Porphyrin photosensitised processes in the prevention and treatment of water- and vector-borne diseases.

Water- and vector-borne diseases are a global burden which is estimated to cause several million deaths and innumerable cases of sickness every year. These infectious illnesses are emerging or resurging as a result of several factors, such as changes in climate, in public health and demography policy, as well as the spread of resistance to insecticide and drug, and genetic changes in pathogens. Integrated prevention strategies must be developed and implemented in endemic disease areas to reverse the trend of emergent/resurgent water- and vector-borne diseases. With this perspective porphyrins and their analogues, that have been shown to act as very efficient photosensitising agents against a broad number of microbial pathogens (bacteria, fungi, protozoa) and parasitic animals, could represent an important tool for the prevention and control of these pathologies. The application of photosensitised processes can be exploited to address environmental problems of high significance, including the decontamination of waste waters, the disinfection of fish-farming tanks and the control of populations of noxious insects. Such diversified applications take advantage of the availability of a truly large number of porphyrin derivatives with chemical structures which can be tailored to comply with the physical and chemical properties, as well as the biological features of several milieus. In addition, the property typical of porphyrins to absorb essentially all the wavelengths in the sun emission spectrum allows the promotion of processes largely based on natural resources with significant energy saving and low impact on the ecosystems.

Mechanisms involved in the photosensitized inactivation of Acanthamoeba palestinensis trophozoites.

AIMS: To advance our understanding of the mechanisms involved in the RLP068 phthalocyanine-photosensitized inactivation of Acanthamoeba palestinensis trophozoites through a precise identification of the targets of the photoprocess in both the cytosolic and mitochondrial compartments. METHODS AND RESULTS: We followed the activities of selected marker enzymes as well as we performed fluorescence and transmission electron microscopy investigations of the alterations induced by the photoprocess in the fine structure of subcellular compartments. RLP068 is preferentially located in the contractile vacuole: the fluorescence in that site is particularly evident in the unirradiated cells and becomes more diffused after irradiation. Electron microscopic analysis of photosensitized A. palestinensis cells clearly shows that the swelling of trophozoites and the appearance of vacuoles spread throughout the cytoplasm after phototreatment. The activity of a typical cytoplasmic enzyme, such as lactate dehydrogenase, underwent a 35% decrease as a consequence of the photoprocess, reflecting the photodamage induced by migrating phthalocyanine molecules in their micro-environment. CONCLUSIONS: The presence of multiple targets for the phthalocyanine-photosensitized process is of utmost importance because this pattern of cell damage makes it unlikely that photoresistant A. palestinensis strains are gradually selected or mutagenic phenomena are developed as a consequence of the photoinduced damage. SIGNIFICANCE AND IMPACT OF THE STUDY: Photosensitization via phthalocyanines appears to represent an efficient and safe approach for achieving a close control of the population of a potentially pathogenic protozoan such as A. palestinensis, opening new perspectives for the disinfection of microbiologically polluted waters.

A novel boronated-porphyrin as a radio-sensitizing agent for boron neutron capture therapy of tumours: in vitro and in vivo studies.

A water-soluble [meso-tetra(4-nido-carboranylphenyl)porphyrin] (H(2)TCP) bearing 36 boron atoms was studied for its accumulation and its radio/photo-sensitization efficiency towards murine melanotic melanoma cells. The amount of H(2)TCP in the cells increased with the porphyrin dose in the incubation medium up to 100 microM with no significant dark toxicity. Fluorescence microscopy observations showed that the porphyrin was largely localized intracellularly. Based on these "in vitro" results our investigations were pursued using the B16F1 melanotic melanoma subcutaneously transplanted in C57BL6 mice as "in vivo" model. Phormacokinetic studies were performed by injection of H(2)TCP intratumorally (1 mg/kg) and intravenously (10 mg/kg). At 0.5h after i.t. administration or at 24 h after i.v. injection, the amounts of (10)B in the tumour were about 60 ppm and about 6 ppm, respectively. The distribution of H(2)TCP in the tumour after intravenous or intratumoural injection was also assessed by fluorescence microscopy analyses. Under these conditions, preliminary BNCT studies were carried out using a new thermal column called HYTOR (HYbrid Thermal spectrum sHifter TapirO Reactor) inserted in the fast nuclear reactor Tapiro at Enea Casaccia, Italy. The mice were exposed to HYTHOR radiation field for 20 min at a reactor power of 5 kW. In spite of different amounts of (10)B in the tumour at the irradiation time, a similar significant delay in tumour growth (5-6 days) was induced by neutron irradiation in intratoumorally and intravenously injected mice. The response of the melanotic melanoma to H(2)TCP-BNCT was compared with that obtained by irradiation after intraperitoneal injection of boron-phenylalanine.

Porphyrin-photosensitized processes: their applications in the prevention of arterial restenosis.

Photodynamic therapy (PDT) is based on the use of a photozensitising compound which is accumulated by rapidly proliferating cells. Subsequent irradiation with light wavelengths specifically absorbed by the photosensitiser promotes the generation of reactive short-lived oxygen species which cause an irreversible and selective damage. Endovascular interventions to correct obstructive arterial disease have been developed worldwide with excellent short term results. However, long term patency is still limited by the onset of restenosis, due to subsequent intimal hyperplasia (IH). IH is characterized by proliferation and migration of smooth muscle cells (SMC) and extracellular matrix production. Targeting of SMC by photozensitisers can be efficiently achieved by taking advantage of the receptors for low density lipoproteins (LDL) expressed by such cells. Thus, preference is given to hydrophobic compounds which readily partition in the lipid matrix of LDL. We developed a liposomal formulation of a highly hydrophobic photozensitising agent, Zn(II)-phthalocyanine (ZnPc). The liposome-delivered ZnPc was readily taken up by cultured SMC cells and preferentially localized in the Golgi apparatus. Red light irradiation of incubated SMC induced cell death. Extension of these investigations to an in vivo rabbit model showed that ZnPc mainly accumulated in the media layer, where PDT induces the main damage through cellular depletion due to apoptosis of SMC, changes in the extracellular matrix with generation of a barrier to cellular migration, and acceleration of re-endothelization. Initial clinical applications showed that PDT safely and effectively prevents restenosis after angioplasty up to a 6 month follow-up.

Photosensitized inactivation of Acanthamoeba palestinensis in the cystic stage.

AIMS: To develop alternative approaches for medical and environmental control of pathogenic Acanthamoeba spp. by means of photodynamic treatment with a tetracationic Zn(II)-phthalocyanine (RLP068). METHODS AND RESULTS: Incubation of cyst cultures with RLP068 for 1 h caused an accumulation of readily detectable concentrations of the phthalocyanine, even at doses as low as 0.5 micromol l(-1). RLP068 exhibited no dark toxicity towards cysts up to 5 micromol l(-1) concentration. A decrease of c. 50% in cyst survival in comparison with controls was measured upon incubation of the cysts with 0.5 micromol l(-1) RLP068, followed by exposure to light (600-700 nm) for 20 min at a fluence rate of 50 mW cm(-2) (60 J cm(-2)). After incubation with 3 and 5 micromol l(-1) RLP068 and irradiation, the cysts lost their excystment ability as early as day 5 and up to day 10, and were clearly damaged when observed under an interference contrast microscope. CONCLUSIONS: These data indicate the promising use of RLP068 in phototreatment of diseases caused by pathogenic amoebae and in initial disinfection of wastewaters. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid and extensive photodamage may be induced in the highly resistant cystic stages by means of 600- to 700-nm light sources.

The Application of Photofrin II as a sensitizing agent for ionizing radiation--a new approach in tumor therapy?

Radiosensitizers represent an enticing concept in tumor therapy. As ionizing radiation affects both neoplastic and normal tissues, its effects are generally non-specific. The aim of applying a radiosensitizing agent is to achieve a maximum effect on tumor tissue, while minimizing the damage to normal tissues. A variety of parameters such as the oxygen supply and the state in the cell cycle, need to be taken into account when evaluating a potential radiosensitizer. Most of the previously known radiosensitizers are neither selective nor tumor specific. In this article, we review the properties and radiosensitizing potential of Photofrin II. Photofrin II is well-known as a photosensitizing agent in photodynamic therapy. In recent years, a radiosensitizing potential of the substance has been demonstrated, specifically increasing the sensitivity of solid tumor tissues, especially of radio-resistant, hypoxic tumor cells, to radiation. This radiosensitizing effect has been demonstrated both by in vitro studies and by animal experiments. Several studies with tissue cultures have demonstrated a radiosensitizing effect of Photofrin II in glioblastoma (U-373MG) and bladder cancer cell lines (RT-4). No effect was noted in colon carcinoma cell lines (HT-29). Unpublished data of additional cell lines will be mentioned in the review. Animal experiments with Lewis sarcoma and with bladder cancer have moreover demonstrated an in vivo effect of Photofrin II as a radiosensitizer. The mechanism of this radiosensitizing effect is not completely understood. In vitro data, however, support the hypothesis that the radiosensitizing action involves OH-radicals in addition to a potential impairment of repair mechanisms after sublethal damage of ionizing radiation. Moreover, early results of a phase I trial are available and document the potential feasibility of the application of Phototofrin II as a radiosensitizing agent in clinical practice.

Porphyrins as radiosensitizing agents for solid neoplasms.

The biological effects of radiation affect both neoplastic and normal tissues. The nature and extent of such effects, however, depend on selected biological parameters (e.g., oxygen supply, cell cycle) and can be modified by chemical agents such as radiosensitizers, radioprotectors and chemotherapeutic agents. A precise control of the mode of action of the radiation is important in order to achieve the maximum effect on tumor tissue, while minimizing the effect on normal tissues. Most of the known and routinely used radiosensitizers are neither selective nor tumor specific. This article reviews a new selective and specific modality that increases the sensitivity of solid tumor tissue, especially of radio resistant, hypoxic tumor cells, to radiation. This modality is currently under early clinical evaluation and encompasses the application of Photofrin II, which is already used as a photosensitizer in photodynamic therapy (PDT) at predetermined times prior to irradiation.

Photofrin as a specific radiosensitizing agent for tumors: studies in comparison to other porphyrins, in an experimental in vivo model.

The use of ionizing radiation for tumor treatment represents a well established therapeutic modality. The efficiency and selectivity of radiotherapeutic protocols can be often enhanced by the addition of specific chemical compounds that optimise the response of the tumor to the incident radiation as compared with peritumoral tissue districts. The results of this study showed that Photofrin, a porphyrin derivative which is presently used as a tumor-photosensitizing agent in photodynamic therapy (PDT), can also act as an efficient tumor radiosensitizer. To test this possibility, we used nude mice subcutaneously implanted with human bladder cancer RT4. The mice were injected with different porphyrin-type photosensitizing agents, including Photofrin, 5-aminolevulinic acid, chlorin e(6), haematoporphyrin, protoporphyrin, Zn-tetrasulphophtalocyanine, and irradiated with 5 and 15 Gy using a Siemens X-ray device. Even though all the porphyrins accumulated in significant amounts in the neoplastic lesion, only Photofrin significantly improved the response of the tumor to irradiation by increasing the doubling time of the tumor volume from 6.2 days in the untreated control group to 10.9 days in the 5 and 15 Gy-irradiated groups. The tumor response was maximal with injected Photofrin doses of 7.5 mg/kg, and was not further enhanced by injection of higher doses. Our hypothesis is, that the radiosensitizing effect of Photofrin seems to be due to some oligomeric constituents which could specifically react with radiogenerated-radicals thereby amplifying the effect of the X-ray radiation.

Application of Photofrin II as a specific radiosensitising agent in patients with bladder cancer--a report of two cases.

BACKGROUND: The effect of ionizing radiation on tumour tissues can be optimised by adding radiosensitising agents to enhance tumour inactivation. Photofrin II has been approved as a photosensitising agent for the photodynamic therapy (PDT) of selected solid tumours. At present, no chemical modifier has been found to act as a selective radiosensitiser. We report here the first use of Photofrin II as a radiosensitising agent to enhance radiation therapy. PATIENTS: Two patients, one female with unresectable bladder cancer and one male with recurrent inoperable bladder cancer, were treated with radiation therapy (44.8 Gy + 14 Gy boost) of the pelvic region. 24 hours before initiation of therapy the patients were intravenously injected with 1 mg kg(-1) Photofrin II (Axcan, Canada). RESULTS: Magnetic resonance imaging of the pelvis with a standardized protocol demonstrated a reduction in tumour volume of approximately 40% in the female patient and 35% in the male patient. The female patient was operated upon after conclusion of radiotherapy, the male patient refused the operation. No severe side effects were observed. CONCLUSION: Photofrin II is a promising radiosensitising agent in the treatment of patients with advanced solid tumours.

Photosensitizing properties of a boronated phthalocyanine: studies at the molecular and cellular level.

A synthetic procedure has been developed for the preparation of a Zn-phthalocyanine peripherally substituted with a dodecaborane. The absorption spectrum of the derivative is typical of the phthalocyanine chromophore. Moreover, the boronated phthalocyanine exhibits a high photosensitizing efficiency against a model biological substrate, such as N-acetyl-L-tryptophanamide, and a singlet oxygen quantum yield of 0.53 in dimethylformamide. Even though the presence of the dodecaborane moiety appears to decrease the affinity of the phthalocyanine for HT-1080 transformed human fibroblasts, the boronated phthalocyanine causes an essentially complete loss of cell viability upon irradiation with 600-700 nm light under mild conditions (1 microM concentration, 5-min irradiation at 10 mW/cm(2)).

Photofrin II as an efficient radiosensitizing agent in an experimental tumor.

BACKGROUND AND OBJECTIVE: The use of ionizing irradiation as radiation therapy (RT) for tumor treatment represents a well-established method. The use of photodynamic therapy (PDT), especially with Photofrin II, for tumor treatment is also known. Chemical modifiers enhancing the action of radiation therapy are well known and widely used in medicine. None of these compounds, however, is a selective radiosensitizer. MATERIALS AND METHODS: Several series of animal experiments were performed. The highly differentiated human bladder cancer cell line RT4 was implanted subcutaneously in nude mice. The mice were injected 10 mg/kg Photofrin II and irradiated with 5 Gy. RESULTS: Photofrin II has proved to be a chemical modifier of ionizing irradiation, enhancing the tumor doubling time (tumor growth) from 6.2 to 10.9 days in the control group with the use of irradiation and injection of porphyrin. CONCLUSION: Photofrin II shows a high activity as radiosensitizer and, in the future, can be used as a selective radiosensitizer for tumor treatment with ionizing radiation.

Photosensitization with zinc (II) phthalocyanine as a switch in the decision between apoptosis and necrosis.

Photodynamic therapy (PDT) of tumors and other diseases is based on the uptake of a photosensitizing dye in target cells, which are damaged by reactive oxygen intermediates generated on irradiation with light in which the wavelengths match the dye absorption spectrum. PDT can induce cell death by necrosis and apoptosis both in vivo and in vitro, but the factors determining the contribution of either mechanism to the overall process are not completely defined. Our studies on the photosensitization of 4R transformed fibroblasts with the second-generation photosensitizer zinc (II) phthalocyanine (ZnPc) aim at determining the effect of important experimental parameters such as time of cell incubation (2 or 24 h) with ZnPc before irradiation and ZnPc concentration in the incubation medium on cell death. Furthermore, we propose possible correlations between the cell death mechanism and primary photo-damage sites; these are mainly determined by the intracellular localization of the photosensitizer. The mechanism of cell death was determined by both electron microscopy analysis of the morphological alterations induced by photosensitization and measurement of caspase 3 activation. The initial photodamage sites were determined by measuring the activities of several functions typical of mitochondria, lysosomes, Golgi apparatus, cytosol, and plasma membrane. The intracellular localization of ZnPc after 2- or 24-h incubation was determined by fluorescence microscopy. Necrosis, associated with early loss of plasma membrane integrity and complete depletion of intracellular ATP, represents the prevailing mode of death for 4R cells dark-incubated for 2 h with ZnPc and irradiated with light doses reducing viability by 99.9%. In contrast, irradiation performed 24 h after ZnPc incubation causes only partial inhibition of plasma membrane activities, and cell death occurs largely by apoptosis. ZnPc is mainly localized in the Golgi apparatus after 2- and 24-h incubation, and in all of the cases this compartment represents a primary target of photodamage. Only after prolonged incubation is mitochondrial localization of ZnPc clearly detected by fluorescence microscopy; this could be a determining factor for promotion of apoptosis. Our data demonstrate that it is possible to modulate the mechanism of cell death by appropriate protocols; this may be relevant for enhancing the therapeutic efficacy of PDT.

meso-tetraphenylporphyrin dimer derivatives as potential photosensitizers in photodynamic therapy. Part 2.

Studies on the synthesis, singlet oxygen and fluorescence yields and pharmacokinetic properties of three different dimeric porphyrins with an amide linkage (D2-D4) are described and compared with the results recently reported for a dimeric porphyrin (D1). The pharmacokinetic behavior of all dimers were examined in Balb/c mice bearing MS-2 fibrosarcomas. The maximal efficiency and selectivity of photosensitizer accumulation in each tumor tissue takes place at 24 h after drug administration of 1.0 mg kg-1 into DL-alpha-dipalmitoylphosphatidylcholine liposomes by intravenous injection. Since the dimeric porphyrins exhibit high quantum yields of singlet oxygen generation, long triplet lifetimes and high photostability, the results obtained suggest that the evaluated dimeric structures may be promising candidates for further use in PDT experiments. The results also allow the possibility to establish a correlation between the chemical structure of the dyes and the efficiency/selectivity of the tumor accumulation and can be used for building up optimal photosensitizing agents for tumors.

Implications of the generation of reactive oxygen species by photoactivated calcein for mitochondrial studies.

Calcein is a fluorescent probe that is widely used in studies of cell viability and mitochondrial function by microscopy fluorescence imaging. It was found to have a strong photosensitizing action that prevalently involves the generation of reactive oxygen species (ROS). The photooxidation properties of calcein in solution were studied in the presence of histidine and tryptophan as oxidizable substrates. The photodegradation of histidine was mainly mediated by singlet oxygen (1O2), as shown by the inhibitory effect of sodium azide, a specific 1O2 scavenger. On the other hand, mixed photosensitization mechanisms were present when tryptophan was used as the target of the calcein-stimulated photoprocess. In addition to 1O2, hydroxyl radicals and hydrogen peroxide were involved as reactive species, as shown by using mannitol and catalase as scavengers. The calcein-photosensitized alterations of mitochondria as a potential source of artifacts in confocal microscopy studies of cells were considered. Irradiation of isolated mitochondria with visible light (500-600 nm) in the presence of calcein induced opening of the permeability transition (PT) pore. The extent of the mitochondrial membrane photodamage, however, was modulated by the nature of the calcein environment. Thus, pore opening was triggered at short irradiation times and low dye concentrations when calcein was dissolved in the bulk medium. On the contrary, calcein concentrated in the matrix space was rather inefficient as photosensitizer even at concentrations 10 times higher than those present in the external medium.

Skin-photosensitizing properties of Zn(II)-2(3), 9(10), 16(17), 23(24)-tetrakis-(4-oxy-N-methylpiperidinyl) phthalocyanine topically administered to mice.

A Zn-phthalocyanine derivative bearing four 4-oxy-N-methyl-piperidinyl peripheral substituents has been formulated in an azone-containing gel for topical administration and its potential as a photodynamic therapy agent has been investigated. The phthalocyanine displays an intense absorbance in the 680 nm range and shows a high photosensitizing activity toward a model biological substrate (N-acetyl-L-tryptophanamide). Upon administration of 20 microg cm(-2) onto the dorsal skin of Balb/c mice, maximal phthalocyanine concentrations (ca. 64.2 ng mg(-1) of skin) are reached at 1 h after the deposition. The photosensitizer appears to be localized in the epidermal layers, since (a) no detectable amounts of phthalocyanine are recovered from the mouse blood and liver; and (b) upon photoactivation with a diode laser at 675 nm, only the epidermis is heavily damaged, as shown by histological and ultrastructural analysis. The photodamage is largely of inflammatory nature and an essentially complete healing of the damaged skin is observed at 72 h after the end of the phototreatment. The minimal phototoxic dose for 20 microg cm(-2) photosensitizer and 675 nm irradiation is found to be (150 mW cm(-2)-120 J cm(-2)) or (180 mW cm(-2)-100 J cm(-2)).

Sunlight-activated insecticides: historical background and mechanisms of phototoxic activity.

Several photosensitizing agents, which are activated by illumination with sunlight or artificial light sources, have been shown to be accumulated in significant amounts by a variety of insects when they are administered in association with suitable baits. The subsequent exposure of such insects to UV/visible light leads to a significant drop in survival. Of the photosensitizers tested so far, xanthenes (e.g. phloxin B) and porphyrins (e.g. haematoporphyrin) appear to be endowed with the highest photoinsecticidal activity. In particular, porphyrins absorb essentially all the UV/visible light wavelengths in the emission spectrum of the sun; hence they are active at very low doses. Thus, 1 h irradiation of Ceratitis capitata, Bactrocera oleae (also known as Dacus oleae) or Stomoxys calcitrans which ingested a few nanomoles of porphyrin per fly with light intensities of the order of 1000 microE s(-1) m(-2) causes about 100% death in laboratory tests. Present evidence suggests that such photosensitizers act on the membranes of the midgut with consequent feeding inhibition, as well as on the neuromuscular sheath. No apparent onset of photoresistance has been observed. The rapid photobleaching of xanthenes and porphyrins when illuminated by visible light, as well as the lack of significant toxicity of such compounds in the dark, minimizes the risk of an important environmental impact of such photoinsecticidal agents.

Porphyrins and related compounds as photoactivatable insecticides. 3. Laboratory and field studies.

The exposure of populations of Ceratitis capitata (fruit fly), Bactrocera oleae (olive fly) and Stomoxis calcitrans (house fly) to a bait containing mumolar concentrations of porphyrin-type photosensitizers resulted in a significant accumulation of the porphyrin by the insects and a consequent development of photosensitivity upon exposure to visible light. The photoinsecticidal activity appeared to increase with increasing hydrophobicity of the porphyrin molecule: thus, the amphiphilic dicationic meso-di(cis-4N-methyl-pyridyl)-cis-diphenyl-porphine (n-octanol/water partition coefficient = 20) was markedly more efficient than its tricationic analogue or the dianionic hematoporphyrin (n-octanol/water partition coefficient = 12). The observed large decrease in the acetylcholinesterase activity of the photosensitized flies suggests that the damage of the nervous system gives an important contribution to the phototoxic action of porphyrins. Studies with C. capitata indicate that the photoinsecticidal action of porphyrins can be utilized to control the population of noxious insects also in open field conditions.

Local photodynamic therapy with Zn(II)-phthalocyanine in an experimental model of intimal hyperplasia.

Photodynamic therapy (PDT) appears to be a novel promising modality to prevent intimal hyperplasia (IH) and restenosis after angioplasty. Local PDT, that consists of local delivery of photosensitizing agents followed by intraluminal local irradiation, represents a recent advancement. This methodology requires optimization in order to achieve the best prompt outcome especially in terms of pharmacokinetics of the photosensitizing agent. We studied the pharmacokinetic properties by using the photosensitizing agent Zn(II)-phthalocyanine (ZnPc), locally released by a channeled balloon. The efficacy of local PDT in reducing IH was evaluated in an experimental rabbit model of arterial injury. The maximum accumulation of ZnPc was found at 30 min: the injured portion of the artery gave a ZnPc recovery of 1.18 micromol/mg, as compared with undetectable amounts of ZnPc in the non injured arteries; within 90 min after the local delivery, clearance of the agent was almost complete. Local PDT produced an effective reduction of IH in our vascular injury model: at 7, 14, 21 and 28 days IH and intima/media ratio (IMR) was significantly reduced as compared with balloon injured arteries. The local delivery of ZnPc showed favourable pharmacokinetic properties, that allow the performance of PDT immediately after the vascular injury. Local PDT performed in these conditions represents a promising approach to prevent IH after balloon injury. Further studies are needed to better clarify the biological response of the injured arterial wall to local PDT.

Quantification of the selective retention of palladium octabutoxynaphthalocyanine, a potential photothermal drug, in mouse tissues.

Palladium octabutoxynaphthalocyanine (PdNc(OBu)8) is a potential photothermal therapy (PTT) agent, absorbing strongly in the near-infrared region with no ability to induce photodynamic-type sensitisation (unlike many related napthalocyanines). We report here on the application of high pressure liquid chromatography (HPLC) with near-infrared absorption detection for the determination of the tissue accumulation and clearance of PdNc(OBu)8 in a tumour-bearing mouse model (Balb/c mice with EMT6 carcinoma tumour). Due to its insolubility in aqueous-based solvents, the drug was delivered intraperitoneally in a Cremophor-containing vehicle. Good selective accumulation of the drug into the tumour versus muscle or skin is observed, with the best combination of selectivity and tumour concentration occurring at 24-72 h after drug administration. Clearance times are quite long. Comparison with other similar drugs as reported in the literature indicates that the Cremophor-containing vehicle is likely in large part responsible for the observed pharmacokinetic behaviour. This drug shows potential for PTT and will be investigated further for therapy in this animal model.

Polylysine-porphycene conjugates as efficient photosensitizers for the inactivation of microbial pathogens.

Porphycenes are electronic isomers of porphyrins which, when neutral, display no appreciable photosensitizing action towards Gram-negative bacteria. The covalent binding of oligomeric polylysine moieties, which are cationic at physiological pH values, endows porphycenes with a significant phototoxic activity against Gram-negative bacteria while retaining their photoefficiency against a variety of microbial pathogens, including Gram-positive bacteria, fungi and mycoplasmas. The effect of the polylysine moiety is dependent on both the polylysine concentration and the degree of oligomerization. A suitable interplay among the various parameters opens the possibility to obtain either a broad spectrum of antimicrobial activity or a selective action toward a specific pathogen while minimizing the damage to human fibroblasts.