Delivery of the tumour photosensitizer zinc(II)-phthalocyanine to serum proteins by different liposomes: studies in vitro and in vivo

Ge(IV) phthalocyanine (GePc) with two axially ligated cholesterol moieties was prepared by chemical synthesis and incorporated in a monomeric state into small unilamellar liposomes (CGP 55398). Upon photoexcitation with light wavelengths around its intense absorption peak at 680 nm, GePc shows an efficient photosensitising activity towards biological substrates through a mechanism which largely involves the intermediacy of singlet oxygen. GePc injected systemically into mice bearing an intramuscularly implanted MS-2 fibrosarcoma is quantitatively transferred to serum lipoproteins and localises in the tumour tissue with good efficiency: at 24 h post injection the GePc content in the tumour is 0.74 and 1.87 micrograms per g of tissue with a tumour/peritumoral ratio of 4.35 and 5.67 for injected doses of 0.76 and 1.52 mg kg-1 respectively. At this time the red-light irradiation of the GePc-loaded fibrosarcoma causes a fast and massive tumour necrosis involving both malignant cells and blood vessels. Images Figure 8 Figure 9 Figure 10 Figure 11 Figure 12

Section: Discussionmentioning

confidence: 99%

Section: Transport Of Gepc In Rabbit Serummentioning

confidence: 91%

CGP 55398, a liposomal Ge(IV) phthalocyanine bearing two axially ligated cholesterol moieties: a new potential agent for photodynamic therapy of tumours

Segalla

Milanesi²,

Jori³

et al. 1994

“…Henderson and Mayhew (1990) observed a good response of subcutaneously implanted RIF (radiation induced fibrosarcoma) in iso-BOSiNc treated mice to light doses (135 J cm2, 75-100 mW cm-2) lower than those used in the present I study. This can be explained by several differences existing between the two experimental protocols: the tumour type and location (intramuscolar vs subcutaneous) often cause different levels of photosensitivity; moreover, the liposomal carriers of iso-BOSiNc were different, which may result in different modalities of photosensitiser transport in the serum and different distribution of the photosensitiser among the tissular compartments (Ginevra et al, 1990). Actually, Henderson and Mayhew (1990) found a large extent of PDT-induced vascular damage in their tumour animal model, while ultrastructural studies on tissue specimens taken from the irradiated MS-2 fibrosarcoma demonstrate a highly preferential direct damage of malignant cells (Jori & Cuomo, unpublished observations).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Liposome-delivered Si(IV)-naphthalocyanine as a photodynamic sensitiser for experimental tumours: pharmacokinetic and phototherapeutic studies

Cuomo

Jori²,

Rihter³

et al. 1990

SummaryThe pharmacokinetic behaviour and phototherapeutic effectiveness of bis(di-isobutyloctadecylsiloxy)-2,3-naphthalocyanatosilicon (iso-BOSiNc) incorporated into dipalmitoyl-phosphatidylcholine (DPPC) liposomes have been studied in Balb/c mice bearing an MS-2 fibrosarcoma. We found that iso-BOSiNc i.v. -injected at a dose of 0.5 mg kg-' b.w. is preferentially transported by serum lipoproteins; in particular, the photosensitiser is associated with LDL (57.8% of total recovery in the serum) and HDL (35.7%) while minor amounts are associated to VLDL (2.63%) and other serum proteins (3.89%), Iso-BOSiNc concentrations greater than 1 gig g-' of tissue are recovered from the tumour at 12 -48 h after administration while the ratio of iso-BOSiNc concentration in tumour and peritumoral tissue is greater than 10. Upon increasing the injected dose, the additional iso-BOSiNc is almost exclusively bound by HDL, which leads to large uptake of the photosensitiser by liver and spleen. The efficiency of iso-BOSiNc as a photodynamic agent was measured upon irradiation with a different dose-rate for a total light dose of 450 J cm-2. The extent of tumour necrotic area increases as a function of the time after the end of PDT treatment and reaches a maximum level after about 24 h. Moreover, the necrotic area is linearly dependent on the irradiation dose-rate up to 100 mW cm-2. In all there is substantial evidence that iso-BOSiNc delivered in a liposomal dispersion is a highly effective photosensitizer for PDT of tumours.Photodynamic therapy (PDT) is a method of cancer treatment, based on photosensitisation of the tumour to selected wavelengths of visible light by phototherapeutic agents (Wilson & Jeeves, 1987). At present PDT is applied at the clinical level using haematoporphyrin-IX (Hp-IX) and haematoporphyrin derivative (HpD) (Dougherty, 1987) as photodynamic agents. However, Hp and HpD show a small efficiency of red light absorption; moreover, HpD is a highly heterogeneous mixture of porphyrins, while the clinically used Hp contains about 15% porphyrin-type impurities (Jori et al., 1983).Other classes of photosensitisers, such as phthalocyanines and chlorins, are provided with better red light-absorbing properties than Hp: their absorption maxima are located around 670 nm with extinction coefficients about 105 M-l cm-'; moreover, they are usually characterised by a good degree of purity (Zhou, 1989). Recently, naphthalocyanines have been proposed as PDT agents (Firey & Rodgers, 1987), since these compounds show intense absorption (a> IO M-l cm-') around 780 nm, namely in a spectral interval where light penetration through the skin is approximately twice that at 630 nm (Wilson & Jeeves, 1987).In this work we have studied the pharmacokinetic and phototherapeutic properties of bis(di-isobutyloctadecylsiloxy) -2,3-naphthalocyanato silicon (iso-BOSiNc) in mice bearing a transplanted tumour. Flash photolysis studies (Firey & Rodgers, 1987;Ford et al., 1988) have shown that isoBOSiNc triplet state has a long natural lifetime (331 ji...

“…Albeit such changes may result in a decrease in their in vivo photoactivity, mono-and di-sulphonated derivatives are capable of cell membrane penetration resulting in increased potency to inflict direct cell kill during PDT (Brasseur et al., 1988;Paquette and van Lier, 1992;Margaron et al, 1996). Among the non-substituted Pcs, the zinc complex (ZnPc) has been studied in great detail (Ginevra et al, 1990;Reddi et al, 1990). Owing to its extreme insolubility in most common solvents, ZnPc needs to be incorporated in liposomes, and a proprietary formulation has been proposed for clinical use (Schieweck et al, 1994).…”

mentioning

confidence: 99%

Serum albumin as a vehicle for zinc phthalocyanine: photodynamic activities in solid tumour models

Larroque

Pèlegrin²,

Lier³

1996

Summary Zinc phthalocyanine (ZnPc) is a second-generation photosensitiser for the photodynamic therapy (PDT) of cancer. Unsubstituted ZnPc is, however, highly insoluble in most common solvents, and for clinical applications the material needs to be incorporated in liposomes. We report a simple, alternative procedure to formulate ZnPc through non-covalent binding to bovine serum albumin (BSA). Intravenous administration of ZnPc-BSA preparations, at a molar ratio of 11: 1 and at a ZnPc dose equivalent to 0.5 mol kg-, to tumourbearing mice followed 24 h later by PDT was shown to provide tumour control in two different models, the EMT-6 tumour in Balb/c mice and the human colon T380 carcinoma in nude mice. Analysis of serum fractions from treated animals showed that ZnPc readily redistributes over the serum high-density lipoprotein (HDL) fraction. We also demonstrated the absence of hepatic toxicity of the ZnPc-BSA preparation by monitoring the hepatic cytochrome P450 activiy in treated animals and the viability of human cultured hepatocytes.