Administration Of Photosensitizer Research Articles

Optimizing Photodynamic Therapy:In vivoPharmacokinetics of Liposomalmeta-(Tetrahydroxyphenyl)Chlorin in Feline Squamous Cell Carcinoma

The aim of the present study was to optimize and simplify photodynamic therapy using a new liposomal formulation of the photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan); liposomal m-THPC (Fospeg)] and to reduce systemic reactions to the photosensitizer. To examine the pharmacokinetics of liposomal m-THPC, we determined tissue and plasma variables in feline patients with spontaneous squamous cell carcinoma. In vivo fluorescence intensity measurements of tumor and skin were done with a fiber spectrophotometer after i.v. injection of m-THPC or liposomal m-THPC in 10 cats. Blood samples, drawn at several time points after photosensitizer administration, were analyzed by high-performance liquid chromatography. None of the liposomal m-THPC-treated cats showed side effects during or after drug injection. Fluorescence intensities, fluorescence ratios (tumor fluorescence divided by skin fluorescence), and bioavailability in the tumor were 2 to 4 times higher with liposomal m-THPC compared with m-THPC. Liposomal m-THPC concentration in the tumor increased constantly to reach a maximum at 4 hours after injection. Plasma concentration and bioavailability were approximately 3 times higher with liposomal m-THPC compared with m-THPC measured at the time points of highest plasma concentration. The distribution half-life was shorter with liposomal m-THPC, resulting in maximal tumor accumulation up to 5.5 times earlier. Maximal tumor accumulation and maximal fluorescence ratio with liposomal m-THPC occurred at the same time point, indicating maximal selectivity. In both groups, all cats responded to therapy. Liposomal m-THPC was well tolerated by all cats and seems to have superior pharmacokinetic properties compared with m-THPC. The efficacy of the drug warrants further study.

Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapy

Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2′-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV–visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compounds to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on average 7-fold higher than tetraphenylporphyrin (TPP) used as reference and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a reduction of 70% in the presence of a competitive concentration of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same experimental conditions and the same photosensitizer concentration, TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm 2, respectively.

Drug Delivery of Aminolevulinic acid from Topical Formulations Intended for Photodynamic Therapy

Topical photodynamic therapy is used for a variety of malignant and pre-malignant skin disorders, including Bowen's Disease and Superficial Basal Cell Carcinoma. A haem precursor, typically 5-aminolevulinic acid (ALA), acting as a prodrug, is absorbed and converted by the haem biosynthetic pathway to photoactive protoprophyrin IX (PpIX), which accumulates preferentially in rapidly dividing cells. Cell destruction occurs when PpIX is activated by an intense light source of appropriate wavelength. Topical delivery of ALA avoids the prolonged photosensitivity reactions associated with systemic administration of photosensitisers but its clinical utility is influenced by the tissue penetration characteristics of the drug, its ease of application and the stability of the active agent in the applied dose. This review, therefore, focuses on drug delivery applications for topical, ALA-based PDT. Issues considered in detail include physical and chemical enhancement strategies for tissue penetration of ALA and subsequent intracellular accumulation of PpIX, together with formulation strategies and drug delivery design solutions appropriate to various clinical applications. The fundamental aspects of drug diffusion in relation to the physicochemical properties of ALA are reviewed and specific consideration is given to the degradation pathways of ALA in formulated systems that, in turn, influence the design of stable topical formulations.

Determinação do mecanismo de destruição de células mediado por meso-tetramesitylporfirina, octaetilporfirina, octaetilporfirina de vanadil e luz visível

A Terapia Fotodinâmica é um tratamento clínico empregado no combate a vários tipos de tumores. Nesta técnica, o paciente recebe uma certa dosagem de uma substância fotossensibilizadora que, por sua vez, acumula-se preferencialmente no tecido tumoral. Em seguida irradia-se luz visível, neste tecido, com a finalidade de se excitar o fotossensibilizador. Esta substância, excitada, pode transferir elétrons e/ou energia para o oxigênio, no estado fundamental, gerando espécies reativas de oxigênio como o radical superóxido e oxigênio singlete. O primeiro é gerado no mecanismo tipo I, pela transferência de elétrons, e o segundo no mecanismo tipo II, pela transferência de energia. Estas espécies reativas geram um estresse oxidativo, no tecido tumoral, levando as células cancerígenas à morte. Neste trabalho, foram avaliadas as propriedades fotossensibilizadoras de três porfirinas e constatou-se que as mesmas são capazes de destruir células, na presença de luz e oxigênio. Este evento foi mais pronunciado, na presença de água deuterada, e inibido por supressores de oxigênio singlete, indicando predominância do mecanismo tipo II.

Foscan®-based photodynamic treatment in vivo: correlation between efficacy and Foscan accumulation in tumor, plasma and leukocytes

The tumoricidal effect of Foscan-mediated photodynamic therapy may involve both vessel and tumor cell destruction. The relevant importance of each mechanism seems to be defined by the time interval between photosensitizer administration and illumination (drug-light interval, DLI). Short drug-light intervals favor vascular damage due to the preferential photosensitizer accumulation in the tumor vasculature, whereas long drug-light intervals trigger direct tumor cell damage due to the dye localization in the tumor. The purpose of this study was to investigate the influence of tumor, plasma and leukocyte concentrations of Foscan at different times after photosensitizer delivery on PDT response. Both pharmacokinetic and tumor-response studies were carried out in nude mice bearing s.c. Colo26 tumors. One to 96 h after i.v. injection of 0.5 mg/kg Foscan, animals were exposed to 10 J/cm(2) 652-nm light delivered at 30 mW/cm(2). Mean tumor regrowth time was determined for each schedule of treatment and correlated to Foscan distribution in the compartments of interest at the time of illumination. PDT efficacy was greatest for irradiations performed at 6 and 12 h post Foscan injection and limited at 96 h. Unlike tumor and plasma Foscan concentrations, photosensitizer accumulation in leukocytes exhibited a good correlation with PDT efficacy. The results suggest that leukocytes could play an important role in the mechanism of PDT-induced vascular damage either by being one of the main effector compartments or by better reflecting Foscan accumulation in endothelial cells compared to plasma. The prevalence of indirect damage was highlighted by the fact that PDT efficacy was not modified by the use of a higher fluence rate of irradiation (160 mW/cm(2)), which depleted intratumor oxygen and did not restrain PDT-induced cell toxicity.

Photodynamic effects of porphyrin and chlorin photosensitizers in human colon adenocarcinoma cells

Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate wavelength of light, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Photofrin®, a complex mixture of porphyrin oligomers has recently received FDA approval for the photodynamic treatment of esophageal and endobronchial carcinoma, but its photodynamic and toxicity profiles are far from ideal. In the present study we evaluated a series of porphyrin-based PSs, some of which newly synthesized by our group, with the aim to identify agents with more favorable characteristics. For the most effective compounds in the porphyrin series, chlorin analogs were also synthesized; for comparison, the screening also included Photofrin®. Cytotoxicity studies were performed by the MTT assay on a cultured human colon adenocarcinoma cell line (HCT116); the results indicate that the 3,4,5-trimethoxyphenyl, 3OH- and 4OH-phenyl, and the sulfonamidophenyl derivatives are significantly more potent than Photofrin®. Flow cytometric studies and fluorescence microscopy indicate that in PDT-treated HCT116 cells death occurs mainly by apoptosis.In summary, novel PSs described in the present study, belonging both to the porphyrin and chlorin series, have proven more effective than Photofrin® in killing colon cancer cells in vitro; extending these observation to in vivo models, particularly regarding the deeper reaching chlorin derivatives, might lead to significant advances in the development of tumor PDT.

Assessment of Photosensitizer Dosimetry and Tissue Damage Assay for Photodynamic Therapy in Advanced‐stage Tumors¶

ABSTRACTPhotodynamic therapy (PDT) efficacy is a complex function of tissue sensitivity, photosensitizer (PS) uptake, tissue oxygen concentration, delivered light dose and some other parameters. To better understand the mechanisms and optimization of PDT treatment, we assessed two techniques for quantifying tissue PS concentration and two methods for quantifying pathological tumor damage. The two methods used to determine tissue PS concentration kinetic were in vivo fluorescence probe and ex vivo chemical extraction. Both methods show that the highest tumor to normal tissue PS uptake ratio appears 4 h after PS administration. Two different histopathologic techniques were used to quantify tumor and normal tissue damage. A planimetry assessment of regional tumor necrosis demonstrated a linear relationship with increasing light dose. However, in large murine tumors this finding was complicated by the presence of significant spontaneous necrosis. A second method (densitometry) assessed cell death by nuclear size and density. With some exceptions the densitometry method generally supported the planimetry results. Although the densitometry method is potentially more accurate, it has greater potential subjectivity. Finally, our research suggests that the tools or methods we are studying for quantifying PS levels and tissue damage are necessary for the understanding of PDT effect and therapeutic ratio in experimental in vivo tumor research.

Antiangiogenic photodynamic therapy (PDT) using Visudyne causes effective suppression of tumor growth

We previously observed that antiangiogenic photodynamic therapy (PDT), namely, laser irradiation at 15 min after administration of photosensitizer, by using stable liposomal benzoporphyrin derivative monoacid ring A (BPD-MA), in which the liposomes were composed of dipalmitoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine, cholesterol, and dipalmitoylphosphatidylglycerol (10:10:10:2.5 as a molar ratio), was quite effective for cancer treatment. On the other hand, Visudyne, a commercialized liposomal formulation of BPD-MA, is based on more fluid lipids, namely, dimyristoylphosphatidylcholine and egg yolk phosphatidylglycerol, and is thought to be less stable in the presence of serum. The data of spin column chromatography indicated a little faster transfer of BPD-MA from Visudyne to lipoprotein fraction when Visudyne was incubated with serum than when the stable liposomal BPD-MA was used. The phototoxicity of Visudyne against a human endothelial cell line, ECV304, was almost the same as that of stable liposomal BPD-MA after PDT treatment. Therefore, we examined the antiangiogenic scheduling of PDT with Visudyne. Tumor growth of Meth-A sarcoma-bearing mice was strongly suppressed when the antiangiogenic scheduling was performed with Visudyne, namely, irradiation at 15 min after injection of the drug, in comparison with the conventional scheduling in which laser irradiation is done at 3 h post-injection. This greater effectiveness of PDT at 15 min was suggested to be caused by hemostasis, based on observations made in a dorsal air sac angiogenesis model. Visudyne-mediated antiangiogenic PDT cured 40 or 60% of Meth-A-bearing mice completely when 0.25 or 0.5 mg/kg BPD-MA, respectively, was used. These data suggest that the antiangiogenic scheduling is effective in Visudyne-mediated cancer PDT despite the transferring of BPD-MA from the liposomal fraction to lipoproteins in the bloodstream.

Assessment of photosensitizer dosimetry and tissue damage assay for photodynamic therapy in advanced-stage tumors.

Photodynamic therapy (PDT) efficacy is a complex function of tissue sensitivity, photosensitizer (PS) uptake, tissue oxygen concentration, delivered light dose and some other parameters. To better understand the mechanisms and optimization of PDT treatment, we assessed two techniques for quantifying tissue PS concentration and two methods for quantifying pathological tumor damage. The two methods used to determine tissue PS concentration kinetic were in vivo fluorescence probe and ex vivo chemical extraction. Both methods show that the highest tumor to normal tissue PS uptake ratio appears 4 h after PS administration. Two different histopathologic techniques were used to quantify tumor and normal tissue damage. A planimetry assessment of regional tumor necrosis demonstrated a linear relationship with increasing light dose. However, in large murine tumors this finding was complicated by the presence of significant spontaneous necrosis. A second method (densitometry) assessed cell death by nuclear size and density. With some exceptions the densitometry method generally supported the planimetry results. Although the densitometry method is potentially more accurate, it has greater potential subjectivity. Finally, our research suggests that the tools or methods we are studying for quantifying PS levels and tissue damage are necessary for the understanding of PDT effect and therapeutic ratio in experimental in vivo tumor research.

This month in Gastroenterology

This month in Gastroenterology

313 Cytotoxicity evaluation of three phthalocyanine photosensitisers on human corneal epithelium cell cultures

Mucocutaneous oropharyngeal candidiasis is predominately caused by Candida albicans. The overall incidence of oral candidiasis in young adults has increased dramatically with the spread of HIV/AIDS. Conventional treatments have been shown to have a fungistatic rather than a fungicidal effect, resulting in an inadequate treatment outcome for patients. In addition, increasing resistance of C. albicans to antifungal agents has made effective treatment more difficult. Accordingly, interest has arisen in development of new prophylaxis/treatment regimens. One such alternative treatment is photodynamic antimicrobial chemotherapy (PACT), in which a combination of a photosensitising drug and visible light cause selective destruction of microbial cells. Due to the highly coloured nature of photosensitisers and the potential for staining of teeth, lips and buccal mucosa, administration of photosensitisers to humans as a liquid mouthwash is undesirable. Targeted delivery of the photosensitiser directly to the site of infection should be the aim. The current study, therefore, reports on a mucoadhesive patch containing toluidine blue O (TBO), as a potential delivery system for use in PACT of oropharyngeal candidiasis. Patches prepared from aqueous blends of poly(methyl vinyl ether/maleic anhydride) and tripropyleneglycol methyl ether possessed suitable properties for use as mucoadhesive drug delivery systems and were capable of resisting dissolution when immersed in artificial saliva. When releasing directly into an aqueous sink, patches containing 50 and 100 mg TBO cm−2 both generated receiver compartment concentrations exceeding the concentration (2.0–5.0 mg ml−1) required to produce high levels of kill (>90%) of both planktonic and biofilm-grown C. albicans upon illumination. However, the concentrations of TBO in the receiver compartments separated from patches by membranes intended to mimic biofilm structures were an order of magnitude below those inducing high levels of kill, even after 6 h release. Therefore, short application times of TBO-containing mucoadhesive patches should allow treatment of recently-acquired oropharyngeal candidiasis, caused solely by planktonic cells. Longer patch application times may be required for persistent disease where biofilms are implicated.

Whole Bladder Photodynamic Therapy for Orthotopic Superficial Bladder Cancer in Rats: A Study of Intravenous and Intravesical Administration of Photosensitizers

Photodynamic therapy after intravenous injection of Photofrin (QLT Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted bladder and skin photosensitivity, which limits its clinical application. In an attempt to overcome these limitations photodynamic therapy after intravesical instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat bladder tumor model was explored and compared with intravenous Photofrin for photodynamic therapy efficacy and phototoxicity. At 2 weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2 mg./ml. intravesically). The ALA concentration for intravesical instillation was 300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda = 630 nm.) was performed 4 hours after drug administration. Tumor control and complications were evaluated. Photodynamic therapy with intravenous Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats 6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no photodynamic therapy related deaths in groups receiving intravesical instillation of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously plus 50 J./cm.(2) (60) were significantly different from that in controls (44). Intravesical instillation of Photofrin or ALA can achieve the same photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat bladder tumor model with less phototoxicity to normal tissues.

Whole Bladder Photodynamic Therapy for Orthotopic Superficial Bladder Cancer in Rats: A Study of Intravenous and Intravesical Administration of Photosensitizers

Whole Bladder Photodynamic Therapy for Orthotopic Superficial Bladder Cancer in Rats: A Study of Intravenous and Intravesical Administration of Photosensitizers

STUDIES OF TIN ETHYL ETIOPURPURIN PHOTODYNAMIC THERAPY OF THE CANINE PROSTATE

Previous studies have demonstrated the technical feasibility of destroying prostate tissue using photodynamic therapy for benign and malignant disease. A series of canine studies was performed to evaluate the systemic uptake and distribution of the photosensitizer tin ethyl etiopurpurin (SnET2) in the prostate and surrounding tissues, and determine the optimal combination of drug dose, light dose and time interval between drug and light administration using transurethral and transperineal interstitial light delivery. Adult male mongrel source dogs received intravenous bolus injections of 0.5 or 1.0 mg./kg. SnET2 in 4 studies. In the first study the concentration of SnET2 in the prostate and surrounding tissue was measured at various time points after dosing. In the second study a tissue dose response relationship of SnET2-PDT was studied after transperineal interstitial light application. The third and fourth studies evaluated the tissue effects of combined transurethral and transperineal interstitial light application on SnET2 sensitized prostates. Substantial amounts of SnET2 were measured in the prostate between 24 and 168 hours after infusion. Drug and light dose dependent prostatic tissue necrosis and volume reduction were documented in the dose response relationship study. The combination of transurethral and transperineal light resulted in the extensive destruction of glandular epithelium with minimal damage to surrounding structures. Average prostate volume decreased 52%. Transperineal interstitial light delivery with multiple diffusers resulted in substantial glandular destruction of the prostate. An average volume reduction of more than 60% was achieved. SnET2-PDT is a viable minimally invasive treatment modality for prostate tissue destruction.

Induction of apoptosis and manganese superoxide dismutase gene by photodynamic therapy in cervical carcinoma cell lines

Background. Photodynamic therapy (PDT) is a cancer treatment modality in which systemic administration of a tumor-localizing photosensitizer is followed by irradiation of the tumor with visible light. Although PDT is undergoing clinical trials for various cancers, the mechanisms of its action are not fully understood. To investigate the mechanism of cell death by PDT, we performed in-vitro PDT, using Photofrin II as a photosensitizer, in two human cervical carcinoma cell lines, HeLa and CaSki.

Effect of photodynamic therapy on recurrent pituitary adenomas: clinical phase I/II trial ‘ an early report

Pituitary adenomas, although histologically benign, are not always curable by surgery alone, principally because of dural infiltration, as well as their peculiar anatomical location. Radiotherapy has been employed as an adjuvant therapy to address residual disease with favourable results. This approach is, however, not without side effects, and it cannot be repeated. We are therefore investigating the effectiveness of photodynamic therapy (PDT) on recurrent pituitary adenomas in humans. This study details the protocol applied to 12 patients with recurrent pituitary adenomas, which involved systemic administration of photosensitizer (Photofrin) followed, after a period of 24-48 h, by intraoperative illumination of the tumour bed using 630 nm laser light. The primary end points were visual, endocrine and radiological improvement. The incidence of side effects was also monitored.The longest follow-up is 2 years. Most patients suffering from visual acuity or field defects have shown improvement when followed for 12 months or more. Three patients showed complete recovery of their visual fields. All those who presented with functional adenomas have shown reduction in their hormone levels.Tumour volume, relative to the preoperative size, was 122, 87, 66, 60 and 46% at 4 days, and 3, 6, 18 and 24 months, respectively. One patient developed severe skin photosensitization due to early exposure to direct sunlight and three others displayed minor skin reactions. There was no treatment-related mortality or morbidity. One patient (operated transcranially) developed hemiparesis postoperatively, which recovered completely. We think this is unrelated to the treatment.This prospective study demonstrates that PDT may be safely applied to the pituitary fossa by the trans-sphenoidal route and indicates the need for a randomized, controlled trial in order to establish its therapeutic potential.

PH‐Dependent Chalcogenopyrylium Dyes as Potential Sensitizers for Photodynamic Therapy: Selective Retention in Tumors by Exploiting pH Differences between Tumor and Normal Tissue

Ideal photosensitizers have long-wavelength absorption and strong tumor selectivity with rapid clearance from normal tissues. The telluroselenopyrylium dye 1 that absorbs light at 795 nm (epsilon = 285,000 M-1 cm-1) has a novel property that enhances the tumor specificity and normal tissue clearance. After intralesional injection to both tumors and surrounding skin, it disappeared from the normal skin of BALB/c mice faster than it did from subcutaneously implanted Colon 26 tumors, which resulted in therapeutic selectivity. In vivo reflectance spectroscopy showed that the half-life in tumor was about 50 min while in skin it was around 12 min. This phenomenon appears to be related to the pH differences in normal skin versus tumor, because the rates of drug hydrolysis in solution were shown to be sensitive to changes in pH. Inhibition of tumor regrowth following intratumoral photosensitizer administration depended on both light dose and drug dose, as well as the time interval between dye injection and irradiation; selectivity depended on the time interval. Although treatment parameters were not optimized efficacy was superior to systemic Photofrin under our standard conditions. We discuss how new, more optimal, photosensitizers can be designed that use rates of hydrolysis to exploit the differences in pH between normal tissue and tumor.

Photodynamic therapy for esophageal carcinoma

Esophageal carcinoma continues to have a poor prognosis with limited treatment options. Potential surgical curative treatment exists only for early stage cancers, with palliative treatment used for the most advanced cancers. Photodynamic therapy (PDT) is a treatment modality for both early and advanced cancers of the esophagus that has shown encouraging results. This article reviews the background, biology, and mechanism of photodynamic therapy in cancer treatment. In particular, the indiciations and contraindications to PDT with regard to esophageal carcinoma are discussed, as well as the need for proper patient selection and pretreatment evaluation. Specific detail will be provided in discussing the technique of administering photodynamic therapy for the treatment of esophageal cancers. The administration of the light photosensitizer, selection of the appropriate light dosimetry, proper endoscopic delivery of the light treatment, and recommended follow-up for both early and late stage cancers after completion of PDT are discussed. Finally, complications that can occur with the use of this relatively new treatment and how to avoid and manage these complications are reviewed.

Relative contributions of apoptosis and random necrosis in tumour response to photodynamic therapy: effect of the chemical structure of Zn(II)-phthalocyanines

Zn(II)-phthalocyanine (ZnPc) and its octapentyl (ZnOPPc) and octadecyl (ZnODPc) derivatives have been intravenously injected at a dose of 1.46 μmol/kg into female Balb/c mice bearing an intramuscularly transplanted MS-2 fibrosarcoma. Pharmacokinetic studies show that in all cases the maximal concentration of phthalocyanine in the tumour is reached at 24 h post-injection: the efficiency and selectivity of tumour targeting slightly increase upon increasing the length of the alkyl substituents. Irradiation of the neoplastic lesion (620–700 nm light, 180 mW/cm 2, 300 J/cm 2) 24 h after photosensitizer administration induces a significant delay of tumour growth, which was largest (∼ 11 days) for ZnPc and smallest (∼ 3.5 days) for ZnODPc. Electron microscopy investigations of irradiated tumour specimens show that ZnPc causes an early direct damage of malignant cells, largely via processes leading to random necrotic pathways, although a limited contribution of apoptotic pathways is detected. The importance of this increased upon using ZnOPPc and especially ZnODPc as the photosensitizers, possibly due to a different partitioning in different compartments of cell membranes.

Antitumor efficacy of the combination of photodynamic therapy and chemotherapy in murine tumors

Photodynamic therapy (PDT) is based on the administration of tumor-localizing photosensitizers followed by light exposure of the tumor mass. The photocytotoxic effects are mainly caused by the generation of singlet oxygen. Recently, PDT has been proposed for use in combination with anticancer chemotherapy with a view to exploiting any additive antitumor effect. We investigated the effect of PDT with photoactivated aluminum disulfonated phthalocyanine (AlS 2Pc) combined with the antiblastic drugs Adriamycin (ADR) and cisplatinum (CDDP) on murine tumors. Mice bearing L1210 leukemia and P388 lymphoma were treated with ADR or CDDP and subsequently treated with PDT. Low chemotherapy doses were ineffective, but the combination of antiblastic drugs+PDT had a significantly additive antitumor effect. In conclusion, with this combined therapy we were able to greatly reduce the effective doses of antiblastic drugs, thus lowering their toxic effects on normal host tissues.