bacteriochlorophylls and Necrosis

Vascular targeted photodynamic therapy (VTP) with WST11 is a novel non-thermal focal treatment for localized prostate cancer that has shown favorable and early efficacy results in previously published studies. In this work, we investigate the efficiency of automatic dosimetric treatment planning. An action model established in a previous study was used in an image-guided optimization scheme to define the personalized optimal light dose for each patient. The calculated light dose is expressed as the number of optical cylindrical fibers to be used, their positions according to an external insertion grid, and the lengths of their diffuser parts. Evaluation of the method was carried out on data collected from 17 patients enrolled in two multi-centric clinical trials. The protocol consisted of comparing the method-simulated necrosis to the result observed on day 7 MR enhanced images. The method performances showed that the final result can be estimated with an accuracy of 10%, corresponding to a margin of 3 mm. In addition, this process was compatible with clinical conditions in terms of calculation times. The overall process took less than 10 min. Different aspects of the VTP procedure were already defined and optimized. Personalized treatment planning definition remained as an issue needing further investigation. The method proposed herein completes the standardization of VTP and opens new pathways for the clinical development of the technique.

Topics: Bacteriochlorophylls; Dose-Response Relationship, Radiation; Humans; Male; Necrosis; Photochemotherapy; Photosensitizing Agents; Prostate; Prostatic Neoplasms; Radiotherapy Planning, Computer-Assisted

Purpose To examine the hypothesis that vascular-targeted photodynamic therapy (VTP) with WST11 and clinically relevant parameters can be used to ablate target tissues in a non-tumor-bearing large-animal model while selectively sparing blood vessels and collagen. Materials and Methods By using an institutional animal care and use committee-approved protocol, 68 ablations were performed in the kidneys (cortex and medulla) and livers of 27 adult pigs. Posttreatment evaluation was conducted with contrast material-enhanced computed tomography in the live animals at 24 hours. Immunohistochemistry was evaluated and histologic examination with hematoxylin-eosin staining was performed at 4 hours, 24 hours, and 7 days. Intravenous infusion of WST11 (4 mg per kilogram of body weight) was followed by using near-infrared illumination (753 nm for 20 minutes) through optical fibers prepositioned in target tissues by using a fixed template. Treated areas were scanned, measured, and statistically analyzed by using the Student t test and two-way analysis of variance. Results Focal WST11 VTP treatment in the liver and kidney by using a single optical fiber resulted in well-demarcated cylindrical zones of nonthermal necrosis concentrically oriented around the light-emitting diffuser, with no intervening viable parenchymal cells. The radius of ablated tissue increased from approximately 5 mm at 150 mW to approximately 7 mm at 415 mW (P < .01). Illumination through fiber triads at 1-cm separation resulted in confluent homogeneous necrosis. Patterns of acute injury within 24 hours were consistent with microcirculatory flow arrest and collagen preservation (demonstrated with trichrome staining). In the peripheral ablation zone, blood vessels at least 40 μm in diameter were selectively preserved and remained functional at 7 days. Ablated tissues exhibited progressive fibrosis and chronic inflammatory cell infiltrates. No histologic changes consistent with thermal injury were observed in blood vessels or collagen. The renal hilum and collecting system did not show treatment effect, despite treatment proximity. Conclusion WST11 VTP induces nonthermal tissue ablation in target tissue while preserving critical organ structures and bystander blood vessels within solid organs. (©) RSNA, 2016 Online supplemental material is available for this article.

Topics: Animals; Bacteriochlorophylls; Contrast Media; Female; Immunohistochemistry; Kidney; Liver; Models, Animal; Necrosis; Optical Fibers; Photochemotherapy; Reactive Oxygen Species; Swine; Tomography, X-Ray Computed

Antiangiogenic and anti-vascular therapies present intriguing alternatives to cancer therapy. However, despite promising preclinical results and significant delays in tumor progression, none have demonstrated long-term curative features to date. Here, we show that a single treatment session of Tookad-based vascular targeted photodynamic therapy (VTP) promotes permanent arrest of tumor blood supply by rapid occlusion of the tumor feeding arteries (FA) and draining veins (DV), leading to tumor necrosis and eradication within 24-48 h.. A mouse earlobe MADB106 tumor model was subjected to Tookad-VTP and monitored by three complementary, non-invasive online imaging techniques: Fluorescent intravital microscopy, Dynamic Light Scattering Imaging and photosensitized MRI. Tookad-VTP led to prompt tumor FA vasodilatation (a mean volume increase of 70%) with a transient increase (60%) in blood-flow rate. Rapid vasoconstriction, simultaneous blood clotting, vessel permeabilization and a sharp decline in the flow rates then followed, culminating in FA occlusion at 63.2 sec+/-1.5SEM. This blockage was deemed irreversible after 10 minutes of VTP treatment. A decrease in DV blood flow was demonstrated, with a slight lag from FA response, accompanied by frequent changes in flow direction before reaching a complete standstill. In contrast, neighboring, healthy tissue vessels of similar sizes remained intact and functional after Tookad-VTP.. Tookad-VTP selectively targets the tumor feeding and draining vessels. To the best of our knowledge, this is the first mono-therapeutic modality that primarily aims at the larger tumor vessels and leads to high cure rates, both in the preclinical and clinical arenas.

Topics: Animals; Arteries; Bacteriochlorophylls; Blood Coagulation; Blood Flow Velocity; Disease Models, Animal; Ear; Mice; Necrosis; Neoplasms; Neovascularization, Pathologic; Permeability; Photochemotherapy; Treatment Outcome; Vasoconstriction; Veins

Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis. It is commonly identified by means of invasive histopathology, which often correlates with morbidity and potential tumor cell dissemination, and limits the reconstruction of the whole necrotic domain. In this study we hypothesized that non covalent association to serum albumin (SA) and covalent binding to ligands for tumor-abundant cell receptors should synergistically drive selective accumulation and prolonged retention of imaging and therapeutic agents in breast tumor necrotic domains enabling in vivo identification, imaging and possibly treatment of such tumors.. Cyclo-Arg-Gly-Asp-D-Phe-Lys (c(RGDfK)) were conjugated to bacteriochlorophyll-derivatives (Bchl-Ds), previously developed as photodynamic agents, fluorescent probes and metal chelators in our lab. The c(RGDfK) component drives ligation to alphaVbeta3 integrin receptors over-expressed by tumor cells and neo-vessels, and the Bchl-D component associates to SA in a non-covalent manner. STL-6014, a c(RGDfK)-Bchl-D representative, was i.v. injected to CD-1, nude female mice bearing necrotic and non-necrotic human MDA-MB-231-RFP breast cancer tumors. The fluorescence signals of the Bchl-Ds and RFP were monitored over days after treatment, by quantitative whole body imaging and excised tumor/tissue samples derived thereof. Complementary experiments included competitive inhibition of STL-6014 uptake by free c(RGDfK), comparative pharmacokinetics of nonconjugated c(RGDfK) Bchl-D (STL-7012) and of two human serum albumin (HSA) conjugates: HSA-STL-7012 and HSA-STL-6014.. STL-6014 and STL-7012 formed complexes with HSA (HSA/STL-6014, HSA/STL-7012). STL-6014, HSA-STL-7012 and HSA-STL-6014, selectively accumulated at similar rates, in tumor viable regions over the first 8 h post administration. They then migrated into the necrotic tumor domain and presented tumor half lifetimes (T1/2) in the range of days where T1/2 for HSA-STL-6014 > STL-6014 > HSA-STL-7012. No accumulation of STL-7012 was observed. Pre-injection of c(RGDfK) excess, prevented the uptake of STL-6014 in the small, but not in the large tumors.. Non-covalent association to SA and covalent binding to c(RGDfK), synergistically enable the accumulation and prolonged retention of Bchl-Ds in the necrotic regions of tumors. These findings provide novel guidelines and strategy for imaging and treatment of necrotic tumors.

Topics: Animals; Bacteriochlorophylls; Breast Neoplasms; Diagnostic Imaging; Drug Design; Female; Humans; Mice; Mice, Nude; Necrosis; Oligopeptides; Serum Albumin; Tissue Distribution

Photodynamic therapy (PDT) is attracting increasing interest for the safe destruction of localised tumours in a range of organs. However, most photosensitising drugs require a delay of hours to days between drug administration and light activation with skin photosensitivity that may last for weeks. WST09 (Tookad) is a new faster acting photosensitiser that clears within a few hours. In normal rat colon, after sensitisation with an intravenous bolus of WST09, light was delivered to a single point on the mucosa and the extent of PDT necrosis measured 3 days later. The lesion diameter was greatest with the highest dose of drug and light and the shortest drug light interval (DLI), falling rapidly with a DLI more than 5 min. In tumours transplanted subcutaneously or into the colon, the extent of necrosis only started falling with a DLI greater than 15 min, suggesting a possible window for tumour selectivity. Histological changes 3 days after PDT were essentially the same as those seen with longer acting photosensitisers. The lesion dimensions were comparable to the largest ones seen with other photosensitisers under similar experimental conditions. We conclude that WST09 is a powerful photosensitiser that produces PDT effects similar to those seen with longer acting drugs, but with the major advantages of a short DLI and rapid clearance.

Topics: Animals; Bacteriochlorophylls; Colonic Neoplasms; Injections, Intravenous; Necrosis; Neoplasms, Experimental; Photochemotherapy; Photosensitivity Disorders; Rats; Rats, Wistar; Skin Neoplasms

To determine the optimal magnetic resonance imaging (MRI) methodology to assess photodynamic therapy (PDT)-induced histopathological responses in the prostate.. Laparotomy was performed in five healthy dogs. Cylindrical diffuser was placed in the prostates to deliver light of 50-300 J/cm at 150 mW/cm and 763 nm to activate IV-injected Tookad (1 mg/kg b.w.). Fast spin echo (FSE) T2-weighted, post-contrast-enhanced T1-(CE-T1) and diffusion weighted images (DWI) were obtained pre- and 2 days, 7 days, and 1 month post-PDT. Radiological-histopathological correlation was performed at 7 days (n = 4) and 1 month (n = 1) after PDT. A qualitative assessment of signal changes and apparent diffusion coefficient (ADC) mapping was performed.. At 2 or 7 days post-PDT, there was good spatial correlation between PDT-induced hemorrhagic necrosis and unenhanced regions on CE-T1 images. There was a rapidly and persistently enhancing rim corresponding to edema and inflammation. FSE T2 and DWI showed altered signal but did not clearly define necrosis in all cases. At 1 month, it was hard to correlate MR images to histopathologic changes as they represented a mixture of necrosis and developing fibrosis, which led to a mixed signal intensity and less demarcated contrast enhancement.. At 7 days after PDT, gadolinium DTPA contrast-enhanced MRI is superior to DWI and T2 imaging in assessing the boundary of Tookad PDT-induced tissue necrosis in the normal canine prostate.

Topics: Animals; Bacteriochlorophylls; Connective Tissue; Contrast Media; Diffusion Magnetic Resonance Imaging; Dogs; Edema; Epithelium; Fibrosis; Gadolinium DTPA; Hemorrhage; Image Enhancement; Leukocytes, Mononuclear; Magnetic Resonance Imaging; Male; Necrosis; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Prostate; Time Factors