Cytocidal Effects of Interstitial Photodynamic Therapy Using Talaporfin Sodium and a Semiconductor Laser in a Rat Intracerebral Glioma Model.

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions.

"Honey pot"-like lesion formation: Impact of catheter contact angle on lesion formation by novel diamond-embedded temperature-controlled ablation catheter in a porcine experimental model.

Background: Novel diamond-embedded catheter enables precise temperature-controlled ablation. However, the effects of contact angle on lesion formation of this catheter are poorly understood.

Objective: The purpose of this study was to evaluate lesion formation using the temperature-controlled ablation catheter embedded with diamond at different angles in a porcine experimental model.

Efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model.

To investigate the therapeutic potential of photodynamic therapy (PDT) for malignant gliomas arising in unresectable sites, we investigated the effect of tumor tissue damage by interstitial PDT (i-PDT) using talaporfin sodium (TPS) in a mouse glioma model in which C6 glioma cells were implanted subcutaneously. A kinetic study of TPS demonstrated that a dose of 10 mg/kg and 90 min after administration was appropriate dose and timing for i-PDT. Performing i-PDT using a small-diameter plastic optical fiber demonstrated that an irradiation energy density of 100 J/cm or higher was required to achieve therapeutic effects over the entire tumor tissue.

Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS.

Background: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury.

Photobiomodulation and nitric oxide signaling.

Nitric oxide (NO) is a well-known gaseous mediator that maintains vascular homeostasis. Extensive evidence supports that a hallmark of endothelial dysfunction, which leads to cardiovascular diseases, is endothelial NO deficiency. Thus, restoring endothelial NO represents a promising approach to treating cardiovascular complications.

Estimation of mechanical properties by transcatheter monitoring using local impedance and contact force.

The mechanical properties of the myocardium in the left ventricle and right atrium were estimated by simultaneously measuring the local impedance (LI) and contact force (CF) using an ablation catheter. Radiofrequency catheter ablation (RFCA) is a well-established arrhythmia treatment. Monitoring the RF power, CF and properties of myocardium during RFCA are necessary to estimate the effect of ablation.

Near-infrared II photobiomodulation augments nitric oxide bioavailability via phosphorylation of endothelial nitric oxide synthase.

There is solid evidence of the beneficial effect of photobiomodulation (PBM) with low-power near-infrared (NIR) light in the NIR-I window in increasing bioavailable nitric oxide (NO). However, it is not established whether this effect can be extended to NIR-II light, limiting broader applications of this therapeutic modality. Since we have demonstrated PBM with NIR laser in the NIR-II window, we determined the causal relationship between NIR-II irradiation and its specific biological effects on NO bioavailability.

Short-Time Impedance Spectroscopy Using a Mode-Switching Nonsinusoidal Oscillator: Applicability to Biological Tissues and Continuous Measurement.

Herein, we propose an impedance spectroscopy method using a mode-switching nonsinusoidal oscillator and apply this method for measuring the impedance of biological tissues and continuous impedance measurement. To obtain impedance spectra over a wide frequency range, we fabricated a novel nonsinusoidal oscillator incorporating binary counters and analog switches. This oscillator could periodically switch oscillation frequency through the mode switching of the feedback resistor.

A three-compartment non-linear model of myocardial cell conduction block during photosensitization.

This study constructed a new non-linear model of myocardial electrical conduction block during photosensitization reaction to identify the vulnerable cell population and generate an index for recurrent risk following catheter ablation for tachyarrhythmia. A three-compartment model of conductive, vulnerable, and blocked cells was proposed. To determine the non-linearity of the rate parameter for the change from vulnerable cells to conductive cells, we compared a previously reported non-linear model and our newly proposed model with non-linear rate parameters in the modeling of myocardial cell electrical conduction block during photosensitization reaction.

Clinical application of the mirror irradiation technique in photodynamic therapy for malignant glioma.

Background: Intraoperative photodynamic therapy (PDT) using talaporfin sodium for malignant glioma is effective both in the experimental and in the clinical setting. Because the irradiation unit is fixed to the objective lens of the operating microscope, blind spots for irradiation exist. To overcome this problem, we developed a mirror reflecting system using a modified dental mirror.

Respiration and Heat Shock Protein After Short-Term Heating/Stretch-Fixing on Smooth Muscle Cells.

Purpose: A treatment device without a stent is needed for peripheral stenotic artery treatment. We have proposed short-term heating balloon angioplasty, photo-thermo dynamic balloon angioplasty (PTDBA). Though smooth muscle cells (SMCs) after PTDBA are fixed in a stretched formation in a porcine model, influences of this stimulus on SMCs have not been investigated.

Diffused light attenuation at 664 nm for PDT in salted cadaver brain.

Background: We investigated light attenuation at 664 nm, which is the excitation wavelength of photodynamic therapy (PDT) using talaporfin sodium, in a salted cadaver brain. Estimation of therapeutic lesions is important to ensure the effectiveness and safety of brain tumor PDT. Previously reported optical properties of the human brain vary widely.

Continuous Optical Monitoring of Red Blood Cells During a Photosensitization Reaction.

An oxygen-enriched photosensitizer solution was created by the addition of red blood cells (RBCs) as an investigative tool for photosensitization reactions (PRs). Although the oxygen levels and reaction progress can be monitored using the optical characteristics of hemoglobin, previously this has only been done using intermittent measurements. An increase in methemoglobin concentration with irradiation time was reported.

Modified optical coefficient measurement system for bulk tissue using an optical fiber insertion with varying field of view and depth at the fiber tip.

To measure the few millimeter-scale macroscopic optical properties of biological tissue, including the scattering coefficient, while avoiding the instability that originates from sample slicing preparation processes, we performed propagated light intensity measurements through an optical fiber that punctures the bulk tissue while varying the fiber tip depth and the field of view (FOV) at the tip; the results were analyzed using the inverse Monte Carlo method. We realized FOV changes at the fiber tip in the bulk tissue using a variable aperture that was located outside the bulk tissue through a short high-numerical aperture (high-NA) multi-mode fiber with a quasi-straight shape. Using a homogeneous optical model solution, we verified the principle and operation of the constructed experimental system.

A Three-Compartment Pharmacokinetic Model to Predict the Interstitial Concentration of Talaporfin Sodium in the Myocardium for Photodynamic Therapy: A Method Combining Measured Fluorescence and Analysis of the Compartmental Origin of the Fluorescence.

To evaluate the effectiveness of photodynamic therapy occurring in the interstitial space of the myocardium, we estimated the interstitial concentration of talaporfin sodium in the canine myocardium by constructing a three-compartment pharmacokinetic model based on measured changes in talaporfin sodium plasma concentration and myocardial fluorescence. Differential rate equations of talaporfin sodium concentration in the plasma, interstitial space, and cell compartment were developed with individual compartment volume, concentration, and rate constants. Using measured volume ratios based on histological examinations, we defined that the myocardial fluorescence consisted of the linear addition of fluorescence generated from these three compartments.

Oxygen-Enriched Photosensitizer Medium with Red Blood Cells to Study Tissue Interaction of Photosensitization Reaction.

Background: It has been reported that the oxygen pressure of a photosensitizer medium decreases during an irradiation leading to decrease in the efficacy of the photosensitization reaction against the target cell in vitro.

Objective: The aim of this study was to obtain solutions with high dissolved oxygen levels in cultivated wells with perceiving oxygen environment and photosensitizer bleaching for photosensitization reaction studies.

Materials And Methods: We used a 10-mm-wide optical cell cuvette with a 1-mm optical path length as the well.

Skin fluorescence following photodynamic therapy with NPe6 photosensitizer.

Background: The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period.

Development of a practical animal model of photodynamic therapy using a high concentration of extracellular talaporfin sodium in interstitial fluid: influence of albumin animal species on myocardial cell photocytotoxicity in vitro.

Photodynamic reaction-induced photocytotoxicity using talaporfin sodium is inhibited by serum proteins binding to talaporfin sodium. The serum albumin binding site for talaporfin sodium differs among animal species. To identify a practical animal therapeutic model, we studied the ability of human, canine, bovine, and porcine albumin to influence talaporfin sodium-induced photocytotoxicity in rat myocardial cells in vitro.

Effect of a photosensitization reaction performed during the first 3 min after exposure of rat myocardial cells to talaporfin sodium in vitro.

To better understand the mechanism of photodynamic cardiac ablation, we studied the effects of a photosensitization reaction (PR) performed during the first 3 min after rat myocardial cells were exposed to talaporfin sodium. A 3-mm-square microelectrode array with 64 electrodes was used to continuously measure the action potentials of the myocardial cells. A 30 μg/mL talaporfin sodium solution, a chlorine photosensitizer, was used, along with a 663-nm red diode laser (86 mW/cm for up to 600 s).

Temperature Influence on Myocardial Cell Cytotoxicity of the Extracellular Photosensitization Reaction with Talaporfin Sodium and Serum Proteins at 17°-37°C.

Background: We investigated the binding of talaporfin sodium with albumin and its photocytotoxicity during temperature changes by measuring absorbance spectra. The targeted tissue temperature differs according to the procedure. The photocytotoxicity efficiency should be investigated quantitatively because efficiency changes arising from temperature changes are expected.

Irradiance dependence of the conduction block of an in vitro cardiomyocyte wire.

Background: To obtain therapeutic condition precisely by in vitro experiment, we studied the irradiance dependence of the electrical conduction blockage caused by a photodynamic reaction using a high extracellular concentration of talaporfin sodium on a novel in vitro cardiomyocyte electrical conduction wire.

Methods: The cardiomyocyte wires were constructed on patterned cultivation cover glass, which had cultivation areas 60μm in width, and a maximum length of 10mm. The talaporfin sodium concentration was set to 20μg/mL.

Phototoxicity of Vascular Endothelial Cells Caused by Contact with Talaporfin Sodium for 15-120 Min: In Vitro and In Vivo Studies.

Objective: To reveal the mechanism of vascular patency in the myocardium after photosensitization immediately after talaporfin sodium (TS) injection in a canine model, we investigated acute injury to vascular endothelial cells (VECs) in vitro and in vivo.

Background Data: There are many reports of vascular shutdown within the target region in photodynamic therapy with TS. Vascular patency within healthy canine myocardium in which a photosensitization reaction starts immediately after injection of TS has been reported.

Dependence of damage within 10min to myocardial cells by a photodynamic reaction with a high concentration of talaporfin sodium outside cells in vitro on parameters of laser irradiation.

Background: To investigate the immediate occurrence of irreparable severe damage to myocardial cells up to 10min after a photodynamic reaction with a high concentration of photosensitizer outside cells, we measured the damage response time and the parameters that govern the response time via rat myocardial Ca(2+) concentration. In our proposed method for catheter ablation of tachyarrhythmia by photodynamic reaction, there are two components to the electrical conduction block: an immediate electrical conduction block of several tens of seconds to several minutes, and a permanent electrical conduction block.

Methods: Rat myocardial intracellular Ca(2+) concentration changes before, during and after the photodynamic reaction with a high concentration of photosensitizer outside myocardial cells were continuously observed using a Fluo-4 AM Ca(2+) probe.