Sensitizing cells to proton radiation
Inventors
Harvey, Adam J. • Kaytor, Michael D. • Cengel, Keith • Diffenderfer, Eric Stanton
Assignees
Humanetics Corp • University of Pennsylvania Penn
Publication Number
US-12403195-B2
Publication Date
2025-09-02
Expiration Date
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Abstract
Materials and methods for enhancing the effectiveness of proton radiation therapy (e.g., high linear energy transfer (LET) proton radiation therapy) against tumor cells are provided herein.
Core Innovation
This invention provides materials and methods for enhancing the effectiveness of proton radiation therapy, particularly high linear energy transfer (LET) proton radiation therapy, by using compositions containing genistein, including nanoparticulate genistein, as sensitizing agents that enhance the effectiveness of radiation against tumor cells. The disclosure states that genistein acts as a selective agonist of estrogen receptor beta and has cell-signaling activities that affect how cells respond to radiation damage, and that compositions (e.g., suspension formulations) that contain genistein as the active ingredient can be used to sensitize tumor tissue to radiation therapy.
The background identifies that mainstream X-ray radiotherapy deposits energy in both normal and tumor tissue and can have detrimental effects on normal tissue, whereas proton radiation can be controlled to deposit maximal energy at a selected position within the body (the Bragg peak) and can be conformed to the shape and depth of a patient's tumor. The invention addresses the need to enhance the effectiveness of proton radiotherapy, and particularly high LET proton radiation, against tumor cells by administering genistein-containing compositions to sensitize tumor cells and thereby improve radiotherapeutic outcomes.
Claims Coverage
The patent includes two independent claims that define two main inventive features related to use of nanoparticulate genistein with high LET proton radiation.
Nanoparticulate genistein at 5 μM to sensitize tumor cells to high LET proton radiation
A method consisting essentially of contacting tumor cells with a composition consisting essentially of one or more pharmaceutically acceptable carriers and nanoparticulate genistein at a concentration of 5 μM, and contacting the tumor cells with high LET proton radiation, wherein the genistein is effective to sensitize the tumor cells such that the tumor cells are reduced in number and therapeutically effectively treated with a dose of high LET proton radiotherapy that is at least 10% less than the dose that would need to be administered to corresponding tumor cells not treated with the genistein composition.
Administering nanoparticulate genistein at 5 μM to sensitize solid tumors in a mammal to high LET proton radiation
A method consisting essentially of administering to a mammal a composition consisting essentially of one or more pharmaceutically acceptable carriers and nanoparticulate genistein so that cells of the solid tumor are contacted with nanoparticulate genistein at a concentration of 5 μM, and exposing the solid tumor to high LET proton radiation, wherein the genistein is effective to sensitize cells of the solid tumor such that the tumor is therapeutically effectively treated and the cells in the tumor are reduced in number with a dose of high LET proton radiotherapy that is at least 10% less than the dose that would need to be administered to a corresponding tumor in a mammal not treated with the composition.
The independent claims focus on (1) contacting tumor cells with nanoparticulate genistein at 5 μM to sensitize them to high LET proton radiation, and (2) administering nanoparticulate genistein to a mammal so that solid tumor cells are contacted with 5 μM genistein prior to high LET proton radiation, each resulting in effective treatment with at least a 10% reduction in required radiation dose.
Stated Advantages
Enhancing the effectiveness of proton radiation therapy, particularly high LET proton radiation, against tumor cells.
Sensitization that enables a tumor to be effectively treated with a dose of high LET proton radiotherapy that is at least 10% less than the dose required without the genistein composition.
The same dose of radiotherapy can have a greater therapeutic effect when combined with genistein (e.g., increased reduction in tumor size or number of tumor cells).
Nanoparticulate genistein formulations can provide increased oral and/or parenteral bioavailability compared to non-nanoparticle genistein, facilitating administration of therapeutically effective amounts using lower amounts of formulated drug substance.
Administration of genistein compositions may result in prolonged survival (e.g., progression-free or overall survival) of cancer patients treated as described.
Documented Applications
Sensitizing tumor cells to proton radiation, including high LET proton radiation, in vitro and in vivo by contacting tumor cells with genistein-containing compositions.
Treating a mammal identified as having a solid tumor and slated to undergo high LET proton radiotherapy by administering nanoparticulate genistein so that tumor cells are contacted with genistein at 5 μM and exposing the tumor to high LET proton radiation.
Use with a range of tumor types explicitly listed: lung (including non-small cell lung cancer), prostate, head and neck, pancreatic, colon/colorectal, bladder, thyroid, breast, liver, ovarian, endometrial, cervical, kidney, brain, melanoma, and non-Hodgkin lymphoma.
Administration of genistein compositions beginning before onset of radiotherapy, continued throughout radiotherapy, and in some cases after completion of radiotherapy, by routes including oral, intramuscular, subcutaneous, or intravenous.
Potential use of genistein to protect healthy tissue and mitigate effects of accidental or nonmedical radiation exposure.
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