival
• synergistic antitumor effects.
• vascular disrupting agents (VDAs)

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.

• SMSDTTS
• combretastatin A4 phosphate
• hypericin.
• necrosis avid contrast agent
• small molecule sequential dual-targeting theragnostic strategy
• vascular disrupting agent