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; 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 (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 ([AlPcS(4)](4-)), a water-soluble sensitizer used in photodynamic therapy, in a binary targeting scheme designed to enhance both its tumor selectivity and phototoxicity. [AlPcS(4)](4-)/DPPlsC:folate liposomes (9.8 microM bulk concentration, 2.5 mM intraliposomal concentration) were substantially more phototoxic to folate-deficient KB cells than 12.5 microM free [AlPcS(4)](4-) after a 30 min irradiation (630-910 nm). Considerable differences in phototoxicity were observed, however, between the commercially-available AlPcS(4)(4-) and an HPLC purified sample of [AlPcS(4)](4-) due to an increased tendency for the latter to aggregate. Experiments with [AlPcS(4)](4-)/DPPC:folate and folate-free [AlPcS(4)](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 [AlPcS(4)](4-) concentrations, rapid plasma clearance of free [AlPcS(4)](4-), and better phototoxic responses, due to higher intracellular [AlPcS(4)](4-) concentrations combined with reduced collateral photodamage arising from misguided sensitizer accumulation, thereby enhancing the selective phototoxicity of PDT treatments.
Qualls
M M
MM
Department of Chemistry, Purdue University, West Lafayette, IN, USA.
Thompson
D H
DH
D000535:Aluminum; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D017484:Dermatitis, Phototoxic; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000378:metabolism; D007624:KB Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008081:Liposomes; D008156:Luciferases / Q000378:metabolism; D018613:Microscopy, Confocal; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000378:metabolism; D010955:Plasmalogens / Q000737:chemistry*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
D004337:Drug Carriers; D007211:Indoles; D008081:Liposomes; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D010955:Plasmalogens; D013778:Tetrazolium Salts; D013844:Thiazoles; C032459:choline plasmalogens; C052736:chloroaluminum tetrasulfophthalocyanine; D005492:Folic Acid; D000535:Aluminum; D008156:Luciferases; C022616:thiazolyl blue