Photodynamic Therapy For Prostate Cancer Research Articles

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer.

Radical prostatectomy is a primary treatment option for localized prostate cancer (PCa), although high rates of recurrence are commonly observed postsurgery. Photodynamic therapy (PDT) has demonstrated efficacy in treating nonmetastatic localized PCa with a low incidence of adverse events. However, its limited efficacy remains a concern. To address these issues, various organic polymeric nanoparticles (OPNPs) loaded with photosensitizers (PSs) that target prostate cancer have been developed. However, further optimization of the OPNP design is necessary to maximize the effectiveness of PDT and improve its clinical applicability. This Review provides an overview of the design, preparation, methodology, and oncological aspects of OPNP-based PDT for the treatment of PCa.

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

PurposeIncomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.MethodsIn vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.ResultsIn vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).ConclusionThis study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

Photodynamic therapy for prostate cancer: Recent advances, challenges and opportunities.

Over the past two decades, there has been a tendency toward early diagnosis of prostate cancer due to raised awareness among the general public and professionals, as well as the promotion of prostate-specific antigen (PSA) screening. As a result, patients with prostate cancer are detected at an earlier stage. Due to the risks of urine incontinence, erectile dysfunction, etc., surgery is not advised because the tumor is so small at this early stage. Doctors typically only advise active surveillance. However, it will bring negative psychological effects on patients, such as anxiety. And there is a higher chance of cancer progression. Focal therapy has received increasing attention as an alternative option between active monitoring and radical therapy. Due to its minimally invasive, oncological safety, low toxicity, minimal effects on functional outcomes and support by level 1 evidence from the only RCT within the focal therapy literature, photodynamic treatment (PDT) holds significant promise as the focal therapy of choice over other modalities for men with localized prostate cancer. However, there are still numerous obstacles that prevent further advancement. The review that follows provides an overview of the preclinical and clinical published research on PDT for prostate cancer from 1999 to the present. It focuses on clinical applications of PDT and innovative techniques and technologies that address current problems, especially the use of nanoparticle photosensitizers in PDT of prostate cancer.

Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer

IntroductionThe first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa.MethodsVarious new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for 111In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection.ResultsIn order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC50 < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (≥ 20 ± 3%ID/g vs 14 ± 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice.ConclusionThe new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy.

Combined effect of heat shock protein inhibitor geldanamycin and free radicals on photodynamic therapy of prostate cancer.

Prostate cancer is the most common malignancy and the second leading cause of cancer-induced death among men. Recently, photodynamic therapy (PDT) has attracted great attention in prostate cancer treatment because of its high accuracy and no trauma. However, the hypoxic microenvironment of the tumor severely reduces the therapeutic efficacy of oxygen-dependent PDT in prostate cancer, which hampers the generation of reactive oxygen species (ROS). In addition, the PDT process induces the overexpression of pro-survival and anti-apoptotic proteins, thereby reducing the efficacy of PDT. This study proposed a novel multifunctional nanosystem for the targeted delivery of indocyanine green (ICG), 2,2'-azobis[2-(2-imidazolinI-2-yl) propane] dihydrochloride (AIBI), and heat shock protein 90 (Hsp90) inhibitor geldanamycin (17-AAG). Under near-infrared light irradiation, the photothermal effect of ICG induces AIBI decomposition and releases oxygen-independent free radicals, which rescues the hindered ICG-mediated ROS generation. Moreover, 17-AAG reduces heat resistance by inhibiting Hsp90, thereby achieving mild hyperthermia. Simultaneously, the inhibition of Hsp90 can inhibit the overexpression of its client proteins such as anti-apoptotic proteins (survivin) and androgen receptor (AR), thereby improving the efficacy of PDT and inducing prostate cancer cell apoptosis. Results show that the nanosystem enhances PDT by combining free radicals and 17-AAG, exhibiting a good anticancer effect on prostate cancer cells but less toxicity on normal cells.

Photodynamic therapy of prostate cancer using porphyrinic formulations.

Prostate cancer (PCa) is the second most frequent cancer diagnosed in men worldwide. Among the common treatment options, photodynamic therapy (PDT) is being considered a promising local therapy to treat this cancer. Although PDT is an established treatment modality approved for several types of cancer, the low solubility, the reduced tumor selectivity, the absorption in the therapeutic window and the poor clearance from the body of the currently approved photosensitizers (PS) hampers its wide clinical application. In this regard, herein we synthesized three fluorinated porphyrinoid derivatives and entrapped them into polyvinylpyrrolidone (PVP) to prevent their aggregation and preserve their desirable photophysical properties under the physiological environment. In vitro studies revealed the negligible dark cytotoxicity of all PVP formulations (PS1@PVP, PS2@PVP and PS3@PVP) at the tested concentrations (5.0 to 20μM), but also confirmed the significant photodynamic effect of PS2@PVP and PS3@PVP towards the PCa cell line PC-3, upon red light irradiation at an irradiance of 17.6mW.cm-2. To provide insight into the underlying mechanisms of cell death under PDT treatment induced by PS2@PVP and PS3@PVP, their intracellular localization in PC-3 cells was firstly investigated by confocal microscopy. Since both PS2@PVP and PS3@PVP nanoparticles were mainly localized in mitochondria, the involvement of this organelle in PDT-induced apoptosis mediated by both formulations was further explored. Western blot analysis revealed that PDT treatment of PC-3 cells with either PS2@PVP or PS3@PVP resulted in the reduction of the expression level of the anti-apoptotic protein Bcl-2. As the photodamage to Bcl-2 after PDT with PS2@PVP and PS3@PVP was accompanied by the further activation of pro-caspase-3, we assumed that upon irradiation the photogenerated reactive oxygen species (ROS) were able to activate a caspase-dependent apoptotic response as a consequence of a post-mitochondrial event. Taken together, these findings demonstrate that among the tested fluorinated porphyrinoids, PS2@PVP and, particularly, PS3@PVP, are significantly more effective in overall PC-3 cell killing than PS1@PVP, thus highlighting their great potential as therapeutic agents for PCa.

The Use of Upconversion Nanoparticles in Prostate Cancer Photodynamic Therapy.

Photodynamic Therapy (PDT) is a cancer treatment that uses light, a photosensitizer, and oxygen to destroy tumors. This article is a review of approaches to the treatment of prostate cancer applying upconversion nanoparticles (UCNPs). UCNPs have become a phenomenon that are rapidly gaining recognition in medicine. They have proven to be highly selective and specific and present a powerful tool in the diagnosis and treatment of prostate cancer. Prostate cancer is a huge health problem in Western countries. Its early detection can significantly improve patients’ prognosis, but currently used diagnostic methods leave much to be desired. Recently developed methodologies regarding UCNP research between the years 2021 and 2014 for prostate cancer PDT will also be discussed. Current limitations in PDT include tissue irradiation with visible wavelengths that have a short tissue penetration depth. PDT with the objectives to synthesize UCNPs composed of a lanthanide core with a coating of adsorbed dye that will generate fluorescence after excitation with near-infrared light to illuminate deep tissue is a subject of intense research in prostate cancer.

Cryoablation, high-intensity focused ultrasound, irreversible electroporation, and vascular-targeted photodynamic therapy for prostate cancer: a systemic review and meta-analysis.

Cryoablation (CA), high-intensity focused ultrasound (HIFU), irreversible electroporation (IRE), and vascular-targeted photodynamic therapy (VTP) have been evaluated as novel strategies for selected patients with prostate cancer (PCa). We aim to determine the current status of literature regarding the clinical outcomes among these minimally invasive therapies. A systematic search of PubMed, EMBASE, and the Cochrane Library for all English literature published from January 2001 to December 2019 was conducted to identify studies evaluating outcomes of CA, HIFU, IRE or VTP on PCa. Proportionality with 95% confidence intervals (CIs) was performed using STATA version 14.0. 56 studies consisting of 7383 participants were found to report data of interest and fulfilled the inclusion criteria in the final meta-analysis. The pooled proportions of positive biopsy after procedure were 20.0%, 24.3%, 24.2%, and 36.2% in CA, HIFU, IRE and VTP, respectively. The pooled proportions of BRFS were 75.7% for CA and 74.4% for HIFU. The pooled proportions of CSS were 96.1%, 98.2%, and 97.9% for CA, HIFU, and IRE, respectively. The pooled proportions of OS were 92.8% for CA and 85.2% for HIFU. The pooled proportions of FFS were 64.7%, 90.4%, and 76.7% for CA, IRE and VTP, respectively. The pooled proportions of MFS were 92.8% for HIFU and 99.1% for IRE. This meta-analysis shows that CA, HIFU, IRE, and VTP are promising therapies for PCa patients with similar clinical outcomes. However, further larger, well-designed randomized controlled trials are required to confirm this assertion.

Photodynamic therapy for prostate cancer - A narrative review.

This article is a review of approaches to treatment of low and high-grade prostate cancer including a discussion of active treatment vs. active surveillance for patients with low-grade prostate cancer. In particular, we will review PDT as an option for active treatment of low-grade prostate cancer considered in light of recent clinical trials. The mechanism and clinical methods of PDT application and the key points from clinical trials using PDT for prostate cancer with the photosensitizers m-tetrahydroxyphenyl chloride, protoporphyrin IX, motexafin lutetium, padoporfin, and padeliporfin between the years 2002 and 2017 are reviewed. Recently developed methodologies for photodynamic prostate cancer treatment that are in the experimental stage, photodynamic diagnosis, fluorescence guided resection, and PSMA-targeted PDT will also be discussed.

Photodynamic therapy on prostate cancer cells involve mitochondria membrane proteins

Photodynamic therapy for prostate cancer has emerged, however the evaluation of its mechanism of action has not yet been clarified. This study aims to explore the mechanism and significance of photodynamic therapy on prostate cancer in vitro. Cultured prostate cancer cells were divided into two groups: untreated and photodynamic therapy treatment. The protein of each group was extracted and analyzed by MALDI-TOF/MSMS method. The significantly expressed proteins were identified in the NCBI human protein database. The change of mitochondrial membrane permeability after photodynamic treatment was examined by transmission electron microscopy. The total protein content and band distribution of photodynamic treatment group were similar to the control group. Two mitochondrial membrane proteins were down-regulated significantly. They are mitochondrial heat shock protein (HSP60) (Entrez Gene ID: 31542947, PI 5.7, MW: 61016.4, Protein Score: 354, Protein Score C.I.%:100), and voltage-dependent anion channel (VDAC) (Entrez Gene ID: 340201, PI 7.49, MW: 31574.6, Protein Score: 178, Protein Score C.I.%:100). Transmission electron microscopy showed the loss of integrity of mitochondrial membranes. Photodynamic therapy changes mitochondrial membrane permeability, leading to the eventual death of cancer cells. The regulation of proteins related to mitochondrial membrane permeability may become an indicator of the efficacy of photodynamic therapy.

PC#34 - Bimodal prostate specific membrane antigen ligands for intra-operative tumor detection and photodynamic therapy of prostate cancer

PC#34 - Bimodal prostate specific membrane antigen ligands for intra-operative tumor detection and photodynamic therapy of prostate cancer

Efficient Photodynamic Therapy of Prostate Cancer Cells through an Improved Targeting of the Cation-Independent Mannose 6-Phosphate Receptor.

The aim of the present work is the development of highly efficient targeting molecules to specifically address mesoporous silica nanoparticles (MSNs) designed for the photodynamic therapy (PDT) of prostate cancer. We chose the strategy to develop a novel compound that allows the improvement of the targeting of the cation-independent mannose 6-phosphate receptor, which is overexpressed in prostate cancer. This original sugar, a dimannoside-carboxylate (M6C-Man) grafted on the surface of MSN for PDT applications, leads to a higher endocytosis and thus increases the efficacy of MSNs.

Activatable Photodynamic Therapy for Prostate Cancer by NIR Dye/Photosensitizer Loaded Albumin Nanoparticles.

Prostate cancer is one of the leading causes of death in men worldwide. Photodynamic therapy (PDT) is a new emerging and promising strategy for the treatment of prostate cancer. PDT uses a combination of light and a photosensitizer (PS) to kill cancer cells. However, most photosensitizers (PS) accumulate in normal tissues, in particular the skin and eyes, and can be activated by sunlight, causing severe side effects such as prolonged skin photosensitivity that have limited the clinical application of PDT. Herein, a novel strategy is presented to overcome these limitations using Indocyanine green (ICG) as an activatable PDT agent. We developed a human serum albumin (HSA)-based nanoplatform loaded with Chlorin e6 (Ce6) and ICG. In vitro and in vivo studies showed that ICG effectively turned "OFF" the phototoxicity of Ce6, and the degradation of ICG by laser irradiation at 808 nm turned "ON" the phototoxicity of Ce6. In addition, ICG produced heat upon NIR irradiation to kill cancer cells, which could be used as a photothermal therapy (PTT). Therapeutic efficacy of HSA-ICG-Ce6 NPs in a prostate cancer model showed that tumors were completely damaged in mice treated by combined PTT with activated PDT. Our designed HSA nanoparticles containing ICG and Ce6 could be used as an activatable PDT combined with PTT for the treatment of prostate cancer.

Photodynamic therapy for prostate cancer: a systematic review and meta-analysis.

PurposePhotodynamic therapy (PDT) is an emerging focal treatment modality for prostate cancer. However, the efficacy, safety, and functional outcomes of PDT are not clear. We performed a meta-analysis of available single-arm studies and control trials which used PDT for prostate cancer.Materials and methodsWe searched Pubmed, Embase, Ovid and the Cochrane library (until March,2018) for studies about PDT in patients with prostate cancer. The negative biopsy rate after PDT, PSA decreasing rate, pooled rate of functional outcome (IPSS or IIEF-5), and adverse events were analyzed.Results14 studies containing 654 patients were included. Nine of the 14 included studies had evaluated a negative biopsy rate after PDT. The pooled rate was 55.0% (95.0% CI: 0.44–0.66, I2 = 85.7%). Twelve of the 14 included studies which evaluated PSA decreasing rate with the pooled rate of 35.0% (95.0% CI: 0.24–0.47, I2 = 88.7%). Six of the included studies evaluated IPSS with decreasing rate of 29.1% (95.0 % CI: 2.7%–55.5%, I2 = 96.9%). Five of the included studies evaluated IIEF-5 with decreasing rate of 14.9% (95.0% CI: 6.8%–23.0%, I2 = 44.2%). The most common adverse events were haematuria (28.1%, 95.0% CI: 17.1%–39.2%, I2 = 79.8%), erectile dysfunction (23.1%, 95.0% CI: 9.7%–36.5%, I2 = 87.7%), and dysuria (18.6%, 95.0% CI: 12.1%–25.0 %, I2 = 53.4 %).ConclusionsThe meta-analysis results shows that PDT for patients with prostate cancer can be considered as effective based on single-arm clinical trials. Meanwhile, this study reveals that there are not only low levels of side effect rates but also insignificant effect on both urinary and erectile function. However, more high-quality RCTs are needed to evaluate the comparative efficacy, safety, and functional outcomes of PDT for patients with prostate cancer.

Theranostic Agents for Photodynamic Therapy of Prostate Cancer by Targeting Prostate-Specific Membrane Antigen.

Prostatectomy has been the mainstay treatment for men with localized prostate cancer. Surgery, however, often can result in major side effects, which are caused from damage and removal of nerves and muscles surrounding the prostate. A technology that can help surgeons more precisely identify and remove prostate cancer resulting in a more complete prostatectomy is needed. Prostate-specific membrane antigen (PSMA), a type II membrane antigen highly expressed in prostate cancer, has been an attractive target for imaging and therapy. The objective of this study is to develop low molecular weight PSMA-targeted photodynamic therapy (PDT) agents, which would provide image guidance for prostate tumor resection and allow for subsequent PDT to eliminate unresectable or remaining cancer cells. On the basis of our highly negatively charged, urea-based PSMA ligand PSMA-1, we synthesized two PSMA-targeting PDT conjugates named PSMA-1-Pc413 and PSMA-1-IR700. In in vitro cellular uptake experiments and in vivo animal imaging experiments, the two conjugates demonstrated selective and specific uptake in PSMA-positive PC3pip cells/tumors, but not in PSMA-negative PC3flu cells/tumors. Further in vivo photodynamic treatment proved that the two PSMA-1-PDT conjugates can effectively inhibit PC3pip tumor progression. The two PSMA-1-PDT conjugates reported here may have the potential to aid in the detection and resection of prostate cancers. It may also allow for the identification of unresectable cancer tissue and PDT ablation of such tissue after surgical resection with potentially less damage to surrounding tissues. Mol Cancer Ther; 15(8); 1834-44. ©2016 AACR.

Final Results of a Phase I/II Multicenter Trial of WST11 Vascular Targeted Photodynamic Therapy for Hemi-Ablation of the Prostate in Men with Unilateral Low Risk Prostate Cancer Performed in the United States

Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is a form of tissue ablation that may be used therapeutically for localized prostate cancer. To study dosing parameters and associated treatment effects we performed a prospective, multicenter, phase I/II trial of WST11 vascular targeted photodynamic therapy of prostate cancer. A total of 30 men with unilateral, low volume, Gleason 3+ 3 prostate cancer were enrolled at 5 centers after local institutional review board approval. Light energy, fiber number and WST11 dose were escalated to identify optimal dosing parameters for vascular targeted photodynamic therapy hemi-ablation. Men were treated with photodynamic therapy and evaluated by posttreatment magnetic resonance imaging and biopsy. Prostate specific antigen, light dose index (defined as fiber length/desired treatment volume), toxicity and quality of life parameters were recorded. After dose escalation 21 men received optimized dosing of 4 mg/kg WST11 at 200 J energy. On posttreatment biopsy residual prostate cancer was found in the treated lobe in 10 men, the untreated lobe in 4 and both lobes in 1. At a light dose index of 1 or greater with optimal dosing in 15 men 73.3% had a negative biopsy in the treated lobe. Six men undergoing retreatment with the optimal dose and a light dose index of 1 or greater had a negative posttreatment biopsy. Minimal effects were observed on urinary and sexual function, and overall quality of life. Hemi-ablation of the prostate with WST11 vascular targeted photodynamic therapy was well tolerated and resulted in a negative biopsy in the treated lobe in the majority of men. Dosing parameters and the light dose index appear related to tissue response as determined by magnetic resonance imaging and biopsy. These parameters may serve as the basis for further prospective studies.

Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro.

Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5-20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer.

Post-treatment MRI aspects of photodynamic therapy for prostate cancer.

ObjectivesPhotodynamic therapy is a new focal therapy for prostate cancer.MethodsIn this technique, a photosensitising agent is introduced intravenously, then activated by local laser illumination to induce tumour necrosis. Treatment efficacy is assessed by magnetic resonance imaging (MRI).Results and ConclusionsWe illustrate specific post-treatment MRI aspects at early and late follow-up with pathological correlations.Teaching points• Dynamic phototherapy is a new and promising focal therapy for prostate cancer. • One-week MRI shows increased volume of the treated lobe and large, homogeneous necrosis area. • Six-month MRI shows significant changes of the prostate shape and signal. • Six-month MRI becomes “base line” appearance for further follow-up or monitoring.

Endoscopic Vascular Targeted Photodynamic Therapy with the Photosensitizer WST11 for Benign Prostatic Hyperplasia in the Preclinical Dog Model

Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia.

Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity

Frequent side effects of radical treatment modalities and the availability of novel diagnostics have raised the interest in focal therapies for localized prostate cancer. To improve the selectivity and therapeutic efficacy of such therapies, we developed a minimally invasive procedure based on a novel polymeric photosensitizer prodrug sensitive to urokinase-type plasminogen activator (uPA). The compound is inactive in its prodrug form and accumulates passively at the tumor site by the enhanced permeability and retention effect. There, the prodrug is selectively converted to its photoactive form by uPA, which is overexpressed by prostate cancer cells. Irradiation of the activated photosensitizer exerts a tumor-selective phototoxic effect. The prodrug alone (8 μmol/L) showed no toxic effect on PC-3 cells, but upon irradiation the cell viability was reduced by 90%. In vivo, after systemic administration of the prodrug, PC-3 xenografts became selectively fluorescent. This is indicative of the prodrug accumulation in the tumor and selective local enzymatic activation. Qualitative analysis of the activated compound confirmed that the enzymatic cleavage occurred selectively in the tumor, with only trace amounts in the neighboring skin or muscle. Subsequent photodynamic therapy studies showed complete tumor eradication of animals treated with light (150 J/cm(2) at 665 nm) 16 hours after the injection of the prodrug (7.5 mg/kg). These promising results evidence the excellent selectivity of our prodrug with the potential to be used for both imaging and therapy for localized prostate cancer.