29th Annual Meeting of the American Society of Photobiology

Downtown Marriot

Chicago, Il.

Chloroaluminum Phthalocyanine Tetrasulfonate Delivered via Acid-Labile Diplasmenylcholine-Folate Liposomes: Intracellular Localization and Synergistic Phototoxicity

Abstract-
Folate-diplasmenylcholine (1,2-di-O-(Z-1-hexadecenyl)-sn-glycero-3-phosphocholine; DPPlsC) liposomes have been shown to greatly enhance the potency of water-soluble antitumor agents via a selective folate-mediated uptake and acid-catalyzed endosomal escape mechanism (Y. Rui et al, J. Am. Chem. Soc. ,1998, 120, 11213). We present an adaptation of this strategy for the delivery of chloroaluminum phthalocyanine tetrasulfonate (AlPcS₄^4-), a water-soluble sensitizer used in photodynamic therapy, in a binary targeting scheme designed to enhance both its tumor selectivity and phototoxicity. AlPcS₄^4-/DPPlsC:folate liposomes (9.8 M bulk concentration, 2.5 mM intraliposomal concentration) were substantially more phototoxic to folate-deficient KB cells than 12.5 M free AlPcS₄^4- after a 30 minute irradiation (630-910 nm). Considerable differences in phototoxicity were observed, however, between the commercially-available AlPcS₄^4- and an HPLC purified sample of AlPcS₄^4- due to an increased tendency for the latter to aggregate. Experiments with AlPcS₄^4-/DPPC:folate and folate-free AlPcS₄^4-/DPPlsC liposomes (acid-insensitive and non-targeted controls, respectively) showed significantly reduced phototoxicities under the same illumination conditions. Our results imply that higher concentrations of water-soluble sensitizers can be delivered to target cells using the folate receptor-mediated pathway, which can change both the biodistribution and intracellular localization of the sensitizer when acid-labile DPPlsC liposomes are used as the delivery vehicle. Potential advantages of this approach include the use of lower bulk AlPcS₄^4- concentrations, rapid plasma clearance of free AlPcS₄^4-, and better phototoxic responses--due to higher intracellular AlPcS₄^4- concentrations combined with reduced collateral photodamage arising from misguided sensitizer accumulation--thereby enhancing the selective phototoxicity of PDT treatments.

Keywords: photodynamic therapy, receptor-mediated endocytosis, aluminum phthalocyanine tetrasulfonate, intracellular localization