Biopharmaceutics of boronated radiosensitizers: liposomal formulation of MnBOPP (manganese chelate of 2,4-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX) and comparative toxicity in mice.
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-(alpha, beta-dihydroxyethyl) deuterioporphyrin IX (BOPP) shows tumor-selective uptake and is active in both treatment modalities. BOPP also chelates paramagnetic ions such as Mn(2+), 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 Mn(2+) 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 micromol/kg, and caused severe necrosis at the injection site at dose levels of 60 micromol/kg or greater. In contrast, MnBOPP formulated in liposomes was well tolerated at the highest tested dose of 135 micromol/kg, with the elimination of local toxicity.
Zhou
R
R
The Department of Pharmaceutics, 539 Cooke Hall, University at Buffalo State University of New York, Amherst, New York 14260-1200, USA.
Balasubramanian
S V
SV
Kahl
S B
SB
Straubinger
R M
RM
D000818:Animals; D001702:Biopharmaceutics; D001835:Body Weight / Q000187:drug effects; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D002152:Calorimetry, Differential Scanning; D003905:Deuteroporphyrins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004337:Drug Carriers; D004339:Drug Compounding; D008051:Lipid Bilayers; D008081:Liposomes; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000098851:Carboranes
D001896:Boron Compounds; D003905:Deuteroporphyrins; D004337:Drug Carriers; D008051:Lipid Bilayers; D008081:Liposomes; D011838:Radiation-Sensitizing Agents; C080251:2,4-(alpha,beta-dihydroxyethyl)deuteroporphyrin IX tetrakiscarborane carboxylate ester; D000098851:Carboranes