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C57BL/6 mice were exposed to 872cGy (LD65/30) or 927cGy (LD95/30) radiation ( Cs,100.3±5.0
cGy/min), injected 24hr later with one dose of single or combinations of peg-HGF, and monitored for 30d
survival (n=20 mice/grp). At LD65, 30d survival was similar in all treatment groups (range 65-85%), and
~2-fold higher than that in vehicle mice (35%). The difference in survival between single and combination
peg-HGF groups was more pronounced at LD95, with 75% survival in mice receiving all three peg-HGF in
combination, compared to 25% in peg-G, 40% in peg-GM, and 65% in peg-IL11 single HGF groups, and 5%
in the vehicle group. Of note, groups containing peg-IL11 singly or in combination with peg-G or peg-GM
exhibited, on average, 2-fold higher survival compared to groups not receiving peg-IL11 (62.5% versus
32.0% survival, respectively). In addition, mean survival time of decedents in peg-IL11-containing groups
were 1.4 (LD95) and 4.4 (LD65) days longer than non-peg-IL11 groups, suggesting possible efficacy against
GI-ARS. While CBC in most groups recovered to levels seen in non-irradiated (NI) mice by day 30, CBC from
mice that received peg-G either singly or in combination appeared to recover more rapidly than mice not
receiving peg-G. There were no apparent treatment-related differences at day 30 in bone marrow (BM)
or spleen cellularity, lineage recovery, or numbers of BM hematopoietic progenitors or cKit+Sca1+lineage-
primitive progenitors. Taken together, these results demonstrate enhanced 30 day survival in mice
treated with BBT peg-HGF in combination compared to single peg-HGF, suggesting additive or synergistic
effects that can improve survival at higher doses of radiation. Supported by NIAID 1U01AI107340-01 and
HHSN272201000046C.
(PS2-87) SMA-011 as a new lead mitochondria-targeted compound for mitigating radiation effects in
1
2
1
mouse model. Aryamitra Banerjee, PhD ; Nathan Sieracki, PhD ; Alexander Zakharov, PhD ; Marcelo
2
1
Bonini, PhD ; Alexander Lyubimov, MD, PhD, Toxicology Research Laboratory (TRL), Dept. of
1
Pharmacology, University of Illinois at Chicago, Chicago, IL and Dept. of Pharmacology, University of
Illinois at Chicago, Chicago, IL
2
Mechanisms such as free radical scavenging, calcium channel blocking, inhibition of lipid
peroxidation, DNA repair enhancement and stimulation of stem cell proliferation are considered
important for radiation protection. Whole body exposure of mice to high doses of gamma radiation leads
to mitochondrial dysfunction, bone marrow damage, apoptosis and necrosis in the gastric mucosa
through the production of reactive oxygen or nitrogen species (ROS/RNS). Removal of excessive
mitochondrial ROS/RNS by electron scavengers and antioxidants is a promising therapeutic strategy to
reduce the detrimental effects of radiation exposure. In this study, a novel lead molecule, SMA-011,
targeting the mitochondria, was used to explore the radiation mitigating effects in a mouse model of
radiation injury. The core scaffold contains a hydroxylamine moiety that protects the cell and
mitochondria from oxidative damage by 2 synergizing mechanisms (enzymatic dismutation of superoxide
radical and possible metal chelating). Dose and route selection and preliminary plasma drug levels
following different routes and doses of SMA-011 were initially investigated in non-irradiated C57Bl/6
mice. Subcutaneous dose was well-tolerated and provided suitable bioavailability. In preliminary studies
1 mg/kg of SMA-011, provided as a single subcutaneous dose at 24 hr post irradiation (8.1 Gy), showed
30% decrease of lethality compared to the control irradiated mice. SMA-011 also showed an evident
antioxidant effect in mitochondria in the heart and jejunum tissues collected from these mice at 48 and
120 hr. Also, at a higher dose of 13 Gy in mice, SMA-011 showed good anti-apoptotic effect in the jejunum
and prominent proliferative activity on Day 4 post irradiation observed through TUNEL and Ki-67 staining
of the jejunum. As the mitigating effect of this molecule was shown at a high total body irradiation dose
185 | P a g e
C57BL/6 mice were exposed to 872cGy (LD65/30) or 927cGy (LD95/30) radiation ( Cs,100.3±5.0
cGy/min), injected 24hr later with one dose of single or combinations of peg-HGF, and monitored for 30d
survival (n=20 mice/grp). At LD65, 30d survival was similar in all treatment groups (range 65-85%), and
~2-fold higher than that in vehicle mice (35%). The difference in survival between single and combination
peg-HGF groups was more pronounced at LD95, with 75% survival in mice receiving all three peg-HGF in
combination, compared to 25% in peg-G, 40% in peg-GM, and 65% in peg-IL11 single HGF groups, and 5%
in the vehicle group. Of note, groups containing peg-IL11 singly or in combination with peg-G or peg-GM
exhibited, on average, 2-fold higher survival compared to groups not receiving peg-IL11 (62.5% versus
32.0% survival, respectively). In addition, mean survival time of decedents in peg-IL11-containing groups
were 1.4 (LD95) and 4.4 (LD65) days longer than non-peg-IL11 groups, suggesting possible efficacy against
GI-ARS. While CBC in most groups recovered to levels seen in non-irradiated (NI) mice by day 30, CBC from
mice that received peg-G either singly or in combination appeared to recover more rapidly than mice not
receiving peg-G. There were no apparent treatment-related differences at day 30 in bone marrow (BM)
or spleen cellularity, lineage recovery, or numbers of BM hematopoietic progenitors or cKit+Sca1+lineage-
primitive progenitors. Taken together, these results demonstrate enhanced 30 day survival in mice
treated with BBT peg-HGF in combination compared to single peg-HGF, suggesting additive or synergistic
effects that can improve survival at higher doses of radiation. Supported by NIAID 1U01AI107340-01 and
HHSN272201000046C.
(PS2-87) SMA-011 as a new lead mitochondria-targeted compound for mitigating radiation effects in
1
2
1
mouse model. Aryamitra Banerjee, PhD ; Nathan Sieracki, PhD ; Alexander Zakharov, PhD ; Marcelo
2
1
Bonini, PhD ; Alexander Lyubimov, MD, PhD, Toxicology Research Laboratory (TRL), Dept. of
1
Pharmacology, University of Illinois at Chicago, Chicago, IL and Dept. of Pharmacology, University of
Illinois at Chicago, Chicago, IL
2
Mechanisms such as free radical scavenging, calcium channel blocking, inhibition of lipid
peroxidation, DNA repair enhancement and stimulation of stem cell proliferation are considered
important for radiation protection. Whole body exposure of mice to high doses of gamma radiation leads
to mitochondrial dysfunction, bone marrow damage, apoptosis and necrosis in the gastric mucosa
through the production of reactive oxygen or nitrogen species (ROS/RNS). Removal of excessive
mitochondrial ROS/RNS by electron scavengers and antioxidants is a promising therapeutic strategy to
reduce the detrimental effects of radiation exposure. In this study, a novel lead molecule, SMA-011,
targeting the mitochondria, was used to explore the radiation mitigating effects in a mouse model of
radiation injury. The core scaffold contains a hydroxylamine moiety that protects the cell and
mitochondria from oxidative damage by 2 synergizing mechanisms (enzymatic dismutation of superoxide
radical and possible metal chelating). Dose and route selection and preliminary plasma drug levels
following different routes and doses of SMA-011 were initially investigated in non-irradiated C57Bl/6
mice. Subcutaneous dose was well-tolerated and provided suitable bioavailability. In preliminary studies
1 mg/kg of SMA-011, provided as a single subcutaneous dose at 24 hr post irradiation (8.1 Gy), showed
30% decrease of lethality compared to the control irradiated mice. SMA-011 also showed an evident
antioxidant effect in mitochondria in the heart and jejunum tissues collected from these mice at 48 and
120 hr. Also, at a higher dose of 13 Gy in mice, SMA-011 showed good anti-apoptotic effect in the jejunum
and prominent proliferative activity on Day 4 post irradiation observed through TUNEL and Ki-67 staining
of the jejunum. As the mitigating effect of this molecule was shown at a high total body irradiation dose
185 | P a g e
