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

Abstract

Folate-diplasmenylcholine (1,2-di-O-(Z-l′-hexadecenyl)-sn-glycero-3-phosphocholine; DPPsC) liposomes have been shown to greatly enhance the potency of water-soluble anti-tumor agents via a selective folate-mediated uptake and acid-catalyzed endosomal escape mechanism (Rui et al. J. Am. Chem. Soc., 1998; 120:11213-18). This study describes an adaptation of this strategy for the delivery of chloroaluminum phthalocyanine tetrasulfonate (AIPcS44-), a water-soluble sensitizer used in photodynamic therapy, in a binary targeting scheme designed to enhance both its tumor selectivity and phototoxicity. AIPcS44-/DPPIsC:folate liposomes (9.8 μM bulk concentration, 2.5 mM intraliposomal concentration) were substantially more phototoxic to folate-deficient KB cells than 12.5 μM free AIPcS44- after a 30 min irradiation (630-910 nm). Considerable differences in phototoxicity were observed, however, between the commercially-available AIPcS44- and an HPLC purified sample of AIPcS44- due to an increased tendency for the latter to aggregate. Experiments with AIPcS44-/DPPC:folate and folate-free Al PcSa4-/DPPIsC liposomes (acid-insensitive and non-targeted controls, respectively) showed significantly reduced phototoicities 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 DPPIsC liposomes are used as the delivery vehicle. Potential advantages of this approach include the use of lower bulk AIPcS44- concentrations, rapid plasma clearance of free Alp and better phototoxic responses, due to higher intracellular AIPcS44- concentrations combined with reduced collateral photodamage arising from misguided sensitizer accumulation, thereby enhancing the selective phototoxicity of PDT treatments. © 2001 Wiley-Liss, Inc.