The Photosensitizer Temoporfin (mTHPC) - Chemical, Pre-clinical and Clinical Developments in the Last Decade.

This review follows the research, development and clinical applications of the photosensitizer 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, temoporfin) in photodynamic (cancer) therapy (PDT) and other medical applications. Temoporfin is the active substance in the medicinal product Foscan® authorized in the EU for the palliative treatment of head and neck cancer. Chemistry, biochemistry and pharmacology, as well as clinical and other applications of temoporfin are addressed, including the extensive work that has been done on formulation development including liposomal formulations. The literature has been covered from 2009 to early 2022, thereby connecting it to the previous extensive review on this photosensitizer published in this journal [Senge, M. O. and J. C. Brandt (2011) Photochem. Photobiol. 87, 1240-1296] which followed its way from initial development to approval and clinical application.

Self-assembled nanoparticles based on supramolecular-organic frameworks and temoporfin for an enhanced photodynamic therapy in vitro and in vivo.

Water-soluble three-dimensional supramolecular-organic frameworks (SOFs) and temoporfin (mTHPC) are discovered to form uniform self-assembled nanoparticles. These nanoparticles demonstrate an improved 1O2 generation efficiency due to the reduced aggregation-caused quenching effect. SOFs and self-assembled nanoparticles are biocompatible. Self-assembled nanoparticles display an improved photo cytotoxicity toward four types of human cancer cells. The tumor model in mice shows that self-assembled nanoparticles could efficiently suppress tumor growth in vivo.

Lipoparticles for Synergistic Chemo-Photodynamic Therapy to Ovarian Carcinoma Cells: In vitro and in vivo Assessments.

PURPOSE: Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers. METHODS: For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice. RESULTS AND CONCLUSION: The mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from -12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.

Periorbital skin cancers subjected to mTHPC-photodynamic therapy: A prospective study.

INTRODUCTION: Photodynamic therapy (PDT) is a relatively new method of treating skin cancers. This prospective study highlights the use of PDT in the management of basal cell carcinomas (BCCs) and T1N0 cutaneous squamous cell carcinomas (SCCs) involving the periorbital area. MATERIALS AND METHODS: Surface illumination PDT was offered under local anaesthesia. mTHPC was administered intravenously. A single-channel 652 nm diode laser was used for illumination, and light was delivered at 20 J/cm2 per site. Lesion response evaluation was carried out according to response evaluation criteria in solid tumours (RECIST). RESULTS: After the first round of treatment, all cutaneous T1N0 SCC patients had complete response (CR) and continued to be in remission until last clinic review. For BCC patients, 12/14 patients had CR. The two remaining patients underwent a second round of treatment and also achieved a CR. All BCC patients were in remission at the last clinic review. Using visual analogue scale (VAS), 15 patients reported that this treatment gave them "excellent" cosmetic outcome (VAS 9-10). CONCLUSION: Photodynamic therapy achieved high efficacy in the treatment of periorbital BCCs and cutaneous SCCs with greatly reduced morbidity and disfigurement.

Non-metastatic cutaneous squamous cell carcinoma treated with photodynamic therapy using intravenous mTHPC.

INTRODUCTION: Photodynamic therapy (PDT) is a method of treating various pathologies. In this retrospective study with prospective intent, a total of 22 patients with T1/T2 N0 cutaneous squamous cell carcinoma (SCC) were treated with intravenous mTHPC (meta-tetrahydroxyphenylchlorin) and surface illumination PDT. Comparisons with the clinical features, rate of recurrence and overall outcome were made. MATERIALS AND METHODS: Surface illumination PDT was offered under local anaesthesia. 0.05 mg/kg mTHPC was administered intravenously into the midcubital vein 48 h prior to tissue illumination. A single-channel 652 nm diode laser was used for illumination and light was delivered at 20 J/cm2 per site. Lesion response evaluation was carried out according to Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: Clinical assessment revealed that 16 patients had lesions of <2 cm in size (T1), while the rest were T2. No nodal involvement was identified in any of the patients. None of the patients had a locally recurrent lesion. During the 3-year follow-up, 20/22 patients had complete response (CR) and this was after one round of treatment. Two patients suffered from recurrent disease within 3 years of the follow-up, and they underwent surgical resection. CONCLUSION: PDT achieved high efficacy in the treatment of T1N0 cutaneous squamous cell carcinoma with greatly reduced morbidity and disfigurement. The technique is simple, can commonly be carried out in outpatient clinics, and is highly acceptable to patients.

The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy.

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. METHODS: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. RESULTS: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. CONCLUSION: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

Combinational Effects of Active Targeting, Shape, and Enhanced Permeability and Retention for Cancer Theranostic Nanocarriers.

Combinatory modulation of the physical and biochemical characteristics of nanocarrier delivery systems is an emergent topic in the field of nanomedicine. Here, we studied the combined effects of incorporation of active targeting moieties into nanocarriers and their morphology affecting the enhanced permeation and retention effect for nanomedicine cancer therapy. Self-assembled lipid discoidal and vesicular nanoparticles with low-polydispersity sub-50 nm size range and identical chemical compositions were synthesized, characterized, and correlated with in vitro cancer cellular internalization, in vivo tumor accumulation and cancer treatments. The fact that folate-associated bicelle yields the best outcome is indicative of the preference for discoidal carriers over spherical carriers and the improved targeting efficacy due to the targeting ligand/receptor binding. The approach is successfully adopted to design the nanocarriers for photodynamic therapy, which yields a consistent trend in in vitro and in vivo efficacy: folate nanodiscs > folate vesicles > nonfolate nanodiscs > nonfolate vesicles. Folate discs not only have shown a higher tumor uptake and photothermal therapeutic efficiency, but also minimize skin photosensitivity side effects. The advantages of nanodiscoidal bicelles as nanocarriers, including well-defined size, robust formation, easy encapsulation of hydrophobic molecules (therapeutics and/or diagnostics), easy incorporation of targeting molecules, and low toxicity, enable the scalable manufacturing of a generalized in vivo multimodal delivery platform.

Effects of meta-tetrahydroxyphenylchlorin photodynamic therapy on isogenic colorectal cancer SW480 and SW620 cells with different metastatic potentials.

The aim of this study is to investigate the antitumor effects and possible mechanisms of meta-tetrahydroxyphenylchlorin-mediated photodynamic therapy (m-THPC-PDT) on human primary (SW480) and metastatic (SW620) colon cancer cell lines. SW480 and SW620 cells were incubated with various concentrations of m-THPC, followed by photodynamic irradiation. Subcellular localization of m-THPC in cells was observed with confocal laser scanning microscopy (CLSM). Photocytotoxicity of m-THPC in the two cells was investigated by using MTT assay. The flow cytometry was employed to detect the cell apoptosis. The migration and long-term recovery ability were determined by scratch test and colony formation assay respectively. CLSM showed that m-THPC was mainly distributed within the endoplasmic reticulum (ER) and lysosome of SW480 cells and within the lysosome and mitochondria of SW620 cells. m-THPC-PDT induced a dose-dependent and light energy-dependent cytotoxicity in SW480 and SW620 cells. Apoptosis rate was approximately 65 and 25% in SW480 and SW620 respectively when the concentration of m-THPC increased to 11.76 µM. However, the rate of necrotic cells had no significant changes in two cell lines. The colony formation and migration ability of the two cell lines were decreased with m-THPC-PDT treatment in a dose-dependent manner. PDT with m-THPC not only could effectively inhibit cell proliferation and decrease migration ability and colony formation ability, but also could effectively kill SW480 and SW620 cells in a dose-dependent manner in vitro. These results suggest that m-THPC is a promising sensitizer that warrants further development and extensive studies towards clinical use of colorectal cancer.

Evaluation of long-term outcome and prognostic factors of feline squamous cell carcinomas treated with photodynamic therapy using liposomal phosphorylated meta-tetra(hydroxylphenyl)chlorine.

OBJECTIVES: The aim of this study was to evaluate the efficacy, long-term outcome and prognostic factors of feline squamous cell carcinoma (SCC) treated with photodynamic therapy (PDT). METHODS: Cats with histologically verified SCC of the head and neck received an intravenous injection of liposomal phosphorylated meta-tetra(hydroxylphenyl)chlorine (mTHPC) and 4 h later 652 nm light was delivered by a diode laser. One group received ⩽10 J/cm2, the other 20 J/cm2. Tumour response and duration were analysed with stage, tumour diameter, location and treatment intensity as prognostic factors. RESULTS: In total, 63 lesions in 38 cats underwent treatment with ⩽10 J/cm2 (n = 22) and 20 J/cm2 (n = 41). Overall response rate was 84% (complete remission 61%, partial remission 22%) with a mean progression-free interval of 35 months (median not reached) and a median overall survival time of 40 months (95% confidence interval 33-47). With regard to tumour stage, invasiveness yielded a highly significant worse outcome ( P <0.017). All patients with invasive tumours showed progression at less than 6 months. Larger lesions were associated with inferior control and treatment intensity, and tumour location did not influence response and duration. CONCLUSIONS AND RELEVANCE: PDT using a systemic photosensitiser leads to excellent long-term tumour control in the majority of cats. However, invasive and large tumours had a clearly inferior outcome, even if treated with the higher-dose intensity. This suggests that advanced lesions are not indications for PDT.

Adjuvant photodynamic therapy in head and neck cancer after tumor-positive resection margins.

OBJECTIVE: In case of close or positive resection margins after oncological resection in head and neck surgery, additional treatment is necessary. When conventional options are exhausted, photodynamic therapy (PDT) can play a role in achieving clear margins. The purpose of the current study was to evaluate the clinical benefit of PDT as adjuvant therapy next to surgery with positive resection margins. The role of the time interval between surgery and PDT on survival outcomes also was investigated. STUDY DESIGN: Retrospective cohort analysis. METHODS: Adjuvant PDT was performed in patients with a malignancy in the head and neck region with close or positive resection margins who were not eligible for conventional treatment options. The primary endpoint was progression-free survival. Secondary endpoints were disease-free survival, overall survival, and optimal time interval between surgery and PDT. RESULTS: Fifty-four patients were treated with surgery followed by meta-tetrahydroxyphenylchlorin-mediated PDT. There was a large diversity in tumor location and histopathology, as well as in time interval between surgery and PDT. The 2-year progression-free survival rate was 30%; 2-year disease-free survival rate was 28%; and 2-year overall survival was 51%. Disease-free survival was significantly better when the time interval between surgery and PDT was ≥ 6 weeks (P = 0.02). CONCLUSION: PDT can be applied as adjuvant therapy after surgery in cases of a malignancy with close or positive tumor resection margins. However, the clinical benefits are yet to be determined. There is a significantly better disease-free survival with a time interval between surgery and PDT of minimal 6 weeks. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:657-663, 2018.

Photodynamic therapy in fibrosarcoma BALB/c animal model: Observation of the rebound effect.

In vivo spectrofluorometric analysis during photodynamic therapy (PDT) is a fundamental tool to obtain information about drug bleaching kinetics. Using a portable spectrofluorometer with an excitation source emitting at 400nm wavelength and a spectral analyzer ranging from 500nm to 800nm, the evolution of the meta-tetra(hydroxyphenyl) chlorin (m-THPC) photosensitizer fluorescence spectrum at the tumoral tissue of BALB/c murines with fibrosarcoma located at their flank was followed up. Ex vivo fluorescence measurements of the tumor and skin were also performed with the aim of better characterizing the in vivo signal at different parts of the tumor. PDT was performed employing a LED 637nm light source. Fluorescence at different parts of the tumor and at the tail and armpit of mice was measured immediately after injection and followed daily. The average fluorescence intensity in the tumor reached a maximum after 24-72h. Subsequently, illuminations 24, 48, 72 and 96h post-injection were performed, and the fluorescence was measured immediately before and after each illumination. Eventually, 24h post-illumination, the fluorescence at certain parts of the tumor increased in comparison with that measured immediately after illumination. This effect, named "rebound effect", was due to the new local accumulation of the drug, and was used to perform a second illumination on some mice to increase the amount of photodynamic reaction and significantly improve the PDT outcome. These results are encouraging to optimize PDT in the proposed animal model, thinking about the possible translation to humans.

Photodynamic treatment outcomes of potentially-malignant lesions and malignancies of the head and neck region: A systematic review.

AIM: The aim of the present study was to systematically review the efficacy of photodynamic therapy (PDT) in the management of oral potentially-malignant disorders (PMDS) and head and neck squamous cell carcinoma (HNSCC). METHODS: From 1985 to 2015, PubMed/Medline, Google Scholar, EMBASE, and ISI Web of Knowledge were searched using different combinations of the following key words: PDT, oral precancer, leukoplakia, erythroplakia, erythroleukoplakia, verrucous hyperplasia, oral submucous fibrosis, and HNSCC. Review articles, experimental studies, case reports, commentaries, letters to the editor, unpublished articles, and articles published in languages other than English were excluded. RESULTS: Twenty-six studies were included in the present study. The number of patients ranged from 2 to 147, with a mean age of 50-67 years. The reported numbers of PMDS and HNSCC ranged between 5 and 225. Photosensitizers used were aminolevulinic acid, meta-tetrahydroxyphenylchlorin, Foscan, hematoporphyrin derivatives, Photofrin, Photosan, and chlorine-e6. Laser wavelength, power density, irradiation duration were 585-652 nm, 50-500 mW/cm2 , and 1-143 minutes, respectively. Complete, partial, and no response to PDT was found in 22.58%-100%, 4%-66%, and 0%-38.70% of PMDS, respectively, and 16%-100% of complete response in HNSCC patients. CONCLUSION: PDT is effective in the management of PMDS and HNSCC.

Macrophage selective photodynamic therapy by meta-tetra(hydroxyphenyl)chlorin loaded polymeric micelles: A possible treatment for cardiovascular diseases.

Selective elimination of macrophages by photodynamic therapy (PDT) is a new and promising therapeutic modality for the reduction of atherosclerotic plaques. m-Tetra(hydroxyphenyl)chlorin (mTHPC, or Temoporfin) may be suitable as photosensitizer for this application, as it is currently used in the clinic for cancer PDT. In the present study, mTHPC was encapsulated in polymeric micelles based on benzyl-poly(ε-caprolactone)-b-methoxy poly(ethylene glycol) (Ben-PCL-mPEG) using a film hydration method, with loading capacity of 17%. Because of higher lipase activity in RAW264.7 macrophages than in C166 endothelial cells, the former cells degraded the polymers faster, resulting in faster photosensitizer release and higher in vitro photocytotoxicity of mTHPC-loaded micelles in those macrophages. However, we observed release of mTHPC from the micelles in 30min in blood plasma in vitro which explains the observed similar in vivo pharmacokinetics of the mTHPC micellar formulation and free mTHPC. Therefore, we could not translate the beneficial macrophage selectivity from in vitro to in vivo. Nevertheless, we observed accumulation of mTHPC in atherosclerotic lesions of mice aorta's which is probably the result of binding to lipoproteins upon release from the micelles. Therefore, future experiments will be dedicated to increase the stability and thus allow accumulation of intact mTHPC-loaded Ben-PCL-mPEG micelles to macrophages of atherosclerotic lesions.

Foscan and foslip based photodynamic therapy in osteosarcoma in vitro and in intratibial mouse models.

Current osteosarcoma therapies cause severe treatment-related side effects and chemoresistance, and have low success rates. Consequently, alternative treatment options are urgently needed. Photodynamic therapy (PDT) is a minimally invasive, local therapy with proven clinical efficacy for a variety of tumor types. PDT is cytotoxic, provokes anti-vascular effects and stimulates tumor cell targeting mechanisms of the immune system and, consequently, has potential as a novel therapy for osteosarcoma patients. This study investigated the uptake and the dark- and phototoxicity and cytotoxic mechanisms of the photosensitizer (PS) 5,10,15,20-tetrakis(meta-hydroxyphenyl) chlorine (mTHPC, Foscan) and a liposomal mTHPC formulation (Foslip) in the human 143B and a mouse K7M2-derived osteosaroma cell line (K7M2L2) in vitro. Second, the tumor- and metastasis-suppressive efficacies of mTHPC formulations based PDT and associated mechanisms in intratibial, metastasizing osteosarcoma mouse models (143B/SCID and syngeneic K7M2L2/BALB/c) were studied. The uptake of Foscan and Foslip in vitro was time- and dose-dependent and resulted in mTHPC and light dose-dependent phototoxicity associated with apoptosis. In vivo, the uptake of both i.v. administered mTHPC formulations was higher in tumor than in healthy control tissue. PDT caused significant (Foscan p < 0.05, Foslip p < 0.001) tumor growth inhibition in both models. A significant (Foscan p < 0.001, Foslip p < 0.001) immune system-dependent suppression of lung metastasis was only observed in the K7M2L2/BALB/c model and was associated with a marked infiltration of T-lymphocytes at the primary tumor site. In conclusion, mTHPC-based PDT is effective in clinically relevant experimental osteosarcoma and suppresses lung metastasis in immunocompetent mice with beneficial effects of the liposomal mTHPC formulation Foslip.

Inclusion complexation with ß-cyclodextrin derivatives alters photodynamic activity and biodistribution of meta-tetra(hydroxyphenyl)chlorin.

Application of meta-tetra(hydroxyphenyl)chorin (mTHPC) one of the most effective photosensitizer (PS) in photodynamic therapy of solid tumors encounters several complications resulting from its insolubility in aqueous medium. To improve its solubility and pharmacokinetic properties, two modified ß-cyclodextrins (ß-CDs) methyl-ß-cyclodextrin (M-ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (Hp-ß-CD) were proposed. The aim of this work was to evaluate the effect of ß-CDs on mTHPC behavior at various stages of its distribution in vitro and in vivo. For this purpose, we have studied the influence of the ß-CDs on mTHPC binding to the serum proteins, its accumulation, distribution and photodynamic efficiency in HT29 cells. In addition, the processes of mTHPC biodistribution in HT29 tumor bearing mice after intravenous injection of PS alone or with the ß-CDs were compared. Interaction of mTHPC with studied ß-CDs leads to the formation of inclusion complexes that completely abolishes its aggregation after introduction into serum. It was demonstrated that the ß-CDs have a concentration-dependent effect on the process of mTHPC distribution in blood serum. At high concentrations, ß-CDs can form inclusion complexes with mTHPC in the blood that can have a significant impact on PS distribution out of the vascular system in solid tissues. Besides, the ß-CDs increase diffusion movement of mTHPC molecules that can significantly accelerate the delivery of PS to the targets cells and tissues. In vivo study confirms the fact that the use of ß-CDs allows to modify mTHPC distribution processes in tumor bearing animals that is reflected in the decreased level of PS accumulation in skin and muscles, as well as in the increased PS accumulation in tumor. Further studies are underway to verify the optimal protocols of mTHPC/ß-CD formulation for photodynamic therapy.

Uptake and photo-toxicity of Foscan®, Foslip® and Fospeg® in multicellular tumor spheroids.

In cancer photodynamic therapy (PDT), an efficient and homogeneous intratumoral accumulation of the photosensitizer (PS) is required to induce cell damages in the entire tumor mass after light activation. Thus, in this study we investigated penetration ability and photodynamic efficiency of meta-tetra(hydroxyphenyl)chlorin (m-THPC) in standard formulation (Foscan®) and in its non PEGylated and PEGylated liposomal formulations, Foslip® and Fospeg®, in HeLa multicellular spheroids, as in vitro avascular models of solid tumors. Confocal microscopy studies demonstrated that m-THPC fluorescence was confined in the external cell layers of spheroids with a slightly higher accumulation of Foslip® and Fospeg® with respect to Foscan®. Irradiation with red light, following 24h incubation of spheroids with the m-THPC formulations, caused however photodamages also in cells located in the central part of spheroids, as documented by transmission electron microscopy analyses. Overall, the photodynamic effects of the three m-THPC formulations on HeLa cell spheroids were comparable in terms of cell viability measured with the MTS assay. It is however worth noting that the delivery of m-THPC by liposomes significantly abolished its cytotoxicity in the dark, slightly improved the cellular uptake and, following PDT, promoted cell loss and spheroid disassembling to a higher extent when compared to Foscan®.

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway.

We and others have shown that stresses, including photodynamic therapy (PDT), can disrupt the de novo sphingolipid biosynthesis pathway, leading to changes in the levels of sphingolipids, and subsequently, modulation of cell death. The de novo sphingolipid biosynthesis pathway includes a ceramide synthase-dependent reaction, giving rise to dihydroceramide, which is then converted in a desaturase-dependent reaction to ceramide. In this study we tested the hypothesis that combining Foscan-mediated PDT with desaturase inhibitor fenretinide (HPR) enhances cancer cell killing. We discovered that by subjecting SCC19 cells, a human head and neck squamous cell carcinoma cell line, to PDT+HPR resulted in enhanced accumulation of C16-dihydroceramide, not ceramide. Concomitantly, mitochondrial depolarization was enhanced by the combined treatment. Enhanced activation of caspase-3 after PDT+HPR was inhibited by FB. Enhanced clonogenic cell death after the combination was sensitive to FB, as well as Bcl2- and caspase inhibitors. Treatment of mouse SCCVII squamous cell carcinoma tumors with PDT+HPR resulted in improved long-term tumor cures. Overall, our data showed that combining PDT with HPR enhanced apoptotic cancer cell killing and antitumor efficacy of PDT. The data suggest the involvement of the de novo sphingolipid biosynthesis pathway in enhanced apoptotic cell killing after PDT+HPR, and identify the combination as a novel more effective anticancer treatment than either treatment alone.

mTHPC mediated, systemic photodynamic therapy (PDT) for nonmelanoma skin cancers: Case and literature review.

BACKGROUND AND OBJECTIVE: Patients with multiple nonmelanoma skin cancers (NMSCs), like immunosuppressed or nevoid basal cell carcinomas, offer a therapeutic challenge. Photodynamic therapy (PDT) using the systemic photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the ability to treat multiple NMSCs up to a depth of 10 mm in a single session. These unique properties offer an attractive alternative to regular therapies (e.g., surgery or radiation) to these patients. STUDY DESIGN: A systemic search was carried out that focused on the main clinical studies using mTHPC-PDT on NMSCs in humans. This review describes some of the basic principles of the treatment, the most effective treatment parameters as well as its possible adverse outcomes, which is illustrated with a short description of our own experiences using this treatment modality on four patients with multiple NMSCs. RESULTS: To date, only four clinical studies have been published. It was demonstrated that mTHPC-PDT could be highly effective. On illuminating 1-2 days after drug administration, plasma drug levels were high and the tumor clearance rates were high (up to 100%), with relative few side effects and excellent cosmetic and functional outcomes. These results were obtained with a relatively low, patient friendly photosensitizer dose (0.04-0.05 mg/kg) as skin photosensitivity was shorter after the procedure. Although the patients personally experienced consistently good cure rates, the healing times varied greatly between anatomical areas. The head and neck areas heal well with good cosmesis, while the lower leg and foot areas show delayed, at times compromised, healing with scarring. CONCLUSIONS: Although mTHPC-PDT is described in the literature as an interesting and promising therapeutic option, especially for multiple NMSCs, a randomized clinical trial is lacking and personal experiences warrant too much skepticism. With the recent introduction of the hedgehog pathway inhibitor vismodegib, mTHPC-PDT seems to be less suitable as a first line of treatment; it should be considered as a last resort therapy.

The use of photodynamic therapy as adjuvant therapy to surgery in recurrent malignant tumors of the paranasal sinuses.

BACKGROUND: Malignant tumors of paranasal sinuses and anterior skull base recur frequently after surgery and adjuvant radiotherapy. The vicinity of essential structures limits additional treatment options, such as salvage surgery and re-radiation. We report the feasibility of photodynamic therapy (PDT) as an adjuvant treatment to surgery. METHODS: Fifteen patients with recurrent tumors of the paranasal sinuses were treated with mtetrahydroxyphenylchlorin (mTHPC) mediated PDT as an adjuvant treatment to salvage surgery. All patients had previously curative radiotherapy. The treated tumors were squamous cell cancer (8), adenocarcinoma (3), undifferentiated carcinoma (2), adenoid cystic carcinoma (1) and radiotherapyinduced sarcoma (1). In five cases there was extension to the skull base. Two approaches of surgery where used, namely in eight cases an open approach, in the other seven endoscopic approach. Complete macroscopic resection with microscopic tumor positive margins was possible in three patients. The remaining twelve patients received debulking surgery followed by PDT. RESULTS: None of the patients had cerebrospinal fluid leak, meningitis, major bleeding or vision loss. Four patients developed temporary diplopia due to edema of the medial rectus muscle, one patient suffered from extensive necrosis leading to oro-nasal fistula. Complete response was observed in five patients. CONCLUSION: Photodynamic therapy can be used with relative safety as adjuvant therapy to surgery in recurrent tumors of the paranasal sinuses and the anterior skull base where complete resection is not achievable.