Lipid-associated methylpheophorbide-a (hexyl-ether) as a photodynamic agent in tumor-bearing mice.
Liposomes are a potential system for more selective delivery of photosensitizers (PS) to tumors. Pheophorbides are one series of new PS under investigation for use in photodynamic therapy. The pharmacokinetics, anti-tumor response and normal tissue effects of methylpheophorbide-a-(hexyl-ether) (MPH) associated with negatively charged phospholipid vesicles composed of high and low transition temperature lipids were determined in mice. In some preparations monosialoganglioside, which is known to impart long circulation time to liposomes was also included. Normally water-insoluble MPH could be quantitatively incorporated in multilamellar liposomes up to at least 20 mol MPH/mol lipid% for most liposome compositions and sonicated to form clear suspensions. Evidence from electron microscopy and entrapment of aqueous space markers indicated that the particles formed by sonication were not standard liposomes. Anti-tumor responses to light treatment (135 J/cm2, 665 nm argon-dye laser) 24 h after MPH (0.4 mumol/kg) administration were slightly but significantly greater (P < 0.05) for lipid associated MPH compared to MPH solubilized in Tween 80. There were no major differences in tumor uptake and tumor cell photosensitization between lipid or Tween 80 formulations of MPH, whereas, dependent on lipid composition and time after MPH administration, the doses of light required to cause occlusive vascular damage were increased for the lipid formulations. Pharmacokinetic studies showed rapid dissociation between lipids and MPH in vivo. Lipid formulations are useful for solubilizing MPH and may improve the therapeutic effects of this PS.
Mayhew
E
E
Department of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263-0001.
Vaughan
L
L
Panus
A
A
Murray
M
M
Henderson
B W
BW
D000818:Animals; D002734:Chlorophyll / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D004337:Drug Carriers; D005260:Female; D005354:Fibrosarcoma / Q000532:radiotherapy*; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D008833:Microcirculation / Q000528:radiation effects; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011136:Polysorbates; D012867:Skin / Q000098:blood supply / Q000528:radiation effects; D012878:Skin Neoplasms / Q000532:radiotherapy*; D014018:Tissue Distribution
D004337:Drug Carriers; D008081:Liposomes; D017319:Photosensitizing Agents; D011136:Polysorbates; C085801:methylpheophorbide-a-(hexyl-ether); D002734:Chlorophyll