Lipid-derivatized poly(ethylene glycol) micellar formulations of benzoporphyrin derivatives.
In this paper, we describe the development of micellar formulations for increasing the solubility of lipophilic benzoporphyrins. Using a simple procedure that is readily adaptable for large-scale manufacturing, both A-ring (1) and B-ring isomers (2) of benzoporphyrins could be readily formulated, at concentrations up to 1-2 mg/ml, into small micelles (<20 nm in diameter) of methoxypoly(ethylene glycol) (M(r) 2000) covalently attached to the lipid anchor distearoylphosphatidylethanolamine (mPEG-DSPE). The formulations spontaneously formed upon hydration of a thin film containing mPEG-lipid and photosensitizer and were stable upon storage at 4 degrees C for at least 1 month. Self-association of the B-ring benzoporphyrin isomer in micelles could be efficiently inhibited by either increasing the molar ratio of mPEG(2000)-DSPE to benzoporphyrin or by increasing the pH of the preparation to pH 8.5. The formulation could be freeze-dried and stored indefinitely in the lyophilized form, with restoration of the original properties upon reconstitution. In vivo, the A-ring benzoporphyrin, verteporfin, had higher levels of delivery and greater tumor control in mice than the B-ring derivative when formulated in mPEG(2000)-DSPE micelles and administered intravenously. mPEG(2000)-DSPE micellar formulations also showed tumor control when administered by a single intratumoral injection followed by light irradiation to the tumor within 45-60 min after drug administration. PEG-containing micellar formulations may be a promising delivery system for benzoporphyrin monoesters for clinical applications.
Zhang
Janny X
JX
Department of Pharmacology, 9-70 Medical Sciences Bldg., University of Alberta, Edmonton, Alta, Canada T6G 2H7.
Hansen
Christian B
CB
Allen
Theresa M
TM
Boey
Anthony
A
Boch
Ron
R
D000818:Animals; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011166:Porphyrins / Q000008:administration & dosage* / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D008823:Micelles; D011166:Porphyrins; D011092:Polyethylene Glycols