RESUMEN
Metal-based photosensitizers are of interest as their absorption and chemical binding properties can be modified via the use of different ligands. Ru(2+) based photosensitizers are known to be effective photodynamic therapy (PDT) agents against bacteria, whereas use for oncological indications in vivo has not been demonstrated with the same level of evidence. We present data showing that premixing the Ru(2+)-complex TLD1433 with transferrin increases the molar extinction coefficient, including longer activation wavelengths, reduces photobleaching rates, and reduces the toxicity of the complex improving overall PDT efficacy. As the transferrin receptor is upregulated in most malignancies, premixing the Ru(2+) complex with transferrin converts the active pharmaceutical ingredient TLD1433 into a drug of potentially considerable clinical utility.
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Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Rutenio/química , Transferrina/química , Animales , Línea Celular , Humanos , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/farmacocinética , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The photo-physical and photo-biological properties of two small (<2 kDa), novel Ru(ii) photosensitizers (PSs) referred to as TLD1411 and TLD1433 are presented. Both PSs are highly water-soluble, provide only very limited luminescence emission at 580-680 nm following excitation at 530 nm, and demonstrate high photostability with less than 50% photobleaching at radiant exposures H = 275 J cm(-2) (530 nm irradiation). It was previously shown that these two photosensitizers exhibit a large singlet oxygen ((1)O2) quantum yield (Φ (Δ) â¼0.99 in acetonitrile). Their photon-mediated efficacy to cause cell death (λ = 530 nm, H = 45 J cm(-2)) was tested in vitro in colon and glioma cancer cell lines (CT26.WT, CT26.CL25, F98, and U87) and demonstrated a strong photodynamic effect with complete cell death at concentrations as low as 4 and 1 µM for TLD1411 and TLD1433, respectively. Notably, dark toxicity was negligible at concentrations less than 25 and 10 µM for TLD1411 and TLD1433, respectively. The ability of the PSs to initiate Type I photoreactions was tested by exposing PS-treated U87 cells to light under hypoxic conditions (pO2 < 0.5%), which resulted in a complete loss of the PDT effect. In vivo, the maximum tolerated doses 50 (MTD50) were determined to be 36 mg kg(-1) (TLD1411) and 103 mg kg(-1) (TLD1433) using the BALB/c murine model. In vivo growth delay studies in the subcutaneous colon adenocarcinoma CT26.WT murine model were conducted at a photosensitizer dose equal to 0.5 and 0.2 MTD50 for TLD1411 and TLD1433, respectively. 4 hours post PS injection, tumours were irradiated with continuous wave or pulsed light sources (λ = 525-530 nm, H = 192 J cm(-2)). Overall, treatment with continuous wave light demonstrated a higher tumour destruction efficacy when compared to pulsed light. TLD1433 mediated PDT resulted in statistically significant longer animal survival compared to TLD1411. Two-thirds of TLD1433-treated mice survived more than 100 days (p < 0.01) whereas TLD1411-treated mice did not survive longer than 20 days. Here we present evidence that two novel PSs have very potent photo-biological properties and are able to cause PDT-mediated cell death in both in vitro cell culture models and in vivo tumour regression.
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Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Rutenio/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Endogámicos BALB C , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Ratas , Rutenio/química , Relación Estructura-ActividadRESUMEN
The anti-viral properties of a small (≈1 kDa), novel Ru(II) photo dynamic compound (PDC), referred to as TLD-1433 (Ruvidar™), are presented. TLD-1433 had previously been demonstrated to exert strong anti-bacterial and anti-cancer properties. We evaluated the capacity of TLD-1433 to inactivate several human pathogenic viruses. TLD-1433 that was not photo-activated was capable of effectively inactivating 50 % of influenza H1N1 virus (ID50) at a concentration of 117 nM. After photo-activation, the ID50 was reduced to <10 nM. The dose of photo-activated TLD-1433 needed to reduce H1N1 infectivity >99 % (ID99) was approximately 170 nM. Similarly, the ID99 of photo-activated TLD-1433 was determined to range from about 20 to 120 nM for other tested enveloped viruses; specifically, a human coronavirus, herpes simplex virus, the poxvirus Vaccinia virus, and Zika virus. TLD-1433 also inactivated two tested non-enveloped viruses; specifically, adenovirus type 5 and mammalian orthoreovirus, but at considerably higher concentrations. Analyses of TLD-1433-treated membranes suggested that lipid peroxidation was a major contributor to enveloped virus inactivation. TLD-1433-mediated virus inactivation was temperature-dependent, with approximately 10-fold more efficient virucidal activity when viruses were treated at 37 °C than when treated at room temperature (â¼22 °C). The presence of fetal bovine serum and virus solution turbidity reduced TLD-1433-mediated virucidal efficiency. Immunoblots of TLD-1433-treated human coronavirus indicated the treated spike protein remained particle-associated.
RESUMEN
Background: A phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design setting and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.
RESUMEN
Photodynamic therapy (PDT) is an approved medical technique to treat certain forms of cancer. It has been used to complement traditional anticancer modalities such as surgery, chemotherapy or radiotherapy, and in certain cases, to replace these treatments. One critical parameter of PDT is the photosensitizer (PS); historically, a purely organic macrocyclic tetrapyrrole-based structure. This short review surveys two recent clinical examples of metal complexes, namely TOOKAD®-Soluble and TLD-1433, which have ideal photophysical properties to act as PDT PSs. We highlight the important role played by the metal ions in the PS for PDT activity.
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Antineoplásicos/química , Complejos de Coordinación/química , Neoplasias/terapia , Fármacos Fotosensibilizantes/química , Antineoplásicos/farmacología , Bacterioclorofilas/química , Bacterioclorofilas/farmacología , Terapia Combinada , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Solubilidad , Relación Estructura-ActividadRESUMEN
SIGNIFICANCE: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient. AIM: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall. APPROACH: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer's specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram. RESULTS: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties. CONCLUSIONS: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer's specific uptake ratio.
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Fotoquimioterapia , Neoplasias de la Vejiga Urinaria , Humanos , Método de Montecarlo , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
The erratum corrects a misspelled author surname.
RESUMEN
BACKGROUND: A common change that occurs with age in the central nervous system is an increase in microglial-associated inflammation. This is usually coupled with an increase in the concentration of the inflammatory cytokine interleukin-1beta (IL-1beta) in the hippocampus and an inhibition in long-term potentiation. OBJECTIVES: To assess the effects of a novel preparation of phospholipid nanoparticles incorporating phosphatidylglycerol, VP025, on inflammatory changes in hippocampus of aged and lipopolysaccharide (LPS)-treated rats. METHODS/RESULTS: We report that a possible initial target cell of the putative anti-inflammatory actions of VP025 may be macrophages, as VP025 is engulfed by, and has the capacity to alter the activity of, these cells. VP025 reversed the increase in IFN-gamma concentration in supernatant taken from peritoneal macrophages harvested from LPS-treated rats. In addition, markers of microglial activity, major histocompatibility complex class II (MHC II) mRNA expression, CD40 expression and IL-1beta concentration were increased, and CD200 expression was reduced, in the hippocampus of these rats. VP025 reversed changes in CD40, IL-1beta and CD200 in aged rats, and also restored long-term potentiation in aged and LPS-treated rats. CONCLUSIONS: We conclude that VP025 has the ability to modulate the activity of macrophage, microglia and neurons in response to stressors such as ageing and LPS treatment.
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Envejecimiento/fisiología , Antiinflamatorios/farmacología , Encefalitis/tratamiento farmacológico , Gliosis/tratamiento farmacológico , Microglía/efectos de los fármacos , Fosfatidilgliceroles/farmacología , Fosfolípidos/farmacología , Adulto , Animales , Antiinflamatorios/química , Encefalitis/inmunología , Encefalitis/fisiopatología , Gliosis/inducido químicamente , Gliosis/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Inmunomodulación/efectos de los fármacos , Inmunomodulación/fisiología , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Microglía/fisiología , Nanopartículas/química , Vía Perforante/efectos de los fármacos , Vía Perforante/metabolismo , Vía Perforante/fisiopatología , Fagocitosis/efectos de los fármacos , Fagocitosis/fisiología , Fosfatidilgliceroles/química , Fosfolípidos/química , Ratas , Ratas Wistar , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Glioblastoma is an aggressive brain cancer in adults with a grave prognosis, aggressive radio and chemotherapy provide only a 15 months median survival. METHODS: We evaluated the tolerability and efficacy of the Ruthenium-based photosensitizer TLD-1433 with apo-Transferrin (Rutherrin) in the rat glioma 2 (RG-2) model. The specific tumor uptake ratio and photodynamic therapy (PDT) threshold of the rat glioblastoma and normal brain were determined, survival and CD8+T-cell infiltration post-therapy were analyzed. Results were compared with those obtained for 5-aminolevulinic acid (ALA)-induced Protoporphyrin IX (PpIX)-mediated photodynamic therapy in the same animal model. As both photosensitizers have different photophysical properties, the number of absorbed photons required to achieve an equal cell kill was determined for in vitro and in vivo studies. RESULTS: A significantly lower absorbed energy was sufficient to achieve LD50 with Rutherrin versus PpIX-mediated PDT. Rutherrin provides a higher specific uptake ratio (SUR) >20 in tumors versus normal brain, whereas the SUR for ALA-induced PpIX was 10.6. To evaluate the short-term tissue response in vivo, enhanced T2-weighted magnetic resonance imaging (MRI) provided the spatial extent of edema, post PpIX-PDT at twice the cross-section versus Rutherrin-PDT suggesting reduced nonspecific damage, typically associated with a secondary wave of neuronal damage. Following a single therapy, a significant survival increase was observed in rats bearing glioma for PDT mediated by Rutherrin versus PpIX for the selected treatment conditions. Rutherrin-PDT also demonstrated an increased CD8+T-cell infiltration in the tumors. CONCLUSION: Rutherrin-PDT was well tolerated providing a safe and effective treatment of RG-2 glioma.
RESUMEN
During photodynamic therapy (PDT), disruption of cell respiration and metabolic changes could be one of the first events. Photophysical characteristics of the photosensitizer (PS) and its specific redox potential define consumption of molecular oxygen followed by generation of reactive oxygen species. The potential PS TLD1433 is based on transition metal Ru(II) and possess an oxygen-dependent luminescence. This enables the study of oxygen consumption by PS-phosphorescence lifetime imaging (PLIM) and simultaneously changes the cellular metabolic state by nicotinamide adenine dinucleotide (NAD(P)H)-fluorescence lifetime imaging (FLIM). Within this study, localization and cellular function of TLD1433 is investigated in bladder carcinoma cells using time-resolved and confocal laser scanning microscopy. Simultaneous FLIM/PLIM of NAD(P)H and TLD1433 during PDT correlated oxygen consumption, redox state and cellular energy metabolism. Our investigations aimed to provide a personalized protocol in theranostic PDT procedures and demonstrate the potential use of TLD1433 PDT also under hypoxic conditions, which are otherwise difficult to treat.
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Complejos de Coordinación/química , Espacio Intracelular/metabolismo , NADP/metabolismo , Imagen Óptica , Oxígeno/metabolismo , Fenantrolinas/química , Fármacos Fotosensibilizantes/química , Rutenio/química , Transporte Biológico , Línea Celular Tumoral , Complejos de Coordinación/metabolismo , Humanos , Oxidación-Reducción , Fenantrolinas/metabolismo , Fármacos Fotosensibilizantes/metabolismoRESUMEN
Cancer remains a major global malaise requiring the advent of new, efficient and low-cost treatments. Photodynamic therapy, which combines a photosensitizer and photons to produce cytotoxic reactive oxygen species, has been established as an effective cancer treatment but has yet to become mainstream. One of the main limitations has been the paucity of photosensitizers that are effective over a wide range of wavelengths, can exert their cytotoxic effects in hypoxia, are easily synthesized and produce few if any side effects. To address these shortfalls, three new osmium-based photosensitizers (TLD1822, TLD1824 and TLD1829) were synthesized and their photophysical and photobiological attributes determined. These photosensitizers are panchromatic (i.e. black absorbers), activatable from 200 to 900 nm and have strong resistance to photobleaching. In vitro studies show photodynamic therapy efficacy with both red and near-infrared light in normoxic and hypoxic conditions, which translated to good in vivo efficacy of TLD1829 in a subcutaneous murine colon cancer model.
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Complejos de Coordinación/química , Complejos de Coordinación/uso terapéutico , Osmio/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Ratones , Espectroscopía de Protones por Resonancia Magnética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The introduction of new disinfection and sterilization methods, such as antimicrobial photodynamic therapy, is urgently needed for the healthcare industry, in particular to address the pervasive problem of antibiotic resistance. This study evaluated the efficacy and the mechanisms of photodynamic antimicrobial chemotherapy (PACT), also known as photodynamic inactivation (PDI) of microorganisms, induced by novel Ru(II)-based photosensitizers against Staphylococcus aureus and methicillin-resistant S. aureus strains. METHODS: The photodynamic antibacterial effects of a new class of Ru(II)-based photosensitizers (TLD1411 and TLD1433) were evaluated against a strain of S. aureus (ATCC 25923) and a methicillin-resistant strain of S. aureus (MRSA, ATCC 33592). Bacterial samples were dosed with a range of photosensitizer concentrations (0.3-12 µM) and exposed to 530 nm light (90J cm(-2)) in normoxic conditions (ambient atmosphere) and in hypoxic conditions (0.5% O2). RESULTS: Both photosensitizers exerted photodynamic inactivation (PDI) of the microorganisms in normoxia, and this activity was observed in the nanomolar regime. TLD1411 and TLD1433 maintained this PDI potency under hypoxic conditions, with TLD1433 becoming even more active in the low-oxygen environment. CONCLUSION: The observation of activity in hypoxia suggests that there exists an oxygen-independent, Type I photoprocess for this new class of compounds in addition to the typical Type II pathway mediated by singlet oxygen. The intrinsic positive charge of the Ru(II) metal combined with the oxygen independent activity demonstrated by this class of photosensitizers presents a new strategy for eradicating both gram-positive and gram-negative bacteria regardless of oxygenation level.
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Desinfección/métodos , Resistencia a la Meticilina/efectos de los fármacos , Resistencia a la Meticilina/efectos de la radiación , Fotoquimioterapia/métodos , Rutenio/administración & dosificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Apoptosis/efectos de la radiación , Fármacos Fotosensibilizantes/administración & dosificación , Staphylococcus aureus/efectos de la radiaciónRESUMEN
BACKGROUND: Vapor-based fumigant systems for disinfection of health care surfaces and spaces is an evolving technology. A new system (AsepticSure) uses an ozone-based process to create a highly reactive oxidative vapor with broad and high-level antimicrobial properties. METHODS: Ozone gas at 50-500 ppm was combined with 3% hydrogen peroxide vapor in a test chamber and upscaled in rooms measuring 82 m3 and 90 m3 in area. Test organisms included methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, Escherichia coli, Pseudomonas aeruginosa, Clostridium difficile, and Bacillus subtilis spores dried onto steel discs or cotton gauze pads. RESULTS: The combination of 80-ppm ozone with 1% hydrogen peroxide vapor achieved a very high level of disinfection, with a ≥6 log10 reduction in the bacteria and spores tested on steel discs and MRSA tested on cotton gauze during a 30- to 90-minute exposure. The entire system was scalable such that it achieved the same high level of disinfection in both the 81-m3 and 90-m3 rooms in 60-90 minutes. CONCLUSION: The ozone hydrogen peroxide vapor system provides a very high level of disinfection of steel and gauze surfaces against health care-associated bacterial pathogens. The system is an advanced oxidative process providing a rapid and effective means of disinfecting health care surfaces and spaces.
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Desinfectantes/farmacología , Desinfección/métodos , Ozono/farmacología , Bacterias/efectos de los fármacos , Microbiología Ambiental , Instituciones de Salud , Humanos , Peróxido de Hidrógeno/farmacología , Viabilidad Microbiana/efectos de los fármacos , Esporas Bacterianas/efectos de los fármacosRESUMEN
Amyloid-beta (Abeta) peptides, the primary component of the amyloid plaques in Alzheimer's disease (AD), exert profound effects on neurons in vitro and negatively impact on neuronal function in vivo. One of the consequences of increased Abeta in the brain, either as a result of overexpression of the precursor amyloid precursor protein in transgenic mice, or injection into the brain is a decrease in one form of synaptic plasticity, long-term potentiation (LTP) in the hippocampus. Here we investigated the effect of infusion of Abeta for 28 days on LTP in dentate gyrus of rats and demonstrate that it was profoundly decreased compared with control-treated rats. We show that this effect is accompanied by increased activity of caspase 3, which is an indicator of cell stress. Significantly these changes were attenuated in animals which were pretreated with particles incorporating phosphatidylglycerol (VP025) and the evidence indicated that even when treatment was given 2 weeks after the start of the Abeta infusion, VP025 was capable of attenuating Abeta-induced changes. The evidence suggests that activation of caspase 3 was mediated by an Abeta-induced increase in sphingomyelinase, with the subsequent production of ceramide which is known to have a detrimental effect on neuronal function.
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Péptidos beta-Amiloides/administración & dosificación , Caspasa 3/efectos de los fármacos , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Animales , Caspasa 3/metabolismo , Estimulación Eléctrica , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Ratas , Ratas WistarRESUMEN
Failure of the ubiquitin-proteasome system to degrade abnormal proteins may underlie the accumulation of alpha-synuclein and dopaminergic neuronal degeneration that occurs in Parkinson's disease. Consequently, a reduction of functional proteasome activity has been implicated in Parkinson's disease. VP025 (Vasogen Inc.) is a preparation of phospholipid nanoparticles incorporating phosphatidylglycerol that has been shown to have neuroprotective effects. We show that VP025 prevents the deficits in motor coordination and dopamine observed in a proteasome inhibitor rat model of PD. Thus, VP025 may have a therapeutic effect on the impairment of dopaminergic-mediated motor activity induced by proteasome inhibition.