Efficiency and Pharmacokinetics of Photosense: A New Liposomal Photosensitizer Formulation Based on Aluminum Sulfophthalocyanine

Abstract

The photodynamic activity and pharmacokinetics of a new liposomal form (LF) of the sensitizer Photosense based on aluminum sulfophthalocyanine salts have been studied in comparison to those of the standard form (SF) representing a 0.2% aqueous solution of the parent substance. The effective therapeutic doze of the LF of Photosense in mice bearing Ehrlich's tumor was 1 mg/kg, which is four times as small as the effective dose of the SF. The selectivity of accumulation in the tumor tissue 24 h after administration for the LF of Photosense was 1.5 times higher than for the SF. The drug accumulation in skin (determined by the fluorescence intensity) on the 7th days of experiment for the LF of Photosense was 1.6 times lower than for the SF. The pharmacokinetics of the LF of Photosense in mice without tumors significantly differs from the behavior of the SF.In recent years, the photodynamic therapy (PDT) and fluorescent diagnostics (FLD) of neoplasms have been extensively developed both in the experimental oncology and on the clinical level. In Russia, several potential photosensitizers for PDT and FLD are currently under clinical investigation [1 -4]. Among these, most thoroughly studied is Photosense -a domestic photosensitizer of the second generation -representing a mixture of sodium salts of sulfonated aluminum phthalocyanine, which is synthesized using an original patented technology developed at the State Research Institute of Organic Semiproducts and Dyes (Moscow) [5,6].Previous investigations into the mechanisms of the photodynamic damage of inoculated tumors by Photosense showed that the therapeutic activity of this drug is a multifactor process including (i) necrosis and apoptosis of tumor cells under the direct action of cytotoxic agents (singlet oxygen, free radicals) generated in the course of PDT and (ii) ischemic necrosis caused by the violated blood flow in vessels of the tumor [7]. The results of pathomorphological investigations [7] showed that the direct photodynamic effect of Photosense on the cells and tissues of parenchyma was more pronounced when the period of time between the photosensitizer administration and irradiation exceeds 24 h. The active components of Photosense have various degrees of sulfonation and, hence, differently penetrate through vessel walls and influence the parenchyma [8,9]. The amphiphilic character of the photosensitizer also significantly influences the ability of Photosense to penetrate through the membranes of tumor cells. The attachment of two biotin residues to the molecule of Photosense provided for nearly optimum amphiphilic properties and significantly increased the efficacy of the drug action [10].

Re-examination of the emission properties of alkoxy- and thioalkyl-substituted phthalocyanines

“…p * in origin this assignment would still be problematic, however. The wavelength of violet emission lies significantly to the blue of a significant portion of the band envelope in the 400-600 nm region, both in the case of Zna(OC 4 H 9 ) 8 Pc [2][3][4][5][6][7][8][9][10][11][12][13][14] and the mixed alkoxy-and thioalkyl-substituted porphyrazines reported by Hoffman and coworkers [15,16]. This pattern can be observed in the emission spectra recorded during the irradiation of a tetrahydrofuran (THF) solution of H 2 a(SC 4 H 9 ) 8 Pc, Fig.…”

“…The photophysical properties, therefore, make these compounds potentially suitable for photodynamic therapy applications in cancer tumour and macular degeneration treatments [1]. Sulfonated AlClPcs are currently being used commercially for this purpose in Russia [2]. In the emission spectra of alkoxy-and thioalkyl-substituted phthalocyanines and porphyrazines [3][4][5][6][7][8][9][10][11][12][13][14][15][16], an S 1 emission peak is observed in the 600-900 nm region, while a second higher energy peak has also frequently been reported in the 400-600 nm region.…”

A Novel Tumor Targeting Drug Carrier for Optical Imaging and Therapy

“…At 96 h post injection, the CPZ average concentrations in primary organs/tissues were reduced to low levels (~150 nM in livers, ~80 nM in kidneys and lower than 10 nM in other organs/tissues). It was remarkable that the clearance rate of ATF-HSA:CPZ or HSA:CPZ was quite fast compared to other ZnPc-type PSs 36 , 63 , which also showed high concentrations in livers and other organs/tissues. The fast clearance and low concentrations in organs/tissues, especially in the skin for ATF-HSA:CPZ or HSA:CPZ, are quite important and can potentially decrease the skin sensitivity to light after the PDT treatment.…”

“…Typical doses used for phthalocyanine-type PSs in in vivo studies are at the mg / kg range, e.g. , 1 mg / kg for Photosense 63 , 0.5 mg / kg for Photocyanine 61 , 62 , or 1 mg / kg for ZnPc-(Lys) 5 36 ; (2) Unambiguous uPAR-specificity not simply related to the EPR effect. Albumin was shown to have retention at the tumor sites 59 , 65 due to the EPR effect.…”

Receptor-Targeting Phthalocyanine Photosensitizer for Improving Antitumor Photocytotoxicity

“…A number of phthalocyanine-based photosensitizers are now in clinical applications [33] , [34] or under clinical trials [35] . None of them is a single component compound.…”