Pharmacokinetics, Brain Hippocampus and Cortex, and Mitochondrial Accumulation of a New Generation of Lipophilic Redox-Active Therapeutic, Mn(III) Meso Tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+, in Comparison with its Ethyl and N-hexyl Analogs, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.

            A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitude of the therapeutic potential of SOD mimics and is valid for all classes of redox-active compounds. Two lead Mn porphyrins are already in five Phase II clinical trials (reviewed in Batinic-Haberle et al, Oxid Med Cell Longevity 2021). Recent research suggests immense potential of MnPs in cardiac diseases. MnTE-2-PyP (AEOL10113, BMX-010) prevents and treats cardiac arrhythmia, while MnTnBuOE-2-PyP (BMX-001) fully suppressed the development of aortic sclerosis in mice. The latter result is relevant to the cancer patients undergoing chemotherapy. In addition to breast cancer, in collaboration with Angeles Alvarez Secord, MD, MHSc, we have recently shown the anticancer effects of Mn porphyrin/ascorbate in cellular and mouse models of ovarian cancer.

            In parallel with synthetic efforts, I have also been interested in the mechanistic aspects of differential actions of Mn porphyrins in normal vs tumor tissue. In-depth studies of chemistry and biology of the reactions of MnPs with redox-active agents relevant to cancer therapy – ascorbate, chemotherapy and radiation – set ground for understanding the role of thermodynamics and kinetics in the mechanism of action of Mn porphyrins. Mechanistic studies have been revealed in Batinic-Haberle et al, Antioxidant Redox Signal 2018, Batinic-Haberle and Tome, Redox Biology 2019 and Batinic-Haberle et al Oxidative Medicine and Cellular Longevity 2021. My research has resulted in over 230 publications, 18 268 citations and an h-index of 64. For my achievements, I have been awarded the 2021 Discovery Award from the Society for Redox Biology and Medicine, SfRBM.

Additional Training

• Postdoctoral fellowship with Professor Alvin Crumbliss in the field of Bioinorganic Chemistry, Department of Chemistry, Duke University
• Postdoctoral fellowship with Professor Irwin Fridovich in the field of Redox Biology, Department of Biochemistry, Duke University School of Medicine