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

Abstract

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...

Carotenoporphyrins as selective photodiagnostic agents for tumours

“…In the lipoprotein family, LDL has been claimed to play a major role in the transport and release of photosensitising agents to tumour cells (Maziere et al, 1990;Jori, 1992). However, this is only a partial explanation because other porphyrin analogues, such as phthalocyanines and naphthalocyanines, which are specifically carried by serum lipoproteins, yield a less pronounced tumour selectivity (Reddi et al, 1990;Cuomo et al, 1990).…”

Liposomal photosensitizers: potential platforms for anticancer photodynamic therapy

“…and entrapment methods in order to improve PS-loaded liposomes. In general, the methods frequently employed to encapsulate PSs are rehydration of a thin lipid film (classic Bangham technique), ethanol injection and freeze/thawing (10)(11)(12). It should also be taken into account that the chosen method -sometimes involving mechanical energy, chemical reactions or temperature variation steps -should neither affect PS properties nor reduce its activity.…”

Tumour-localising and -photosensitizing properties of liposome-delivered Ge(IV)-octabutoxy-phthalocyanine

“…Pharmacokinetic studies of GePc biodistribution at time intervals longer than 1 week from injection were carried out with healthy mice. On the other hand, the distribution of GePc among lipoproteins was studied with New Zealand white rabbits (Cuomo et al, 1990), whose lipoprotein pattern is similar with that typical of humans.…”

“…administration (0.5 mg kg-') .using a quartz/halogen lamp (Teclas, Lugano, Switzerland), with the 700-800nm wavelength range isolated by optical filtering (Cuomo et al, 1990). The irradiation dose-rate was 180 mW cm-2 (total light emitted).…”

“…DPPC liposomes were prepared by an injection method (Reddi et al, 1990 Cuomo et al (1990). This method, originally developed for Sinaphthalocyanin was found to give accurate recoveries also of GePc from both serum and tissues.…”