New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at ...submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones.METHODS: Cholesterol, mixed and ...pigment stones from cholecystectomy patients were incubated with hypericin or solvent. After 72 h, the stones were analysed for fluorescence（365 nm） and treated with 2-propanol/dimethyl sulfoxide for high performance liquid chromatography（HPLC） analysis. Rats with virtual gallbladder containing human cholesterol, mixed or pigment gallstones（VGHG） received 5 mg/kg hypericin or solvent and VGHG rats with cholesterol stones were given different hypericin doses（5-15 mg/kg）. Twelve hours later, the stones were analysed at 365 nm. Biliary excretion and metabolites of hypericin were assessed in common bile duct（CBD） cannulated rats for 9 h using fluorospectrometry, HPLC and matrixassisted laser desorption/ionization-time-of-flight mass spectrometry（MALDI-TOF MS）.RESULTS: Homogeneous high fluorescence was seen on cholesterol stones either pre-incubated with hypericin or extracted from VGHG rats receiving hypericin. Mixed stones showed a dotted fluorescent pattern, whereas pigment and solvent-treated ones lacked fluorescence. HPLC showed 7.68, 6.65 and 0.08 × 10-3 M of cholesterol in extracts from cholesterol, mixed, and pigment gallstones, respectively. Hypericin accounted for 2.0, 0.5 and 0.2 × 10-6 M in that order. On cholesterol stones from VGHG rats receiving different hypericin doses, a positive correlation was observed between dose and fluorescence. In the bile from CBD-cannulated rats, fluorescence represented 20% of the injected dose with two peaks in 9 h. HPLC analysis revealed that hypericin conjugates reached 60% of the peak area. By MALDI-TOF MS, hypericinglucuronide was detected. CONCLUSION: This study proves the potential use of hypericin for differential fluorescent detection of human gallstones regarding their chemical composition.
To test the hypothesis that targeting the microenvironment (soil) may effectively kill cancer cells (seeds) through a small-molecular weight sequential dual-targeting theragnostic strategy, or ...dual-targeting approach.
With approval from the institutional animal care and use committee, 24 rats were implanted with 48 liver rhabdomyosarcomas (R1). First, the vascular-disrupting agent combretastatin A4 phosphate (CA4P) was injected at a dose of 10 mg/kg to cause tumor necrosis, which became a secondary target. Then, the necrosis-avid agent hypericin was radiolabeled with iodine 131 to form (131)I-hypericin, which was injected at 300 MBq/kg 24 hours after injection of CA4P. Both molecules have small molecular weight, are naturally or synthetically derivable, are intravenously injectable, and are of unique targetablities. The tumor response in the dual-targeting group was compared with that in vehicle-control and single-targeting (CA4P or (131)I-hypericin) groups with in vivo magnetic resonance imaging and scintigrams and ex vivo gamma counting, autoradiography, and histologic analysis. Tumor volumes, tumor doubling time (TDT), and radiobiodistribution were analyzed with statistical software. P values below .05 were considered to indicate a significant difference.
Eight days after treatment, the tumor volume of rhabdomyosarcoma in the vehicle-control group was double that in both single-targeting groups (P < .001) and was five times that in the dual-targeting group (P < .0001), without treatment-related animal death. The TDT was significantly longer in the dual-targeting group (P < .0001). Necrosis appeared as hot spots on scintigrams, corresponding to 3.13% of the injected dose of (131)I-hypericin per gram of tissue (interquartile range, 2.92%-3.97%) and a target-to-liver ratio of 20. The dose was estimated to be 100 times the cumulative dose of 50 Gy needed for radiotherapeutic response. Thus, accumulated (131)I-hypericin from CA4P-induced necrosis killed residual cancer cells with ionizing radiation and inhibited tumor regrowth.
This dual-targeting approach may be a simple and workable solution for cancer treatment and deserves further exploitation.
To study the effect of co-injecting unlabelled hypericin (Hyp) on biodistribution, necrosis uptake and tumour retention of iodine-123 or iodine-131 labelled hypericin ((123/131)I-Hyp), a necrosis ...avid agent for an anticancer radiotherapy.
(123/131)I-Hyp was prepared with Iodogen as oxidant and formulated in 0.6 μg/kg no-carrier-added (NCA) or 0.25 mg/kg unlabelled Hyp carrier-added (CA) forms using dimethyl sulfoxide/polyethylene glycol-400/propylene glycol/water (25/25/25/25% v/v/v/v), as solvent mixture. Comparisons on biodistribution and necrosis uptake of NCA and CA(123)I-Hyp were conducted on rats (n=24) of reperfused liver infarction (RPLI) in 48h p.i. Tumour retention of CA(131)I-Hyp was assessed in severe combined immunodeficiency (SCID) mice with fibrosarcoma (RIF-1) tumours (n=25) over 40 days. To cause intratumour necrosis, mice were pre-treated with a vascular disrupting agent CA4P at 10mg/kg. Tissue-gamma counting (TGC), autoradiography and histology were performed.
TGC revealed no significant difference in organ biodistribution between RPLI-rats injected with NCA and CA(123)I-Hyp, except in intestines, liver, lungs and stomach (P<0.05). Both preparations showed hepatobiliary excretion since intestines and faeces retained the most radioactivity. NCA and CA(123)I-Hyp exhibited high avidity and selectivity for hepatic infarction. From the day after injection onward, CA(123)I-Hyp showed greater target accumulation (7-11%ID/g) than (123)I-Hyp alone (~4%ID/g; P<0.05). In RIF-1-SCID mice receiving CA(131)I-Hyp, prolonged high retention in tumour necrosis was detected over 40 days p. i. TGC findings were confirmed by histological and autoradiographic analysis.
The study demonstrated the co-injection of unlabelled Hyp affected necrosis uptake but almost no biodistribution of radioiodinated Hyp. Long-term high retention into tumour necrosis characterizes the carrier-added (131)I-Hyp.
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.
OBJECTIVE:To compare a commercial contrast agent (CA) Dotarem and a necrosis-avid CA (NACA) for their ability to evaluate the therapeutic necrosis with a vascular disrupting agent (VDA) on magnetic ...resonance imaging in rodent liver tumors to determine which could better correlate with the histopathologic outcome.
METHODS:After the VDA treatment, 16 rats with 32 liver rhabdomyosarcomas were randomized into Dotarem and NACA groups (n = 8 per group) for both interindividual and intraindividual comparisons. T2-weighted imaging, T1-weighted imaging (T1WI), contrast-enhanced T1-weighted imaging (CE-T1WI), and diffusion-weighted imaging were performed at baseline, after VDA treatment and CA injections. The enhancing efficacy of CAs at immediate and delayed enhancement on CE-T1WI in viable tumor and necrosis was compared. Tumor necrosis ratios calculated from NACA and Dotarem were compared and correlated with gold-standard histopathology.
RESULTS:On the immediate CE-T1WI, viable tumor was enhanced by either CA. On the delayed CE-T1WI at 30 minutes, both CAs failed to demarcate viable tumor from necrosis. At 24 hours post-NACA, the necrosis was clearly distinguished from viable tumor and thus derived necrosis ratio matched that from histopathology (P = 0.99); necrosis ratio from Dotarem was significantly lower than that from NACA and histopathology (P < 0.05, both), with a higher correlation of NACA than that of Dotarem with histopathology (r = 0.99 vs. r = 0.82).
CONCLUSIONS:NACA better evaluated VDA-induced tumor necrosis than nonspecific CA on T1WI in tumor models of rat liver. NACA showed a closer correlation with histopathology than nonspecific CA for the delineation of true necrosis. Delayed enhancement on T1WI with nonspecific CA is not suitable for the assessment of VDA-induced tumor necrosis.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiac lipomatous metaplasia (LM) occurs in patients with chronic ischemic heart disease and heart failure with unclear mechanisms. We studied coronary occlusion/reperfusion-induced myocardial ...infarction (MI) in rabbits during a 9-months follow-up using 3.0 T magnetic resonance scanner, and confirmed the presence of MI in acute phase and LM in chronic phase using histopathology.
MI was surgically induced in 10 rabbits by 90-min coronary artery occlusion and reperfusion. Forty-eight hours later, multiparametric cardiac magnetic resonance imaging (cMRI) was performed at a 3.0 T clinical scanner for MI diagnosis and cardiac function analysis. Afterwards, seven rabbits were scarified for histochemical staining with triphenyltetrazolium chloride (TTC), and hematoxylin-eosin (HE), and 3 were scanned with cMRI at 2 days, 2 weeks, 2 months and 9 months for longitudinal observations of morphological and functional changes, and the fate of the animals. Post-mortem TTC, HE and Masson's trichrome (MTC) were studied for chronic stage of MI.
The size of acute MI correlated well between cMRI and TTC staining (r(2)=0.83). Global cardiac morphology-function analysis showed significant correlation between increasing acute MI size and decreasing ejection fraction (p<0.001). During 9 months, cMRI documented evolving morphological and functional changes from acute MI to chronic scar transformation and fat deposition with a definite diagnosis of LM established by histopathology.
Acute MI and chronic LM were induced in rabbits and monitored with 3.0 T MRI. Studies on this platform may help investigate the mechanisms and therapeutic interventions for LM.
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.
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