Chloroaluminum phthalocyanine tetrasulfonate delivered via acid-labile diplasmenylcholine-folate liposomes: Intracellular localization and synergistic phototoxicity

Folate-diplasmenylcholine (1,2-di-O-(Z-1 ' -hexadecenyl)sn-glycero-3-phosphocholine; DPPIsC) 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 (Rui et ol, i, Am. Chem, Sec., 1998; 120:11213-18). This study describes an adaptation of this strategy for the delivery of chloroaluminum phthalocyanine tetrasulfonate (AlPcS44-), a water-soluble sensitizer used in photodynamic therapy, in a binary targeting scheme designed to enhance both its tumor selectivity and phototoxicity, AlPcS44-/DPPIsC:folate liposomes (9.8 muM bulk concentration, 2.5 mM intraliposomal concentration) were substantially more phototoxic to folate-deficient KB cells than 12.5 muM free AlPcS44- after a 30 min irradiation (630-910 nm), Considerable differences in phototoxicity were observed however, between the commercially-available AlPcS44- and an HPLC purified sample of AlPcS44- due to an increased tendency for the latter to aggregate. Experiments with AlPcS44-/DPPC:folate and folate-free AlPcS44-/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 AlPcS44- concentrations, rapid plasma clearance of free AlPcS44-, and better phototoxic responses, due to higher intracellular AlPcS44- concentrations combined with reduced collateral photodamage arising from misguided sensitizer accumulation, thereby enhancing the selective phototoxicity of PDT treatments. (C) 2001 Wiley-Liss, Inc .