HIF-1 modulator paint formulation and uses thereof
Inventors
Nicolls, Mark R. • Rajadas, Jayakumar • GURTNER, Geoffrey C. • Jiang, Xinguo • Dhillon, Gundeep • Semenza, Gregg L.
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-10220009-B2
Publication Date
2019-03-05
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. suspended in a carrier compatible with the tissue of interest, is topically applied to the surface of tissues at the site of anastomosis. The nanoparticles are comprised of the active agent and a pharmaceutically acceptable stabilizer.
Core Innovation
The invention provides formulations and methods to improve the clinical outcome of solid organ transplants, particularly lung transplantation. The methods involve topically applying a nanoparticle formulation comprising an effective dose of an iron chelator active agent in nanoparticle form, such as deferoxamine (DFO), deferasirox (DFX), or deferiprone (DFP), suspended in a carrier compatible with the tissue of interest, to the surface of tissues at the site of anastomosis during transplantation surgery.
The problem being addressed is the high mortality and complications associated with lung transplantation, especially due to ischemia and poor tolerance of the lung against ischemia, which results in only 20% of candidate lungs being transplanted. Short-term airway complications at bronchial anastomoses, caused by ischemia from sacrificing bronchial circulation during surgery, are a major source of morbidity and mortality. The lung's unique lack of bronchial arterial revascularization leads to impaired microcirculation and relative tissue hypoxia, which further predisposes the transplant to infections and chronic rejection.
The invention targets enhancing microvascular anastomosis formation and perfusion through stabilization of hypoxia-inducible factor-1α (HIF-1α), a key regulator of neovascularization under ischemic conditions. The nanoparticle formulations comprising iron chelators act as HIF-1α stabilizers, promoting angiogenic growth factor expression, improving endothelial cell function, and limiting reactive oxygen species damage. Encapsulating the active agent in nanoparticles and suspending them in a physiologically compatible carrier provides sustained release and targeted delivery, enhancing penetration into tissue and ultimately alleviating airway tissue ischemia and hypoxia to improve transplant function and reduce complications.
Claims Coverage
The patent includes one independent claim describing a method for reducing graft failure following lung transplantation by improving microvascular perfusion and anastomosis formation using a nanoparticle formulation. Below are the main inventive features extracted from that claim.
Use of iron chelator nanoparticles comprising deferoxamine or deferasirox
The method involves topically painting at least one inner or outer surface involved in lung anastomosis with a nanoparticle formulation containing iron chelator nanoparticles selected from deferoxamine (DFO) and deferasirox (DFX).
Stabilization of nanoparticles with lecithin and phospholipids
The nanoparticles are stabilized with lecithin and phospholipids as a stabilizer component.
Nanoparticle composition and suspension concentration
The nanoparticles comprise from about 40% to about 60% by weight active agent and are suspended at a concentration of from about 5% to about 25% nanoparticles as weight/volume in a physiologically acceptable oil carrier comprising medium chain triglycerides compatible with lung tissue.
Therapeutic effect on airway graft microvascular perfusion and graft failure
The method improves airway graft microvascular perfusion and anastomosis formation by 10 days post transplantation relative to untreated airways, resulting in reduced graft failure.
The claims cover the method of treating lung transplant anastomosis sites by topical application of iron chelator nanoparticle formulations stabilized with lecithin/phospholipids suspended in a compatible oil carrier to enhance microvascular perfusion and reduce graft failure, specifically using deferoxamine or deferasirox nanoparticles within defined composition and concentration parameters.
Stated Advantages
Promotes healing of the bronchial anastomosis.
Increases airway perfusion and relieves hypoxia.
Decreases acute organ failure.
Prevents or delays chronic rejection.
Limits fibrotic airway remodeling associated with rejection.
Reduces invasiveness of pathogens by alleviating tissue ischemia.
Documented Applications
Improving the function and clinical outcome of solid organ transplants, particularly lung transplants.
Limiting airway complications by alleviating airway tissue ischemia and hypoxia during lung transplantation.
Topical application of nanoparticle formulations to the trachea or bronchial surfaces at the site of anastomosis during lung transplant surgery.
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