Biopharmaceutics of boronated radiosensitizers: Liposomal formulation of MnBOPP (manganese chelate of 2,4‐(α,β‐dihydroxyethyl) deuterioporphyrin IX) and comparative toxicity in mice

• Published in: Journal of pharmaceutical sciences 1999-09, Vol.88 (9), p.912-917
• Main Authors: Zhou, Rong, Balasubramanian, Sathyamangalam V., Kahl, Stephen B., Straubinger, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biopharmaceutics; Body Weight - drug effects; Boron Compounds - administration & dosage; Boron Compounds - pharmacokinetics; Boron Compounds - toxicity; Calorimetry, Differential Scanning; Deuteroporphyrins - administration & dosage; Deuteroporphyrins - pharmacokinetics; Deuteroporphyrins - toxicity; Drug Carriers; Drug Compounding; Lipid Bilayers; Liposomes; Medical sciences; Mice; Radiation therapy and radiosensitizing agent; Radiation-Sensitizing Agents - administration & dosage; Radiation-Sensitizing Agents - pharmacokinetics; Radiation-Sensitizing Agents - toxicity; Treatment with physical agents; Treatment. General aspects; Tumors
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js980454i

Binary treatment modalities such as photodynamic therapy (PDT) and neutron capture therapy (NCT) combine low‐toxicity electromagnetic irradiation with an appropriate radiation sensitizer to enhance selectivity for tumor targets. The porphyrin derivative tetrakiscarborane carboxylate ester of 2,4‐(α,β‐dihydroxyethyl) deu‐terioporphyrin IX (BOPP) shows tumor‐selective uptake and is active in both treatment modalities. BOPP also chelates paramagnetic ions such as Mn2+, and therefore its tissue accumulation and selectivity can be detected noninvasively by using magnetic resonance imaging. However, local and systemic toxicity appears elevated for the Mn2+ chelate (MnBOPP), but is poorly characterized. Here we have developed a liposomal formulation of MnBOPP and compared its toxicity with that of MnBOPP administered to mice in saline. The optimal liposome composition and maximal capacity to accommodate MnBOPP were investigated by differential scanning calorimetry and by encapsulation efficiency. MnBOPP was encapsulated quantitatively at up to 12 mol % (drug:lipid) in liposomes of varying composition, and remained incorporated during extended dialysis. Phase separation of drug‐ and lipid‐rich domains was observed above 12% drug. MnBOPP in buffered saline was lethal to animals at 90 µmol/kg, and caused severe necrosis at the injection site at dose levels of 60 µmol/kg or greater. In contrast, MnBOPP formulated in liposomes was well tolerated at the highest tested dose of 135 µmol/kg, with the elimination of local toxicity.