Iron chelators and use thereof for reducing transplant failure during rejection episodes
Inventors
Nicolls, Mark R. • Jiang, Xinguo • GURTNER, Geoffrey C. • Semenza, Gregg L. • Rajadas, Jayakumar
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-9763899-B2
Publication Date
2017-09-19
Expiration Date
2033-08-30
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Abstract
Formulations and methods are provided for improving the function, i.e. clinical outcome, of solid organ transplants. Lung transplantation is of particular interest. In the methods of the invention, a nanoparticle formulation comprising an effective dose of an iron chelator active agent in nanoparticle form, including without limitation, deferoxamine (DFO), deferasirox (DFX), and deferiprone (DFP), etc. is topically applied to the surface of tissues during episodes of graft rejection.
Core Innovation
The invention provides formulations and methods for improving the clinical outcome of solid organ transplants, particularly lung transplants, by promoting neovascularization at critical sites during episodes of graft rejection. The methods involve the topical application of a nanoparticle formulation comprising an effective dose of an iron chelator active agent, such as deferoxamine (DFO), deferasirox (DFX), or deferiprone (DFP), to the surface of tissues during rejection episodes. Such administration increases hypoxia-inducible factor 1-alpha (HIF-1α) stability, enhancing microvascular perfusion and graft health.
The problem addressed by the invention arises from the high mortality and complication rates in lung transplantation, which is marked by airway ischemia and hypoxia due to lack of bronchial arterial revascularization. This leads to impaired microcirculation and ischemic injury at the transplant site, promoting acute organ failure and chronic rejection. Despite surgical advances and immunosuppressive drugs, short-term airway complications related to ischemia and poor oxygenation remain significant contributors to morbidity and mortality in lung transplant patients.
The invention recognizes that ischemia stimulates neovascularization regulated chiefly by HIF-1, whose alpha subunit is stabilized under hypoxic conditions. Iron chelators such as DFO stabilize HIF-1α by inhibiting prolyl hydroxylase activity through iron depletion, thereby promoting angiogenesis. By delivering iron chelators in nanoparticle form topically during rejection episodes, the invention enhances targeted and sustained HIF-1α stabilization, leading to improved microvascular repair and function in the transplanted tissues.
Claims Coverage
The patent includes one independent claim focusing on a method of improving lung transplant clinical outcomes using iron chelator nanoparticles. It discloses eight main inventive features concerning the composition, administration, and properties of the nanoparticles.
Method of improving clinical outcome by nanoparticle iron chelator delivery
A method wherein a bronchial passage is directly contacted during a rejection episode with an effective dose of a nanoparticle formulation containing an iron chelating agent, reducing ischemia and hypoxia and thereby improving clinical outcome.
Administration via pulmonary inhalation aerosol
The formulation is administered through pulmonary inhalation of an aerosol formulation allowing topical delivery to the lung tissues during rejection episodes.
Use of specific iron chelators
The iron chelator used in the nanoparticle is selected from deferoxamine (DFO), deferasirox (DFX), or deferiprone (DFP), with DFO being specifically highlighted.
Nanoparticle composition and stabilizer inclusion
Nanoparticles comprise the iron chelator and a pharmaceutically acceptable stabilizer, with a range of 5% to 75% of the nanoparticle weight being iron chelator. Stabilizers include cationic lipids, phospholipids, lecithin, and proteins, with preferred mixtures of protein and cationic lipids.
Nanoparticle formation methods
Nanoparticles are formed by precipitation of the iron chelating agent and stabilizer from a liquid suspension, controlling morphology and size for delivery effectiveness.
Nanoparticle size control
Nanoparticles have diameters from about 10 nm to about 5 μm, with preferred sizes from about 100 nm to 5 μm to optimize delivery and tissue penetration.
Formulation suspension in physiologically acceptable carrier
Nanoparticles are formulated as suspensions in carriers suitable for aerosol generation and pulmonary delivery.
Packaging for aerosol generation
The nanoparticle formulation is provided in containers with carriers suitable for aerosol generation for efficient pulmonary delivery.
The claims collectively cover a method of administering iron chelator nanoparticles via aerosol inhalation to lung transplant patients during rejection episodes. The nanoparticles have defined composition, size, and stabilizers to increase microvascular perfusion and improve graft outcomes by reducing ischemia and hypoxia.
Stated Advantages
Improved microvascular perfusion at the transplant site, leading to better graft health and function.
Enhanced neovascularization mediated by stabilized HIF-1α, promoting vascular repair during rejection episodes.
Sustained and targeted delivery of iron chelators via nanoparticles provides effective and prolonged therapeutic activity.
The nanoparticle formulation enables efficient tissue penetration and cellular uptake, improving drug bioavailability.
Documented Applications
Improvement of clinical outcomes following lung transplantation by topical administration of iron chelator nanoparticles during graft rejection episodes.
Aerosol administration of iron chelator nanoparticles to treat acute rejection episodes in lung transplant recipients to enhance microvascular perfusion and reduce ischemia and hypoxia.
Use of nanoparticle formulations comprising deferoxamine, deferasirox, or deferiprone for treatment of airway ischemia and complications related to lung transplantation.
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