Oxygen-generating cryogels
Inventors
MEMIC, ADNAN • Bencherif, Sidi A. • Sitkovsky, Michail • Colombani, Thibault • Hatfield, Stephen
Assignees
Northeastern University Boston
Publication Number
US-12303618-B2
Publication Date
2025-05-20
Expiration Date
2039-08-08
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Abstract
Disclosed are nanocomposite oxygen-generating cryogels and their uses in reducing hypoxia in a biological tissue, such as a tumor. Methods of treating cancer with the disclosed cryogels are also provided.
Core Innovation
The invention discloses nanocomposite oxygen-generating cryogels designed for use in reducing hypoxia within biological tissues such as tumors. These cryogels, which can be prepared from polymerized hyaluronic acid and further comprise peroxides, oxides or percarbonates as oxygen-generating species, are designed to be administered via injection, catheter, or surgical implantation. Catalase, specifically acrylate-PEG-catalase, is included to efficiently degrade hydrogen peroxide byproducts and enhance biocompatibility.
The problem addressed by this invention is the challenge of local hypoxia in biological tissues, particularly in the tumor microenvironment where low oxygen levels support tumor aggressiveness, immunosuppression, and resistance to therapies. Traditional hydrogels and biomaterials have been limited by invasiveness, poor oxygen delivery, mechanical weaknesses, or safety concerns related to byproduct accumulation. There is a need for minimally invasive, sustained, and biocompatible oxygen delivery systems that locally reverse hypoxia and restore immune function.
This invention provides a solution by offering cryogels with a highly interconnected macroporous network, which allow for effective oxygen diffusion and sustained release over periods ranging from four hours to several days. The cryogels retain essential physical properties such as injectability, shape-memory, and cytocompatibility, and can incorporate additional therapeutic agents, including various checkpoint inhibitors. They are shown to restore oxygen levels in hypoxic tissues, downregulate immunosuppressive factors, and reactivate anti-tumor cytotoxic immune cells, making them suitable for use in cancer therapy and as platforms for additional immunotherapeutic interventions.
Claims Coverage
The patent includes one independent claim describing a method for reducing hypoxia in biological tissue using an oxygen-generating cryogel, with a number of defined inventive features.
Reducing hypoxia in biological tissue by administering an oxygen-generating cryogel
The claimed method comprises administering an oxygen-generating cryogel to biological tissue by injection, catheter, or surgery. The cryogel must include: - A lyoprotectant (for example, sucrose, trehalose, or mannitol) - A peroxide, oxide or percarbonate (such as calcium peroxide, magnesium peroxide, encapsulated hydrogen peroxide/polyvinylpyrrolidone, sodium percarbonate, zinc oxide, manganese dioxide, or hydrogen peroxide) - Catalase, wherein the catalase is acrylate-PEG-catalase - Polymerized hyaluronic acid Additional inventive features may include conjugation with G4RDGSP (such as acrylate-PEG-G4RDGSP), incorporation of checkpoint inhibitors (such as adenosine receptor antagonists for A2a, A2b or A3, anti-CTLA4, anti-CD73, anti-PD1, and anti-PD-L1), specific particle size ranges for injectability, sustained oxygen release (for at least about 4, 16, 24, 48, or 96 hours), ability to increase oxygen concentrations to physioxic or normoxic levels, and reduction of hypoxia-induced immunosuppression or extracellular adenosine to levels present in normoxic tissue.
In summary, the independent claim covers methods of using an oxygen-generating cryogel with defined chemical composition and properties for reducing hypoxia in tissues, particularly describing specific polymers, catalysts, and active agents that enable minimally invasive, sustained, and biocompatible local oxygen delivery.
Stated Advantages
Allows rapid and sustained reversal of local hypoxia in biological tissues, including tumors.
Restores anti-tumor cytotoxic T cell activity previously inhibited by hypoxic conditions.
Enables minimally invasive administration via injection or catheter, overcoming the limitations of surgical implantation.
Reduces immunosuppressive extracellular adenosine and downregulates hypoxia-inducible genes associated with tumor aggressiveness.
Maintains high biocompatibility and cytocompatibility, with low toxicity due to efficient removal of hydrogen peroxide byproducts.
Provides a mechanically robust, shape-memory, interconnected macroporous scaffold suitable for cell infiltration, nutrient diffusion, and waste removal.
Can be combined with other therapeutic agents and checkpoint inhibitors, enabling synergistic cancer immunotherapy.
Documented Applications
Reduction of hypoxia in biological tissues, including locally within solid tumors.
Treatment of cancer by administering cryogels into tumors to restore oxygenation and reverse tumor-associated immunosuppression.
Platform for combining with checkpoint inhibitors or adenosine receptor antagonists as co-adjuvant therapy to enhance immunotherapy.
Support for cancer vaccination applications by combining cryogels with cytokines, adjuvants, or tumor-associated antigens.
Research tool for studying the impact of hypoxia and local oxygenation on tumor development, immune cell function, and immune responses.
Injectable material for localized oxygen delivery in regenerative medicine and tissue engineering contexts.
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