Synthesis and biological evaluation of mixed-ligand cyclometalated iridium(III)-quinoline complexes.

With the aim of gaining new insight into the underlying apoptosis mechanisms and in vivo efficacy of cyclometalated Ir(III) complexes as metalodrugs, six new cyclometalated Ir(III)-quinoline complexes, [Ir(1a)(2pq)2] (2a), [Ir(1b)(2pq)2] (2b), [Ir(1c)(2pq)2] (2c), [Ir(1d)(2pq)2] (2d), [Ir(1e)(2pq)2] (2e), and [Ir(1f)(2pq)2] (2f) (2pq = 2-phenylisoquinoline), have been synthesized using 5,7-dihalo-8-hydroxylquinoline ligands (1a-1f) and [Ir(2pq)2Cl]2 precursors and characterized. Complexes 2a-2f have shown potent anticancer activity against cisplatin-resistant SK-OV-3/DDP and A549/DDP cells (IC50 = 0.11-1.83 µM), following the order 2e > 2f > 2b > 2c > 2d > 2a. Confocal microscopy images suggest that 2e and 2b could act as red-color probes for specific cell imaging and efficiently initiate apoptosis and autophagy in the mitochondria, cell cytosol, and nucleus. Overexpression of beclin1, caspase-9, cytochrome c, LC3II, and apaf-1; inhibition of p62, cyclin D1, cyclin A2, and CDK2; and a substantial rapid accumulation suggest a paraptotic mode of cell death induced by autophagy, DNA damage, and mitochondrial stress. In addition, the inhibitory rate of 2e on A549/DDP tumor growth was 64.1% at a concentration of 10.0 mg kg-1, which is clearly higher than that of cisplatin. According to the biological assay, the cyclometalated Ir(III)-quinoline complex 2e exhibited a higher anticancer effect than 2b, which may be associated with the electronic effect of the methyl group of the 1e ligand of 2e playing a key role in the mechanism.

Ir-Ho bimetallic complex-mediated low-dose radiotherapy/radiodynamic therapy in vivo.

We report a bimetallic complex [Ir4Ho2(pq)8(H2dcbpy)4(OAc)2] (denoted as Ir4Ho2, pq = 2-phenylquinoline, H2dcppy = 2,2'-bipyridine-3,3'-dicarboxylic acid) and its application for radiotherapy/radiodynamic therapy (RT/RDT). In a tumor xenograft mouse model, Ir4Ho2 exerted a tumor-suppressive effect through efficient low-dose RT/RDT.

Discovery of unique and ENM- specific pathophysiologic pathways: Comparison of the translocation of inhaled iridium nanoparticles from nasal epithelium versus alveolar epithelium towards the brain of rats.

The biokinetics of inhaled nanoparticles (NP) is more complex than that of larger particles since NP may NP deposited on the nasal mucosa of the upper respiratory tract (URT) may translocate to the olfactory bulb of the brain and also via the trigeminus (URT neuronal route); and (b) NP deposited in the lower respiratory tract (LRT) may cross the ABB into blood and enter the brain across the blood-brain-barrier (BBB) or take a neuronal route from enervated tracheo-bronchial epithelia via the vagus nerve. Translocation from both - the URT and the LRT - are quantified during the first 24h after a 1-hour aerosol inhalation of 20nm-sized, (192)Ir radiolabeled iridium NP by healthy adult rats using differential exposures: (I) nose-only exposure of the entire respiratory tract or (II) intratracheal (IT) inhalation of intubated and ventilated rats, thereby bypassing the URT and extrathoracic nasal passages. After nose-only exposure brain accumulation (BrAcc) is significantly nine-fold higher than after IT inhalation since the former results from both pathways (a+b) while the latter exposure comes only from pathway (b). Interestingly, there are significantly more circulating NP in blood 24h after nose-only inhalation than after IT inhalation. Distinguishing translocation from URT versus LRT estimated from the differential inhalation exposures, the former is significantly higher (8-fold) than from the LRT. Although the BrAcc fraction is rather low compared to total NP deposition after this short-term exposure, this study proofs that inhaled insoluble NP can accumulate in the brain from both - URT and LRT which may trigger and/or modulate adverse health effects in the central nervous system (CNS) during chronic exposure.

Dual-Enzyme Characteristics of Polyvinylpyrrolidone-Capped Iridium Nanoparticles and Their Cellular Protective Effect against H2O2-Induced Oxidative Damage.

Polyvinylpyrrolidone-stabilized iridium nanoparticles (PVP-IrNPs), synthesized by the facile alcoholic reduction method using abundantly available PVP as protecting agents, were first reported as enzyme mimics showing intrinsic catalase- and peroxidase-like activities. The preparation procedure was much easier and more importantly, kinetic studies found that the catalytic activity of PVP-IrNPs was comparable to previously reported platinum nanoparticles. Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) characterization indicated that PVP-IrNPs had the average size of approximately 1.5 nm and mainly consisted of Ir(0) chemical state. The mechanism of PVP-IrNPs' dual-enzyme activities was investigated using XPS, Electron spin resonance (ESR) and cytochrome C-based electron transfer methods. The catalase-like activity was related to the formation of oxidized species Ir(0)@IrO2 upon reaction with H2O2. The peroxidase-like activity originated from their ability acting as electron transfer mediators during the catalysis cycle, without the production of hydroxyl radicals. Interestingly, the protective effect of PVP-IrNPs against H2O2-induced cellular oxidative damage was investigated in an A549 lung cancer cell model and PVP-IrNPs displayed excellent biocompatibility and antioxidant activity. Upon pretreatment of cells with PVP-IrNPs, the intracellular reactive oxygen species (ROS) level in response to H2O2 was decreased and the cell viability increased. This work will facilitate studies on the mechanism and biomedical application of nanomaterials-based enzyme mimic.

Evaluation of Cuprimine® and Syprine® for decorporation of radioisotopes of cesium, cobalt, iridium and strontium.

Cuprimine® and Syprine® are therapeutics approved by the USFDA to treat copper overload in Wilson Disease (a genetic defect in copper transport) by chelation and accelerated excretion of internally-deposited copper. These oral therapeutics are based on the respective active ingredients D-penicillamine (DPA) and N,N'-bis (2-aminoethyl) -1,2-ethanediamine dihydrochloride (Trien). Cuprimine is considered the primary treatment, although physicians are increasingly turning to Syprine as a first-line therapy. Both drugs exhibit oral systemic activity and low toxicity; their biological effects and safety are established. Previous in vivo studies using a rodent animal model established the decorporation potential of Cuprimine and Syprine for (60)Co and (210)Po. Currently these studies are being expanded to evaluate the in vivo decorporation efficacy of these drugs for several additional radionuclides. In this report, results of this investigation are discussed using the radionuclides (137)Cs, (60)Co, (192)Ir and (85)Sr. Short-term 48-h pilot studies were undertaken to evaluate DPA and Trien for their in vivo decorporation potential using male Wistar-Han rats. In these studies, a radionuclide solution was administered to the animals by intravenous (IV) injection, followed by a single IV dose of either DPA or Trien. Control animals received the radionuclide alone. Results show effective decorporation of (60)Co by DPA within the time frame evaluated. DPA and Trien were also modestly effective in decorporation of (137)Cs and (85)Sr, respectively. The study did not find DPA or Trien effective for decorporation of (192)Ir. Based on these encouraging findings, further studies to evaluate the dose-response profiles and timing of the chelator administration post exposure to radionuclides are warranted.

Changes of postoperative impedances in cochlear implant patients: the short-term effects of modified electrode surfaces and intracochlear corticosteroids.

OBJECTIVE: The objective of this study was to investigate the effect of intraoperative application of steroid suspension and coating of the electrode contacts with a thin film of iridium oxide on the short-term, time-dependent development of the intracochlear impedance in adults implanted with the Nucleus 24 Contour electrode. STUDY DESIGN: The time-dependent development of intracochlear impedances was investigated in four different groups of adult patients at daily and later weekly intervals until the first fitting. The four groups were as follows: 1) standard Nucleus 24 Contour (control, n = 7); 2) standard Nucleus 24 Contour with intraoperative application of steroids (Group S, n = 6); 3) iridium-coated Nucleus 24 Contour control (Group I, n = 8); and 4) iridium-coated Nucleus 24 Contour with intraoperative application of steroids (Group I + S, n = 5). All patients had postlinguistic onset of severe to profound sensorineural hearing loss and no or little benefit of conventional hearing aids. Absence of ossification or any other cochlear anomaly and also absence of signs of retrocochlear or central origin to the hearing impairment bilaterally had to be confirmed preoperatively. RESULTS: Steroid application reduced impedances significantly (Groups S and I + S), whereas iridium coating lowered variance of the impedance among patients but did not reduce the impedance significantly. The steroid-induced reduction is more pronounced at basal electrode contacts. Furthermore, there is some indication that the tissue growth could be faster in patients having the iridium-coated Contour electrode. CONCLUSION: Provided that the reduction of electrode impedances with application of steroids is persisting, intracochlear application of steroids can be considered on a regular basis. Iridium coating of the electrode contacts seems not to be justified to be included as standard procedure.

Reducing radiation dose to pelvic small bowel in cervical cancer patients treated with Ir-192 intracavitary brachytherapy by using urinary bladder distension.

OBJECTIVES: Several techniques and devices have been used in an attempt to minimize radiation dose to gastrointestinal tract while giving pelvic radiation. We evaluated the effect of urinary bladder distension to displace pelvic small bowel out of intracavitary brachytherapy field to minimize radiation dose to small bowel in cervical cancer patients. MATERIAL AND METHOD: Eleven cervical cancer patients who received Ir-192 intracavitary brachytherapy with tandem and transverse ovoids were included in this study. Oral contrast material was used to visualize pelvic small bowel. Urinary bladder was distended by injection 125-200 ml. normal saline solution. Pelvic radiograph, anteroposterior and lateral view, was performed before and after bladder distention for brachytherapy treatment planning and comparing radiation dose at small bowel. RESULTS: The average maximum radiation dose at small bowel before and after bladder distension were 3123 cGy and 1998 cGy respectively. The summation of small bowel dose was reduced 54.17% (p = 0.002). CONCLUSION: Urinary bladder distension could effectively displace pelvic small bowel and reduce the radiation dose to small bowel from Ir-192 intracavitary brachytherapy in cervical cancer patients.

Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low.

Recently it was speculated that ultrafine particles may translocate from deposition sites in the lungs to systemic circulation. This could lead to accumulation and potentially adverse reactions in critical organs such as liver, heart, and even brain, consistent with the hypothesis that ultrafine insoluble particles may play a role in the onset of cardiovascular diseases, as growing evidence from epidemiological studies suggests. Ultrafine (192)Ir radio-labeled iridium particles (15 and 80 nm count median diameter) generated by spark discharging were inhaled by young adult, healthy, male WKY rats ventilated for 1 h via an endotracheal tube. After exposure, excreta were collected quantitatively. At time points ranging from 6 h to 7 d, rats were sacrificed, and a complete balance of (192)Ir activity retained in the body and cleared by excretion was determined gamma spectroscopically. Thoracic deposition fractions of inhaled 15- and 80-nm (192)Ir particles were 0.49 and 0.28, respectively. Both batches of ultrafine iridium particles proved to be insoluble (<1% in 7 d). During wk 1 after inhalation particles were predominantly cleared via airways into the gastrointestinal tract and feces. This cleared fraction includes particles deposited in the alveolar region. Additionally, minute particle translocation of <1% of the deposited particles into secondary organs such as liver, spleen, heart, and brain was measured after systemic uptake from the lungs. The translocated fraction of the 80-nm particles was about an order of magnitude less than that of 15-nm particles. In additional studies, the biokinetics of ultrafine particles and soluble (192)Ir was studied after administration by either gavage or intratracheal instillation or intravenous injection. They confirmed the low solubility of the particles and proved that (1) particles were neither dissolved nor absorbed from the gut, (2) systemically circulating particles were rapidly and quantitatively accumulated in the liver and spleen and retained there, and (3) soluble (192)Ir instilled in the lungs was rapidly excreted via urine with little retention in the lungs and other organs. This study indicates that only a rather small fraction of ultrafine#10; iridium particles has access from peripheral lungs to systemic circulation and extrapulmonary organs. Therefore, the hypothesis that systemic access of ultrafine insoluble particles may generally induce adverse reactions in the cardiovascular system and liver leading to the onset of cardiovascular diseases needs additional detailed and differentiated consideration.

Rapid renal single-photon emission tomography by continuous infusion of iridium-191m.

Continuous infusion of iridium-191m (t1/2 = 5 s), produced with an 191Os/191mIr generator, was used to obtain rapid high-resolution single-photon emission tomography (SPET) of renal blood flow in the rabbit. SPET scans of the abdomen were obtained with a triple-detector SPET system (MS3, Siemens Gammasonics). The generator was eluted at a flow rate of 3 ml/min, which delivered a steady-state dose of 170 MBq (4.5 mCi) of 191mIr. The total 191Os breakthrough was 850 kBq (23 microCi). A 5-min SPET acquisition recorded a total of 2.8 million counts, resulting in images of high technical quality. Volume-rendered images clearly showed the abdominal aorta, splenic artery, spleen, renal arteries, kidneys and splanchnic vasculature. Tomographic slices through the kidneys revealed tracer primarily within the renal cortices without visualization of the collecting system. The estimated effective dose equivalent for a 5 min infusion of 191mIr at a steady-state dose of 170 MBq is 0.74 mSv compared with 2.7 mSv from a 170 MBq dose of 99mTc-DMSA. This study demonstrates the feasibility of high-resolution SPET of regional renal perfusion in the rabbit by continuous intravenous infusion of 191mIr. The renal distribution of continuously infused 191mIr is largely within the cortices, with minimal or no detectable activity in the region of the renal pelvicalyceal system. Using this technique, cortical renal SPET can be completed much more rapidly (< 5 min) than with conventional renal cortical imaging agents, which suggests that this technique could be applied to the observation of rapid changes in renal perfusion such as those resulting from pharmacologic intervention, obviating the need for the patient to return for additional visits. Additional studies are required to (a) validate the methodology in larger animals prior to considering the potential for use in human beings, (b) optimize the generator design for continuous infusion, and (c) evaluate the changes in the distribution of 191mIr that occur in animal models of altered renal perfusion.

Two-year follow-up after catheter-based radiotherapy to inhibit coronary restenosis.

BACKGROUND: Although early trials indicate the treatment of restenosis with radiation therapy is safe and effective, the long-term impact of this new technology has been questioned. The possibility of late untoward consequences, such as aneurysm formation, perforation, and accelerated vascular disease, is of significant concern. Furthermore, it is not known whether the beneficial effects of radiation therapy will be durable or whether radiation will only delay restenosis. METHODS AND RESULTS: A double-blind, randomized trial was undertaken to compare 192Ir with placebo sources in patients with previous restenosis after coronary angioplasty. Patients were randomly assigned to receive a 0.76-mm (0. 03-in) ribbon containing sealed sources of either 192Ir or placebo. All patients underwent repeat coronary angiography at 6 months. All living patients were contacted 24 months after their index study procedure. Patients were assessed with respect to the need for target-lesion revascularization or nontarget-lesion revascularization, occurrence of myocardial infarction, or death. Over a 9-month period, 55 patients were enrolled; 26 were randomized to 192Ir and 29 to placebo. Follow-up was obtained in 100% of living patients at a minimum of 24 months. Target-lesion revascularization was significantly lower in the 192Ir group (15.4% versus 44.8%; P<0. 01). Nontarget-lesion revascularization was similar in 192Ir and placebo patients (19.2% versus 20.7%; P=NS). There were 2 deaths in each group. The composite end point of death, myocardial infarction, or target-lesion revascularization was significantly lower in 192Ir-treated versus placebo-treated patients (23.1% versus 51.7%; P=0.03). No patient in the 192Ir group sustained a target-lesion revascularization later than 10 months. CONCLUSIONS: At 2-year clinical follow-up, treatment with 192Ir demonstrates significant clinical benefit. Although further follow-up (including late angiography) will be necessary, no clinical events have occurred to date in the 192Ir group to suggest major untoward effects of vascular radiotherapy. At the intermediate follow-up time point, vascular radiotherapy continues to be a promising new treatment for restenosis.

Remotely controllable temporary afterloading brachytherapy for malignant brain tumors.

We present the results of six patients with recurrent malignant brain tumors who underwent an alternative system of interstitial brachytherapy. In each patient, the neurosurgeon initially inserted several small catheters into the tumor target through a stereotactic procedure or open craniotomy. Later, the patient was treated using an intracatheter temporary implant of a high-dose-rate 192Iridium. We delivered a mean dose of 6 Gy per fraction into the rim of the tumor margin and limited it to 2 Gy at a distance of 1 cm outwards. Each patient received one fraction, 3 to 5 minutes every 2 days, for a total of three fractions. In between these treatments, patients performed regular daily activities and had nursing care as usual. There was no surgical mortality in this study. One patient had late-onset anemia. This treatment modality has the advantage of combining cytodiagnosis/reduction and radiation within one very short therapeutic time period.

[Contribution of curietherapy in the treatment of ENT tumors]. / Apport de la curiethérapie dans le traitement des tumeurs de la sphére ORL.

Considerable improvement has been made in head and neck brachytherapy since the historical radium era. This technique now allows a conservative treatment for buccal cavity and oropharynx tumors with a local control similar to surgery. When combined with external beam radiotherapy, brachytherapy allows to give a lesser dose to the critical organs. We review the brachytherapy techniques and results for various head and neck location.

Braquiterapia de alta taxa de dose / High dose rate brachytherapy

A braquiterapia de alta taxa de dose utiliza fonte unica de '192 ANT. IND Ir' com atividade nominal inicial de 10Ci em equipamento com controle remoto. Esta tecnica permite que o tratamento seja realizado em regime ambulatorial, sem os inconvenientes da braquiterapia classica, como anestesia geral ou raquidiana, imobilizacao prolongada no leito e exposicao de pessoa a irradiacao. O servico de radioterapia possui cinco protocolos de tratamento em estudo: carcinoma de colo uterino, endometrio, pulmao, esofago e tumores do sistema nervoso central. Desde a instalacao do Micro Selectron HDR foram tratados 90 pacientes, com um total de 257 procedimentos. As aplicacoes sao semanais, perfazendo tres a quatro fracoes. Devido ao pouco tempo de atividade, os resultados sao preliminares, mas perfeitamente comparaveis aos primeiros meses dos tratamenos classicos. Nao tivemos nenhuma complicacao durante os procedimentos ou imediatamente apos. Muitos estudos devem ser realizados para se estabelecer criterios de dose, fracionamento e associacao ideais, a fim de se alcancar um alto nivel de taxa terapeutica.

[Breast preserving therapy: shorter treatment duration by the peroperative introduction of iridium guide needles]. / Mammasparende therapie: kortere behandelingsduur door peroperatief plaatsen van iridiumgeleidenaalden.

In the Deventer Radiotherapeutic Institute from January 1981 through December 1989, 359 patients who had undergone a breast-saving operation were irradiated. Since 1987, iridium guiding needles were introduced peroperatively in 79 of these patients. Subsequently, irradiation was administered. With this method the total duration of treatment was 16 days shorter on average than in patients who postoperatively were treated with iridium or external irradiation; also, the patients treated peroperatively needed only to be anaesthetized once. In addition, better positioning of the needles was possible, reducing the risk of faulty localization. The follow-up was short but the preliminary results of the treatment were good (one local recurrence after an average follow-up of 20 months) and no adverse effect on wound healing was seen.

Safety of 125iodine and 192iridium implants to the canine carotid artery. Long-term results.

Thirty-nine healthy dogs underwent a simulated radical neck dissection followed by implantation of either 125Iodine (125I) or 192Iridium (192Ir) in various dose regimes randomized prospectively from 3,000 to 30,000 rad. Bilateral selective carotid angiography was performed immediately postoperatively and at 6, 12, 18, and 24 months. No significant effects occurred to the animals who received 15,000 rad 125I or 6,000 rad 192Ir. In the higher dosed animals the 125I-treated group fared better than the 192Ir-treated group, probably due to the lower dose rate delivery. Fewer and less serious complications occurred in the 125I-treated group, but this group developed more complications after one year than the Iridium group.