chlorophyll-a and Carcinoma--Basal-Cell

Photodynamic therapy (PDT) is a promising strategy for treating cancer. PDT involves three components: a photosensitizer (PS) drug, a specific wavelength of drug-activating light, and oxygen. A challenge in PDT is the unknown biodistribution of the PS in the target tissue. In this preliminary study, we report the development of a new approach to image in three dimensions the PS biodistribution in a noninvasive and fast manner.. A mesoscopic fluorescence tomography imaging platform was used to image noninvasively the biodistribution of 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH) in preclinical skin cancer models. Seven tumors were imaged and optical reconstructions were compared to nonconcurrent ultrasound data.. Successful imaging of the HPPH biodistribution was achieved on seven skin cancer tumors in preclinical models with a typical acquisition time of 1 minute. Two-dimensional fluorescence signals and estimated three-dimensional PS distributions were located within the lesions. However, HPPH distribution was highly heterogeneous with the tumors. Moreover, HPPH distribution volume and tumor volume as estimated by ultrasound did not match.. The results of this proof-of-concept study demonstrate the potential of MFMT to image rapidly the HPPH three-dimensional biodistribution in skin cancers. In addition, these preliminary data indicate that the PS biodistribution in skin cancer tumors is heterogeneous and does not match anatomical data. Mesoscopic fluorescence molecular tomography, by imaging fluorescence signals over large areas with high spatial sampling and at fast acquisition speeds, may be a new imaging modality of choice for planning and optimizing of PDT treatment.

Topics: Administration, Topical; Animals; Carcinoma, Basal Cell; Chlorophyll; Dermoscopy; Imaging, Three-Dimensional; Mice; Mice, Transgenic; Microscopy, Fluorescence; Photosensitizing Agents; Reproducibility of Results; Sensitivity and Specificity; Skin Absorption; Skin Neoplasms; Spectrometry, Fluorescence; Tissue Distribution; Tomography, Optical

"Radachlorin"(®), also known in the EU as Bremachlorin, a composition of 3 chlorophyll a derivatives in an aqueous solution, was introduced into the Russian Pharmacopoeia. Its GMP (Good Manufacturing Practice) facility based manufacturing method was patented. Laboratory experiments and clinical phase I were performed. Protocols were designed for PDT of basal cell carcinoma of the skin to result in GCP (Good Clinical Practice)-conformed randomized phase II clinical studies. "Radachlorin"(®) solution for intravenous infusions 0.35% 10mL in the doses of 0.5-0.6 and 1.0-1.2mg/kg and a gel for topical application 0.1% 25g in the dose of 0.1g/cm(2) were photoactivated by 2.5W 662nm semiconductor laser "LAKHTA-MILON(®)" (St. Petersburg, Russia) in light doses of 200, 300 (solution), 400, 600, 800 (gel) J/cm(2). Safety study showed no side effects and a good tolerability of "Radachlorin"(®) by patients. There was no normal skin/subdermal tissue damage after both laser and sun light exposure. The main part (98%) of the drug was excreted or metabolized in the first 48h. Drug administration at a dose of 1.0-1.2mg/kg and irradiation at 3h with 662±3nm light at a dose of 300J/cm(2) (solution) and 4 PDT sessions at an interval of 1 week with 3h gel exposure, followed by 400J/cm(2) light exposure (gel) were found to be the optimal treatment regimes. Having successfully passed clinical trials, "Radachlorin"(®) achieved marketing authorization in Russia in 2009 and a conditional approval in South Korea in 2008. It is a candidate for phase III clinical trials in the EC and may be commercialized as a prospective second-generation photosensitizer.

Topics: Carcinoma, Basal Cell; Chlorophyll; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Male; Photochemotherapy; Photosensitizing Agents; Porphyrins; Skin Neoplasms

Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal carcinoma, high-grade dysplasia associated with Barrett's esophagus, carcinoma of the lung, or multiple basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous phototoxicity responses were determined, as a function of time after HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating HPPH metabolites, and in vitro incubation of HPPH with human liver microsomal preparations resulted in no metabolite or glucuronic acid-HPPH conjugate production.

Topics: Adult; Aged; Aged, 80 and over; Barrett Esophagus; Blood Proteins; Carcinoma, Basal Cell; Chlorophyll; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Esophageal Neoplasms; Humans; Lung Neoplasms; Middle Aged; Neoplasms; Photochemotherapy; Photosensitizing Agents; Skin; Skin Neoplasms

Topics: Carcinoma; Carcinoma, Basal Cell; Chlorophyll; Enzymes; Humans; Skin Neoplasms