Lipid-derivatized poly(ethylene glycol) micellar formulations of benzoporphyrin derivatives.

Abstract

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.

• Authors: Janny X Zhang, Christian B Hansen, Theresa M Allen, Anthony Boey, Ron Boch
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 86 Issue 2-3 Pg. 323-38 (Jan 17 2003) ISSN: 0168-3659 [Print] Netherlands
• PMID: 12526828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Micelles
• Porphyrins
• Polyethylene Glycols

Topics

• Animals
• Chemistry, Pharmaceutical
• Dose-Response Relationship, Drug
• Humans
• Mice
• Mice, Inbred DBA
• Micelles
• Polyethylene Glycols (administration & dosage, chemistry)
• Porphyrins (administration & dosage, chemistry)
• Tumor Cells, Cultured (drug effects)
• Xenograft Model Antitumor Assays (methods)