Photodynamic Effect of some Phthalocyanines on Enveloped and Naked Viruses.

Activity of three photosensitizing phthalocyanine derivatives was tested for photodynamic inactivation towards two coated and two non-enveloped viruses - bovine viral diarrhea virus (BVDV), influenza virus A(H3N2), poliovirus type 1 (PV-1) and human adenovirus type 5 (HAdV5). In the case of coated viruses, a combination of virucidal and irradiation effects was registered by octa-methylpyridyloxy-substituted Ga phthalocyanine (Ga8) toward BVDV, whereas tetra-methylpyridyloxy-substituted Ga phthalocyanine (Ga4) revealed a marked photoinactivation only. No such effect was observed towards influenza A virus. In contrast, the photoinactivating potential of Ga4 and Ga8 marked very high values on naked viruses, especially on HAdV5, at which both the virucidal as well as the irradiation effects became combined.

2-Acetylindan-1,3-dione and its Cu(2+) and Zn(2+) complexes as promising sunscreen agents.

In continuation of a previous spectroscopic and quantum chemical study on 2-acetylindan-1,3-dione (2AID), the spectral properties and photostability of 2AID and its Cu(2+) and Zn(2+) complexes in different solvents are reported. Comparison is made with the photostability of two commercially available sunscreens: benzophenone-3 and octylmethoxycinnamate. 2AID exhibits a higher photostability, high molar absorption coefficient (42 000 m(-1) cm(-1)) at lambda(max) and broad-spectrum UV-protection properties. The hypothesis that the strong intramolecular H-bonding is responsible for the higher photostability was confirmed by studying the photodegradation upon irradiation with UV light of 2AID in hydrogen bond-breaking solvent, DMSO. The data obtained show that 2AID undergoes rapid degradation in this solvent. It is found that Cu(2+) and Zn(2+)-2AID complexes show higher photostability in DMSO than 2AID itself.

Effect of delivery system on the pharmacokinetic and phototherapeutic properties of bis(methyloxyethyleneoxy) silicon-phthalocyanine in tumor-bearing mice.

A Si(IV)-phthalocyanine bearing two methoxyethyleneglycol axial ligands bound to the central metal ion (SiPc) has been prepared by chemical synthesis and analyzed for its phototherapeutic activity after administration in a Cremophor or liposome formulation to C57B1/6 mice bearing a subcutaneously transplanted Lewis lung carcinoma (LLC). The maximum drug accumulation in the tumor is found at 24 h after intraperitoneal injection, independent of the delivery system. However, the tumor concentration of SiPc in the Cremophor formulation is about two-fold higher, while the drug concentration in liver and skin shows similar trends with the two delivery systems. The drug accumulation and retention in the brain is much larger when using Cremophor emulsion. Photodynamic therapy (672 nm, 370 mW m-2, 360 J cm-2) at 24 h after the injection of Cremophor emulsion- or DPPC liposome-formulated SiPc causes a very efficient and similar response for the LLC (approximately 8 versus 22 mm mean tumor diameter for the control groups at 21 days after phototreatment). These very promising effects, obtained both at higher and lower tumor drug concentrations, clearly demonstrate the potential phototherapeutical activity of the newly synthesized SiPc.

Naphthalocyanine complexes as potential photosensitizers for photodynamic therapy of tumors.

In the present paper information about the synthesis and results on the pharmacokinetic and experimental photodynamic therapy (PDT) of naphthalocyanines are given. The photodynamic activity of differently substituted zinc(II)- and silicon(IV)-naphthalocyanines using liposomes or Cremophor EL as drug-delivery systems is shown on different tumor models. For the evaluation of the phototherapeutic effect different assessment criteria were used, including light and electron microscopy observations. The main conclusions which can be arrived at on the basis of our findings are the following: silicon(IV)-naphthalocyanine seems to be not a very effective tumor sensitizer, especially in the treatment of pigmented melanoma, while zinc(II)-naphthalocyanines appear to be very promising for PDT of tumors. Their selective targeting and slow clearance from tumor tissue, fast clearance from skin and pronounced phototherapeutic effect on different tumor models and especially at melanotic tumors, even after application of low drug doses, make this group of photosensitizers very attractive for successful PDT of cancer. © 1999 Society of Photo-Optical Instrumentation Engineers.

Si(IV)-methoxyethylene-glycol-naphthalocyanine: synthesis and pharmacokinetic and photosensitizing properties in different tumour models.

A Si(IV)-naphthalocyanine bearing two methoxyethylenglycol axial ligands to the centrally coordinated metal ion (SiNc) was prepared by chemical synthesis and assayed for the phototherapeutic activity after administration in a Cremophor formulation to C57BI/6 mice bearing a subcutaneously transplanted Lewis lung carcinoma or B16 pigmented melanoma. Pharmacokinetic studies indicate that the maximal accumulation in the tumour occurs at 24 h after intraperitoneal injection of 0.5 mg kg-1 of SiNc, although the naphthalocyanine concentration in the Lewis lung carcinoma (0.70 microgram g-1) is significantly larger than that in the B16 pigmented melanoma (0.15 microgram g-1). This results in a higher selectivity of tumour targeting in the case of the lung carcinoma. Photodynamic therapy (782 nm, 370 mW cm-2, 360 J cm-2) at 24 h after SiNc injection causes an efficient tumour response for Lewis lung carcinoma (50% lower tumour diameter on day 19 post-treatment as compared to untreated controls) while the pigmented melanoma shows only a minor response regarding the rate of tumour growth.

Tetraamido-substituted 2,3-naphthalocyanine zinc(II) complexes as phototherapeutic agents: synthesis, comparative photochemical and photobiological studies.

The aim of this study is to report the synthesis and photochemical and phototherapeutic activities of tetraamido-substituted 2,3-naphthalocyanine zinc(II) complexes (ZnNcs 5-8). Four naphthalocyanine complexes, tetrabenzamido- (ZnNc 5), tetramethoxybenzamido- (ZnNc 6), tetrahexylamido- (ZnNc 7) and tetradodecylamido- (ZnNc 8) naphthalocyanine zinc complexes absorbing at around 770 nm were synthesized. The dye-sensitized photo-oxidation of 1,3-diphenylisobenzofuran via 1O2 was studied in more detail in order to compare the quantum yields of these different sensitizers. Pharmacokinetic and photodynamic therapy studies of Lewis lung carcinoma in mice were carried out after administration of liposome incorporated ZnNcs 5-8. The phototherapeutic efficiency was evaluated by changes in the mean tumour diameter with time, regrowth delay (days), average survival time (days) and electron microscopy observations. According to all assessment criteria used, the most promising photosensitizer seems to be tetrabenzamido-substituted ZnNc 5. We suggest that mainly structural properties are the reason for the better results observed. The morphological analysis confirms the mechanism of photonecrosis, which was observed in our previous work with unsubstituted and substituted ZnNcs 1-4. Direct photodamage to the membrane, mitochondria and rough endoplasmic reticulum in the neoplastic cells and delayed photodestruction of the endothelial cells surrounding the tumour tissue were detected. Also, changes in lysosomes were observed. The data presented through different parameters are compared with such obtained for other photodynamic therapy sensitizers.

Hydrophobic Zn(II)-naphthalocyanines as photodynamic therapy agents for Lewis lung carcinoma.

Four Zn(II) 2,3-naphthalocyanines (unsubstituted ZnNc1, tetracetylamido substituted ZnNc2, tetramino substituted ZnNc3 and tetramethoxy substituted ZnNc4) incorporated into unilamellar liposomes of dipalmitoylphosphatidylcholine have been injected intra-peritoneally (i.p.) (0.25-0.3 mg kg-1) to male C57/Black mice bearing a transplanted Lewis lung carcinoma. The pharmacokinetic investigations show that three of the four studied ZnNcs, 1, 2 and 4, are good tumor-localizers in Lewis lung carcinoma. The highest concentration is detected after ZnNc1 administration. The lowest tumor concentration as well as the lowest phototherapeutic effect were established with ZnNc3. In previous work it was shown that this ZnNc did not differ from the other three studied ZnNcs regarding the quantum yield of 1O2-formation and the photoinduced electron transfer. Obviously not only the good photochemical properties but also the tumor drug uptake can be an important factor of effective PDT. The biodistribution investigations also show that 72 h after drug injection, the skin concentration of the studied ZnNcs returns to the original base line. Indeed, we can expect that the skin photosensitivity will last for no longer than three days after PDT. The established higher drug concentration in the tumor rather than in the liver tissue (20 h after injection) shows again the tumor targeting selectivity of the applied liposome-sensitiser delivered procedure. Evaluating the PDT effect as reflected in the dynamics of the mean tumor diameter, we obtained unambiguous data on the potential capacity of ZnNcs 1,2,4 as PDT-photosensitisers. The data obtained from the assessment of the cytotoxic effect of PDT on the basis of the degree of induced necrosis, gave an adequate characterization of the tumor tissue destruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Liposome-delivered Zn(II)-2,3-naphthalocyanines as potential sensitizers for PDT: synthesis, photochemical, pharmacokinetic and phototherapeutic studies.

The aim of this investigation is to report the synthesis and fundamental photochemical properties of naphthalocyanines with potential interest for photodynamic therapy (PDT), as well as their pharmacokinetics and phototherapeutic effects in a tumor model. Four zinc naphthalocyanines (ZnNc), unsubstituted ZnNc 1, tetraacetylamido-substituted ZnNc 2, tetraamino-substituted ZnNc 3 and tetramethoxy-substituted ZnNc 4 absorbing around 760-770 nm, were synthesized. The dye-sensitized photo-oxidation of 1,3-diphenylisobenzofuran via 1O2 was studied in dimethylsulfoxide (DMSO). Quantum yields for this photoreaction are 0.135-0.164 and are relatively independent of the kind of substituent. In addition, the photoinduced electron transfer studied in N,N-dimethylformamide-water in the presence of methylviologen and mercaptoethanol is only slightly influenced by the kind of substituent. The pharmacokinetic properties of ZnNc 1 in hamsters bearing a transplanted rhabdomyosarcoma were studied using dipalmitoylphosphatidylcholine liposomes. Experimental PDT of rhabdomyosarcoma was carried out using liposome-delivered ZnNc 1-4. The phototherapeutic effect was evaluated by tumor photonecrosis, the mean tumor diameter during the observation period and the percentage of cured animals. The best effect was found after PDT with ZnNc 2 (50% of the treated animals were cured). A slightly lower effect was observed after application of ZnNc 4 (40% cured animals). No effect at all was noted after PDT with ZnNc 3 and a very low efficiency was found after treatment with ZnNc 1 as photosensitizer. Obviously, the photodynamic effect depends on the biological characteristics as well as on the nature of the substituents.

Comparative pharmacokinetic and photodynamic studies with zinc(II) phthalocyanine in hamsters bearing an induced or transplanted rhabdomyosarcoma.

Comparative pharmacokinetic studies in hamsters bearing an induced or first-generation transplanted rhabdomyosarcoma that were injected with liposome-incorporated zinc(II) phthalocyanine (ZnPc) show a higher drug concentration in the induced tumour. The selectivity of tumour targeting is underlined by the fact that, 24 h after injection, larger amounts of ZnPc are found in the tumour than in the liver. Photodynamic therapy investigations were carried out using 673 nm light from an argon-dye laser. On the basis of different assessment criteria (changes in mean tumour diameter with time, tumour mass regression, survival time of the treated groups of animals, and histological determination of the necrotic tissue) the photosensitizing effect of ZnPc appears to be comparable for both kinds of tumour in spite of the higher uptake of photosensitizer by the induced tumour.