Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation

Abstract

The objective of this study was to determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL10150, reduces the severity of long-term lung injury induced by fractionated radiation (RT). Fisher 344 rats were randomized into five groups: RT+AEOL10150 (2.5 mg/kg BID), AEOL10150 (2.5 mg/kg BID) alone, RT+ AEOL10150 (5 mg/kg BID), AEOL10150 (5 mg/kg BID) alone and RT alone. Animals received five 8 Gy fractions of RT to the right hemithorax. AEOL10150 was administered 15 min before RT and 8 h later during the period of RT treatment (5 days), followed by subcutaneous injections for 30 days, twice daily. Lung histology at 26 weeks revealed a significant decrease in lung structural damage and collagen deposition in RT+AEOL10150 (5 mg/kg BID) group, in comparison to RT alone. Immunohistochemistry studies revealed a significant reduction in tissue hypoxia (HIF1alpha, CAIX), angiogenic response (VEGF, CD-31), inflammation (ED-1), oxidative stress (8-OHdG, 3-nitrotyrosine) and fibrosis pathway (TGFbeta1, Smad3, p-Smad2/3), in animals receiving RT+ AEOL10150 (5 mg/kg BID). Administration of AEOL10150 at 5 mg/kg BID during and after RT results in a significant protective effect from long-term RT-induced lung injury. Low dose (2.5 mg/kg BID) delivery of AEOL10150 has no beneficial radioprotective effects.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…MnTDE-2-ImP 5þ was administered for 10 weeks (10 and 30 mg=kg=day, subcutaneous osmotic pumps) starting at 24 h after 28-Gy right hemithorax radiation (257). Similar effects were observed with fractionated radiation, in which the injection of MnP started 15 min before radiation (258). Recently, we performed extended rat-lung radioprotective studies (28 Gy to right lung hemithorax) by using hydrophilic MnTE-2-PyP 5þ (6 mg=kg=day for 14 days, via osmotic pumps or subcutaneously) in comparison to lipophilic MnTnHex-2-PyP 5þ (0.05 mg=kg=day for 14 days, via osmotic pumps or subcutaneously) (123).…”

“…When mice were treated 14 days before whole-body radiation with MnTM-2-PyP 5þ at 5 mg=kg, *80% survival was observed. The imidazolyl derivative, MnTDE-2-ImP 5þ , also was radioprotective in two studies with single and fractionated radiation (257,258). At 26 weeks after single-dose irradiation, and 16 weeks after the administration of Mn porphyrin ceased, rat pulmonary radioprotection was detected with respect to oxidative stress, lung histology, and collagen deposition.…”

Effects of genistein following fractionated lung irradiation in mice

“…Other SOD-catalase mimetics, AEOL 10113 and 10150, have also been reported to alleviate increases in breathing rate, TGB-β1 activity, hydroxyproline levels, and collagen content following hemithoracic radiation in rats [120][121][122]. Two Mn porphyrinbased SOD mimetics also showed protective effects by scavenging ROS [123].…”

Oxidase Activity of Iron and Manganese Porphyrins with Antioxidant 2,6-Di-tert-butylphenol Groups

“…[1] Photosan, Photohem применяются в фотодинамической терапии опухолевых заболеваний; [2] порфирин марганца AEOL 10150, как миметик супероксиддисмутазы, проходит клинические испытания в качестве препарата для борьбы с окислительным стрессом. [3][4][5][6] Однако вследствие структурного и функциональ-ного сходства с активными центрами гемовых белков (оксигеназ) металлопорфирины проявляют каталитическую активность в реакциях окисления различных органических субстратов. В результате, использование порфиринов, например, в качестве сенсибилизаторов в терапии и диагностике опухолевых заболеваний осложняется неконтролируемыми побоч-ными процессами окисления важных биологических субстратов -компонентов белков, ДНК и липидов.…”