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

• Published in: Journal of controlled release Vol. 86; no. 2; pp. 323 - 338
• Main Authors: Zhang, Janny X., Hansen, Christian B., Allen, Theresa M., Boey, Anthony, Boch, Ron
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17.01.2003; Elsevier
• Subjects: Animals; Benzoporphyrin; Biological and medical sciences; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; General pharmacology; Humans; Medical sciences; Mice; Mice, Inbred DBA; Micelles; Mouse tumor model; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Photodynamic therapy; Photoradiation therapy and photosensitizing agent; Photosensitizer; Poly(ethylene glycol); Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Porphyrins - administration & dosage; Porphyrins - chemistry; Treatment with physical agents; Treatment. General aspects; Tumor Cells, Cultured - drug effects; Tumors; Xenograft Model Antitumor Assays - methods; Photodynamic therapy; Benzoporphyrin; Photosensitizer; Micelles; Mouse tumor model; Poly(ethylene glycol); Antineoplastic agent; Pharmaceutical technology; Intravenous administration; Rodentia; Micelle; Lipids; Drug carrier; Intratumoral administration; Malignant tumor; In vitro; Biological activity; Ethylene oxide polymer; In vivo; Vertebrata; Mammalia; Mouse; Porphyrin; Storage stability; Animal; Dosage form
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(02)00442-X

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 °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.