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

Lipid-derivatized poly(ethylene glycol) micellar formulations of benzoporphyrin derivatives
January 2003
Janny X. Zhang, Christian B. Hansen, Theresa M. Allen, Anthony Boey and Ron Boch
Journal of Controlled Release, Volume 86, Issues 2-3, 17 January 2003, Pages 323-338
Science Direct
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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) (Mr 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 ?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 mPEG2000-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 mPEG2000-DSPE micelles and administered intravenously. mPEG2000-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.