Acute and chronic mitochondrial electron transport chain dysfunction treatments and graphenic materials for use thereof
Inventors
Tour, James M. • Nilewski, Lizanne • Sikkema, William • MENDOZA, Kimberly • Kent, Thomas Andrew • DALMEIDA, Jr., William • DERRY, Paul J. • TSAI, Ah-Lim • HEGDE, Muralidhar L. • DHARMALINGAM, Prakash • HEGDE, Pavana Dixit • MITRA, Sankar • MITRA, Joy
Assignees
Houston Methodist Research Institute • Baylor College of Medicine • William Marsh Rice University • University of Texas System • Government of the United States of America
Publication Number
US-12329780-B2
Publication Date
2025-06-17
Expiration Date
2038-04-30
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Abstract
Modified hydrophilic carbon clusters (HCCs), poly(ethylene glycol)-hydrophilic carbon clusters (PEG-HCCs) and similarly structured materials like graphene quantum dots (GQDs), PEGylated GQDs, small molecule antioxidants, and PEGylated small molecule antioxidants. These materials have been modified with an iron chelating moiety, deferoxamine, or a similar chelating moiety. By exploiting common binding sites, the carbon nanostructure facilitates intracellular transport including in mitochondria, reduces oxidative breakdown of the chelator moiety prior to treatment, and reduces both the cause and consequences of metal induced oxidative stress within the body thus providing a novel form of therapy for a range of oxidative and metal-related toxicities. Graphenic materials can be used for the treatment of acute and chronic mitochondrial electron transport chain dysfunction.
Core Innovation
The invention relates to modified hydrophilic carbon clusters (HCCs), poly(ethylene glycol)-hydrophilic carbon clusters (PEG-HCCs), graphene quantum dots (GQDs), PEGylated GQDs, small molecule antioxidants, and PEGylated small molecule antioxidants, which are modified with an iron chelating moiety such as deferoxamine. These modified carbon nanostructures facilitate intracellular transport including in mitochondria, reduce oxidative breakdown of the chelator moiety prior to treatment, and reduce both the cause and consequences of metal induced oxidative stress within the body, providing novel therapy for oxidative and metal-related toxicities.
The invention further discloses a newly discovered function of graphenic materials to serve as an electron transport chain bypass mechanism in cases of mitochondrial injury, capturing electrons from superoxide and reducing oxidized species in the electron transport chain without substituting existing electron transport chain members. This electron transport shuttle mechanism is termed the Kent Electron Transport Shuttle (KETS). This extends potential use of these antioxidant materials to conditions involving mitochondrial injury.
The background addresses the problem of traumatic brain injury (TBI), where oxidative stress plays a major role, especially when complicated by secondary trauma such as hemorrhagic hypotension. Existing antioxidants have severe limitations including mechanism of action transferring radicals to other unstable species, need for regeneration, limited capacity, and high selectivity that may be disadvantageous. These limitations hinder clinical benefit especially when treatment occurs after injury onset rather than pretreatment.
The invention provides therapeutic compositions comprising antioxidant nanoparticles with both antioxidant and pro-oxidant properties covalently modified with metal-chelating moieties, such as deferoxamine, achieving significantly enhanced chelation efficacy compared to chelators alone. Such compositions act as high capacity oxidants, directly transport electrons, reduce key mitochondrial enzymes, protect against oxidative stress, improve DNA damage response, and treat mitochondrial injury.
Claims Coverage
The patent includes several independent claims defining therapeutic compositions, methods of treatment, and methods of making therapeutic compositions involving antioxidant nanoparticles covalently modified with chelating moieties. The main inventive features focus on the composition's enhanced chelation efficacy, antioxidant and pro-oxidant properties, and electron transport shuttle functionality in mitochondria.
Therapeutic composition with antioxidant nanoparticle covalently modified with chelating moiety
A composition comprising an antioxidant nanoparticle with both antioxidant and pro-oxidant properties covalently modified with a metal-chelating moiety, preferably deferoxamine, where the composition acts as a high capacity oxidant, directly transports electrons, reduces mitochondrial enzymes, and provides chelation efficacy at least ten times greater than the chelating moiety alone. The antioxidant nanoparticle can be PEG-HCCs, PEG-GQDs, or PEG-PDI, with ratios of PEG to chelating moiety between 1:3 and 3:1.
Increased chelation efficacy of therapeutic composition
The therapeutic composition exhibits a chelation efficacy that is at least 100 times greater compared to the same amount of the chelating moiety without the antioxidant nanoparticle.
Metal selectivity of chelating moiety
The chelating moiety targets metals selected from arsenic, cadmium, copper, iron, lead, zinc, and their combinations.
Therapeutic efficacy in mitochondrial injury
The therapeutic composition is operable to treat, reduce, or prevent mitochondrial injury in a subject.
The independent claims collectively cover therapeutic compositions comprising antioxidant nanoparticles covalently linked to metal-chelating moieties with enhanced chelation efficacy and dual antioxidant/pro-oxidant properties, methods for administering these compositions to treat mitochondrial injury and oxidative stress, and methods of synthesizing these compositions. These inventive features provide enhanced treatment efficacy for oxidative and metal-related toxicities, particularly in mitochondrial dysfunction.
Stated Advantages
The therapeutic compositions enhance intracellular delivery and mitochondrial localization of chelating agents, reducing required doses and systemic toxicity.
They provide combined antioxidant and chelation activity, reducing oxidative stress and preventing oxidative degradation of the chelating moiety, thereby improving stability and shelf life.
The graphenic materials serve as an electron transport chain bypass, reducing electron leakage and reactive oxygen species generation in mitochondrial injury, extending therapeutic scope.
The compositions demonstrate improved protection against reactive oxygen species in cell culture and in vivo models, improving outcomes in traumatic brain injury and ischemia.
Documented Applications
Treatment of acute and chronic mitochondrial electron transport chain dysfunctions.
Treatment of traumatic brain injury, including mild traumatic brain injury complicated by hemorrhagic hypotension.
Treatment of intracerebral hemorrhage and other brain injuries caused by free iron-induced oxidative stress.
Treatment of metal-induced oxidative stress and metal toxicity involving metals such as iron, lead, mercury, copper, arsenic, and zinc.
Treatment of ischemia and reperfusion injury.
Treatment of cyanide poisoning and arsenic poisoning by providing an electron transport chain bypass.
Use in systemic shock, neurodegenerative disorders (including Alzheimer's and Parkinson's diseases), hereditary mitochondrial genetic mutation disorders, genetic disorders of metal metabolism, acute and chronic poisoning with mitochondrial toxins, stroke, systemic injuries, and disorders involving oxidative stress.
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