Shielding catalytic biomaterial and image guidance delivery platform

Abstract

Compositions and methods are presented to improve the efficacy and reduce the side-effects of radiological cancer treatments. Nanoparticles of cerium oxide are dispersed within a biodegradable polymer matrix to form a biomaterial that can be implanted in a patient at a selected location and remain at that location for a period of time encompassing all or part of a radiation therapy course of treatment. Among other functions of the implanted biomaterial, it may act as a spacer such that organs at risk are moved away from tissues targeted by the radiation therapy. Another function of the implanted biomaterial is as a fiducial marker. The use of cerium oxide will assist in achieving both the fiducial marker and spacer functions, particularly in view of the catalytic activity of cerium oxide in reducing a number of reactive oxygen species to non-reactive compounds The composition may permit higher doses of radiation and improved survival rates resulting therefrom.

Description

Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 SHIELDING CATALYTIC BIOMATERIAL AND IMAGE GUIDANCE DELIVERY PLATFORMCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 680, 171 filed on August 7, 2024, the contents of which are hereby incorporated by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under grants CA229417 and CA239042, awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD

[0003] The present application utilizes biomaterials that may include smart radiotherapy biomaterials (SRBs). Radiation therapy for cancer patients includes exposing tissue to beams of radiation as well as brachytherapy, i.e., insertion of radioactive materials as close to the cancer as possible. The objects of the biomaterial of the present application are the same regardless of how radiation is delivered to the targeted tissue. Radiation therapy has the goal of controlling cell growth and proliferation by damaging the DNA of cancerous tissue leading to death of cancerous cells.

[0004] Biomaterials are used as spacers in radiation therapy (RT) treatment to protect non-cancerous tissues adj acent to the area of RT treatment from the effects of radiation. Besides this shielding function, biomaterials are upgraded to “smart” RT biomaterials, designed to do more than shielding healthy tissue. Disclosed herein are SRBs designed to respond to stimuli and perform additional desirable functions like controlled delivery of therapy-enhancing payloads directly into the tumor sub-volume while minimizing normal tissue toxicities. Such RT biomaterials may include functionalized nanoparticles that can be activated to boost RT efficacy and to enable improved imaging technologies and techniques.

[0005] One function performed by a SRB, as disclosed herein, is a three-dimensional (3D) near real time intra-operative image guidance system for smart biomaterial delivery procedures. Comprehensive intra operative 3D spatial image guidance has the potential to enhance biomaterial delivery. Embodiments of the imaging and guidance system disclosedAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 herein may include software or a cloud-based platform that can be integrated to current C-arm machines, cone-beam CT scanner and similar imaging equipment.BACKGROUND

[0006] Interventional oncology is an evolving branch of image-guided interventions that includes a set of minimally invasive image-guided procedures such as curative, diagnostic and enhancing interventions for malignant tumor treatments. Enhancing procedures are those that enhance the quality and safety of treatment. One such enhancing procedure places a hydrogel spacer utilizing image-guided techniques. The hydrogel spacer may include a drug, e.g., a immunotherapy and / or chemotherapy drug, or nanoparticles permitting various functionality. For example, nanoparticles that result in a particular imaging signal may be used for various purposes including material placement and verification. Such techniques can offer a number of benefits in managing devastating cancer types like pancreatic cancer and reducing side-effects, including physiological impacts on neighboring tissue.

[0007] Pancreatic cancer currently has a 5-year overall survival rate (OS) under 10% and is the third leading cause of cancer-related death in the U.S. One treatment utilized against pancreatic cancer is image-guided radiotherapy (IGRT), which delivers a physician-prescribed dose of radiation to the target tumor. IGRT is shown to be an effective treatment in killing cancerous cells. However, minimization of damage to the surrounding healthy tissue is also very important when using IGRT.

[0008] IGRT dose escalation to the tumor has the potential to increase OS at two years to between 19% and 36%; at three years, OS is potentially increased to between 9% and 31%. However, the organs directly adjacent to the pancreas, often called radiosensitive organs at risk (OARs), limit such dose escalation. Such OARs for pancreatic cancer are the duodenum, stomach, and bowel. Smart radiotherapy biomaterial (SRBs), including hydrogel spacers, can be delivered to the patient prior to IGRT so as to increase the spacing between tumors and OARs. The effect of high-dose radiation on the OARs can be significantly reduced for a given dose of radiation. Among other benefits, the upper-limit of dose escalation may be significantly increased, thereby increasing the efficacy of radiation therapy.

[0009] In light of the importance of targeting cancerous tissue and avoiding OAR, image-guided interventional oncology procedures can greatly enhance the outcome of any cancer treatment. This is particularly true for pancreatic cancer, given the importance of dose escalation, the complicated anatomy of the OARs and the potential use of hydrogel spacers in a complicated OAR volume. Proper delivery of SRBs can increase cancer therapy's quality,Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 effectiveness, and safety. Image guidance can considerably improve the safety and robustness of SRB delivery.

[0010] A generative deep-learning platform that highly prioritizes clinical practicality and provides the most informative intra-operative feedback for image-guided SRB delivery would be an immensely useful tool in RT generally and in treating pancreatic cancer in particular. Positive aspects of such platform would include (i) synthesis of a computed tomography (CT) from small field-of-view radiographs; (ii) images and reconstruction of the intra-operative SRB spacer distribution; (iii) robustness; and (iv) a soft-contrast cost function. The ultimate goal of such a platform would be to reconstruct the 3D intra-operative hydrogel spacer distribution and all anatomical features with extremely high, precisely accurate, and repeatable fidelity.SUMMARY

[0011] A radiation therapy biomaterial composition is presented in this application, the composition comprising cerium oxide nanoparticles dispersed within a polymer matrix. The polymer matrix may be a biodegradable hydrogel adapted to be injected in a space between a cancerous tissue and an organ at risk. The cerium oxide nanoparticles may be adapted to catalytically reduce reactive oxygen species including hydroxyl radicals, hydroxide ions, superoxide anions, and hydrogen peroxides.

[0012] The composition may also include one or more pharmaceutical compound or other therapeutic materials or biomaterials dispersed within the polymer matrix. The compound or other material may be a chemotherapy agent or an agent for treating a condition related to radiation therapy or chemotherapy. The composition may include an immunoadjuvant and, an optional antigen related to the immunoadjuvant.

[0013] The hydrogel composition in any embodiment may comprise 2% (w / v) chitosan and 4% (w / v) sodium alginate in a 1 : 1 ratio. Further, a 20% (wt) cerium oxide nanoparticles in water dispersion may be mixed with the hydrogel at ratio of 4:1 of hydrogel to nanoparticle dispersion. The composition may also include an antibody dispersed within the polymer matrix. The nanoparticles may have a size from about 2 nm to about 15 nm in diameter.

[0014] The hydrogel in the composition may be a biodegradable hydrogel that includes chitosan or sodium alginate or combinations thereof. In any embodiment of the composition, the cerium oxide nanoparticles may be adapted to reduce reactive oxygen species catalytically.

[0015] An embodiment also encompasses a method of treating cancer that includes determining a base radiation therapy plan for a patient that includes a base radiation dosageAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 determined to achieve a maximum benefit to the patient and implanting in the patient a biomaterial composition in one or more spaces between a cancerous tissue and an organ at risk, thus achieving one or more spacer distances. The biomaterial composition may include cerium oxide nanoparticles dispersed within a polymer matrix and the polymer matrix may be a biodegradable hydrogel and the cerium oxide nanoparticles may be adapted to catalytically reduce reactive oxygen molecules. An aggressive radiation therapy plan may then be determined that includes an increased radiation dosage greater than the base radiation dosage. The aggressive plan may be based on an expected reduced exposure to radiation of organs at risk considering factors including the one or more spacer distances between the cancerous tissue and the organ at risk achieved with the biomaterial composition; the interaction of the biomaterial composition, the radiation dosage, the cancerous tissue and the organ at risk, wherein a first interaction is generation of one of more reactive oxygen species; and catalytically reducing the reactive oxygen species by the cerium oxide nanoparticles.

[0016] The method of treating cancer may also include generating one or more three-dimensional (3D) images of the biomaterial composition that has been implanted in the spaces between the cancerous tissue and the organs at risk. In addition, the one or more 3D images may be generated from a plurality of images from one of more medical imaging techniques selected from x-ray, computed tomography (CT), magnetic resonance, and ultrasound. The biodegradable hydrogel used in the methods may include chitosan and sodium alginate. Further, the reactive oxygen species may include one or more of hydroxyl radicals, hydroxide ions, superoxide anions and hydrogen peroxides. The method may include a biomaterial composition that has an additional agent dispersed within the polymer matrix, the agent including an antibody, a chemotherapy agent, an agent for treating a condition related to radiation therapy, an agent for treating a condition related to chemotherapy, an immunoadjuvant or an antigen. The method may also include implanting the biomaterial composition using an endoscope.

[0017] In another embodiment, a method of treating cancer in a patient may include generating one or more three-dimensional (3D) representations of a cancerous tissue and one or more organs at risk and implanting in the patient a biomaterial composition in one or more spaces between the cancerous tissue and the organs at risk. The biomaterial composition may include cerium oxide nanoparticles dispersed within a polymer matrix. Also, the polymer matrix may include a biodegradable hydrogel and cerium oxide nanoparticles that are adapted to catalytically reduce reactive oxygen molecules. The method may also include assessing theAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 placement of the biomaterial composition, including quantifying one or more spacer distances achieved by the biomaterial composition and determining a base radiation therapy plan for a patient that includes a base radiation dosage followed by determining an aggressive radiation therapy plan having radiation dosage greater than the base plan radiation dosage. The aggressive plan may be based on an expected reduced exposure to radiation of organs at risk considering factors that include the spacer distances between the cancerous tissue and the organ at risk, the interaction of the biomaterial composition, the radiation dosage, the cancerous tissue and the organs at risk.

[0018] The methods of cancer treatment may have a first interaction of the radiation dosage and the patient that results in generation of one of more reactive oxygen species and a second interaction includes a catalytic reduction of the reactive oxygen species by the cerium oxide nanoparticles. Also, the one or more 3D images may be generated from a plurality of images from one of more medical imaging techniques selected from the group consisting of x-ray, computed tomography (CT), magnetic resonance, and ultrasound.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the present teachings and together with the description, serve to explain the principles of the present teachings. In the figures:

[0020] FIG. 1A illustrates a several human organs.

[0021] FIG. IB illustrates the human organs of FIG. 1A wherein a spacer has been injected.

[0022] FIG. 2A is an illustration of a cerium oxide nanoparticle interacting with potential radical oxygen species generated by radiation therapy.

[0023] FIG. 2B is a graph of radiation dose (Gy) vs. nanoparticle concentration (ng • g1)-

[0024] FIG. 3 shows a process flowchart transforming 2-dimensional medical images into 3 -dimensional representations.

[0025] FIG. 4 shows a process flowchart providing additional detail to the transforming function of FIG. 3.

[0026] FIG. 5 is an illustration showing before-and-after MRI scans and CT scans of a human cadaver.

[0027] FIG. 6 is an illustration of the initial steps for a murine cancer tumor model.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02

[0028] FIG. 7A and FIG. 7B are graphs of days post-treatment vs. tumor size (mm3) for test examples and controls.

[0029] FIG. 8 is a graph of days post-treatment vs. probability of survival (%) for test examples and controls.

[0030] FIG. 9A and FIG. 9B are graphs of days post-treatment vs. tumor size (mm3) for test examples and controls.

[0031] FIG. 10 is a graph of days post-treatment vs. probability of survival (%) for test examples and controls.DETAILED DESCRIPTION

[0032] Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings and figures. In the following detailed description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it will be apparent to one of ordinary skill in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, circuits, and networks have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.

[0033] It will also be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first object or step could be termed a second object or step, and, similarly, a second object or step could be termed a first object or step, without departing from the scope of the present disclosure. The first object or step, and the second object or step, are both, objects or steps, respectively, but they are not to be considered the same object or step.

[0034] The terminology used in the description herein is for the purpose of describing particular embodiments and is not intended to be limiting. As used in this description and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the term “and / or” as used herein refers to and encompasses any possible combinations of one or more of the associated listed items. It will be further understood that the terms “includes,” “including,” “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. Further, as used herein, the term “if’ may beAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 construed to mean “when” or “upon” or “in response to determining” or “in response to detecting,” depending on the context.

[0035] Attention may be directed to processing procedures, methods, techniques, and workflows that are in accordance with some embodiments. Some operations in the processing procedures, methods, techniques, and workflows disclosed herein may be combined and / or the order of some operations may be changed.

[0036] Smart radiotherapy biomaterials (SRBs) are used to improve outcomes, reduce side-effects and otherwise improve patient quality of life in any cancer treatment that involves radiotherapy. One use of SRBs is to act as spacers. By way of example, image-guided radiation therapy (IGRT) for treatment of pancreatic cancer may be preceded by the patient being injected with a hydrogel spacer to establish and / or increase separation between cancerous and healthy tissue. In the case of pancreatic cancer, separation between the affected portion of the pancreas and any organs at risk (OAR), e.g., the duodenum, is a desired outcome.

[0037] As illustrated in FIG. 1A, the duodenum 40 is adjacent and, to an extent, wraps around the pancreas 42 and, in particular, the head of the pancreas (HOP) 44. Thus, it can be a significant challenge to treat pancreatic tumors with radiation, especially tumors associated with the HOP 44, without inadvertently irradiating the duodenum or another OAR to some degree. On a related note, since there is a positive relationship between the dosage of radiation applied to a pancreatic tumor and the overall survival rate (OS) of the patient, reduction in levels of OAR irradiation per dosage of radiation applied may permit greater dosages of radiation to be safely administered.

[0038] FIG. 1A and FIG. IB also illustrate one means by which a spacer, e.g., a hydrogel spacer 46, may be placed to act as a separator between the pancreas 42 and duodenum 40. An endoscope 50 may be utilized externally to deliver the hydrogel spacer 46 to the patient’s body. A distal end of the endoscope 50 is shown in FIGs. 1A and IB, including a distal tip 52, may be introduced through a patient’s mouth or nose, pass through the esophagus and stomach and into the patient’s duodenum. Associated with the distal tip 52 is a needle 54 for piercing the wall 48 of the duodenum. A lumen (not shown) extending through the endoscope 50 is connected to the needle 54, such that the hydrogel 46 pumped through the lumen and needle 54 is delivered adjacent the needle tip. The distal tip 52 of endoscope 50 may also include other typically integrated functionality with an endoscope such as illumination, camera functionality and ultrasound transceiver elements. The ultrasound capable endoscope 50 may be utilized to perform an endoscopic ultrasound guided procedure.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02

[0039] Important factors in choosing the ingredients of a hydrogel spacer are biocompatibility, eventual bioabsorption (biodegradable) and a viscosity profile consistent with the manner in which the hydrogel is delivered as well as the function of acting as a spacer for a set period of time. While a low viscosity material may be easy to deliver with a given device, higher viscosity may provide benefits towards performance of the spacer for a required time period. One example of a material that may be used as a primary constituent of a hydrogel spacer 46 is polyethylene glycol. One advantage of polyethylene glycol (PEG) is the ability to select a grade of PEG with a particular viscosity profile because many grades are available.

[0040] More can be achieved , however, by SRBs than merely acting as a spacer. A broad selection of possible ingredients or constituents may be added to SRBs to achieve a number of goals in enhancing functionality. Such ingredients or constituents may form part of a liquid or gel, e.g., be in solution, thus becoming an ingredient in the ultimate hydrogel formulation. Alternatively, they may also be in the form of beads, nanoparticles, colloidal suspensions or other solids that are suspended in the liquid or hydrogel without significantly affecting its properties. Although an SRB may be a gel, hydrogel or liquid, throughout this disclosure the term “hydrogel” may be used without excluding a gel or liquid or other form otherwise acceptable as a SRB.

[0041] Potential hydrogel additives include pharmaceuticals, biopharmaceuticals and nutraceuticals. Alternatively, added constituents may have an impact on the physical parameters of the hydrogel including, for example, impacting how the delivered radiation interacts with the hydrogel. That is, constituents of the hydrogel may increase the ability of the hydrogel spacer to absorb or reflect radiation or otherwise act to prevent radiation from impacting healthy, i.e., non-cancerous, tissue. Moreover, cancer patients often receive image-guided radiation therapy (IGRT) along with other treatment modalities like chemotherapy, surgery, or immunotherapy. In these cases, SRBs can be loaded with nanoparticles or other immunoadjuvants to provide contrast for computed tomography and magnetic resonance imaging or can deliver specific chemical payloads useful in cancer treatment. Such payloads may take the form of compounds dissolved in solution, different polymers and designs, gels, nanoparticles, polymeric films, rods, or wafers that are used for drug delivery. In addition, any kind of protein, peptide, polypeptide, antibody or biopharmaceutical product may be incorporated in the payload.

[0042] An example of a specific ingredient added to hydrogel spacer 46 is one or more immunologic adjuvants. Immunoadjuvants are substances that enhance the strength andAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 duration of the antigen-specific immune response within an organism when given in combination with specific antigens.

[0043] Medical imaging involves equipment, techniques and processes of imaging the interior of a body. Imaging results may be utilized for clinical analysis as well as for medical intervention and may involve imaging of the function of some organs or tissues to diagnose and treat disease. A fiducial marker or fiducial is anything placed in the field of view of an imaging system that appears in the image produced. A fiducial may be used as a point of reference or measurement. It may be either something placed into or on the imaging subject, or a mark or set of marks in the reticle of an optical instrument. In the context of this application, a fiducial is a component of a SRB or other biomaterial disposed within a subject.

[0044] In an embodiment, the SRB may take the form of a liquid immunogenic fiducial eluter (LIFE) biomaterial. The LIFE SRB acts as a spacer to spare OAR from radiation and may deliver cancer therapy drugs, nanoparticles or any other payload listed previously. The LIFE biomaterial may be used as the basis for a Radiotherapy Spacer Hydrogel with Image Enhancer for Limiting Damage (Radio SHIELD) that can effectively shield the surrounding healthy tissue, i.e., OAR, around tumors like pancreatic cancer during RT. Radio SHIELD may include cerium oxide nanoparticles in the hydrogel. Nanoparticles of cerium oxide dispersed in a SRB hydrogel will enhance imaging contrast and may be used to guide radiotherapy delivery while limiting damage to the surrounding healthy tissue. That is, one function of the cerium oxide nanoparticles is as a fiducial marker.

[0045] Besides acting as a fiducial, i.e., offering imaging contrast benefits, cerium oxide nanoparticles also protect healthy tissues from irradiation. One mode of damage occurring in irradiated tissue involves the radiolysis of water creating reactive oxygen species that damage the DNA and other biomolecules. Reactive oxygen species include hydroxyl radicals, hydroxide ions, superoxide anions, and hydrogen peroxide. The creation of reactive oxygen species is one of the most critical mechanisms of radiation injury. Traditional scavengers of reactive oxygen species that are often used as radioprotectants, such as amifostine, ascorbate, carotene, and lipoic acid derivatives or thiols, have short pharmacokinetic half-lives, poor availability at the radical production site, have side effects and provide little to no imaging contrast. Cerium oxide nanoparticles may provide selective protection to normal cells during radiotherapy due to catalytic removal of reactive oxygen species, which mitigates indirect DNA damage leading to apoptosis in healthy cells. The rapid reversible transformation, i.e., catalysis, of the oxidation state between ceric (Ce4+) and cerousAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 (Ce3+) ions permit scavenging of the most reactive species, hydroxyl radical, hydrogen peroxide, and hydrogen radical, generated by radiolysis of water.

[0046] FIG. 2A illustrates water exposed to radiation producing reactive oxygen species, e.g., hydroxyl radical and hydrogen peroxide. Interaction of reactive oxygen species, e.g., OH+, with cerium oxide nanoparticles 70 results in oxidation of cerium from Ce3+to Ce4+and elimination of the OH+reactive oxygen species. Cerium oxide nanoparticles are also highly desirable because regeneration of the Ce4+back to the Ce3+state is automatic and does not consume or radicalize oxygen or oxygen containing compounds. Thus, the cerium oxide acts as a true catalyst. FIG. 2B is a graph of the concentration of cerium oxide nanoparticles in nanograms per gram (ng-g'1) needed to eliminate most reactive oxygen species in a clinically relevant radiation dose ranging from 0 to 6 gray (Gy).

[0047] An important advantage of the ceric-cerous catalysis is that the reactions do not consume oxygen. When cerium is available in the form of cerium oxide nanoparticles, oxygen exchange between adsorbed species and the nanoparticle surface occurs, and the cerium oxide nanoparticles serve as auto-regenerative redox status modulators. Therefore, normal cellular functions or the action of exogenous pharmaceuticals are not impeded by hypoxic conditions, which is often the case with other radiation scavengers, e.g., ferrous ion.

[0048] Since Ce is a high-Z material, it also has the undesired potential to enhance the radiation dose to tissue via direct interaction with the incident radiation, in which photoelectric absorption yields densely ionizing secondary electrons. However, cerium oxide nanoparticles will not result in significant radiation dose enhancement if concentrations are kept low. This is because the rate of scavenging reactions that remove reactive oxygen species is far greater than the rate of photoelectric interactions with the incident radiation. Using known experimental reaction rates for the removal of OH* and H2O2, it has been determined (FIG. 2B) that the required cerium oxide nanoparticle concentrations for protecting normal cells from locally administered radiation doses up to 6 Gy, which is used in accelerated partial breast radiation therapy, is 9 nanograms of cerium oxide nanoparticle per 1 gram of tissue. Radiation transport computations were performed to ascertain that this concentration does not yield undesirable dose enhancement. Results show that using 2 nm cerium oxide nanoparticles with relevantenergy incident x-rays, the highest relative dose enhancement is less than 1%. Therefore, dose enhancement is not a concern and should not prevent the use of cerium oxide nanoparticle for radioprotection.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02

[0049] Liquid immunogenic fiducial eluter (LIFE) biomaterial may comprise a combination of natural polymers. Two natural polymers that may be used in the LIFE biomaterial are chitosan and sodium alginate. Chitosan and sodium alginate, among other natural polymers, may both be sourced as powders which, when mixed with a liquid, result in a gel. A hydrogel may be formed if the powders are mixed with water or water solution. In an embodiment, the powdered natural polymer(s) may be dissolved in a water solution containing about 1% acetic acid. To prepare a “2% (w / v) chitosan” product, 2 grams (g) of chitosan powder are mixed with 100 milliliters (mL) of liquid, e.g., water containing 1% acetic acid.

[0050] In an embodiment of the SRB hydrogel, a 2% (w / v) chitosan hydrogel and a 4% (w / v) sodium alginate hydrogel are prepared and mixed in a 1:1 ratio. Both the chitosan and sodium alginate may be sourced from Sigma Aldrich, St. Louis, MO, USA. In addition, two solutions containing nanoparticles were prepared separately. One of the prepared solutions contained 0.85 g / mL of titanium dioxide (TiO? Anatase, 99.5%, 5 nm, US Research Nanomaterials Inc., Houston, TX, USA). The other solution contained 0.287 g / mL of Omniscan™ gadodiamide gadolinium-based (GdNP) nanoparticles (GE Healthcare, Silver Spring, MD, USA). The TiO? and the GdNPs solutions were mixed in a 1:1 ratio and added to the hydrogel mixture in a 4:1 ratio. For example, 4 mL of the 2% chitosan and 4% sodium alginate hydrogel 1:1 mixture is mixed with 1 mL of the TiO? and GdNP nanoparticle containing solution to realize an embodiment of the LIFE hydrogel.

[0051] In an alternative embodiment of SRB hydrogel, a 20% (wt) cerium oxide nanoparticles in water dispersion is added to the 1:1 chitosan hydrogel and sodium alginate hydrogel mixture in a 4: 1 ratio. For example, 4 mL of the 2% chitosan and 4% sodium alginate hydrogel 1 : 1 mixture is mixed with 1 mL of the cerium oxide nanoparticle aqueous solution to realize an embodiment of the LIFE hydrogel. Any embodiment of the SRB hydrogel may be maintained at 4°C until treatment.

[0052] For a 20 wt% nanoparticles / nanopowder in water dispersion of cerium oxide (CeCh, 99.99%, 10 nm, www.us-nano.com / inc / sdetail / 49514) a balance of amount of cerium oxide providing optimum protection of healthy tissue and organs at risk versus minimizing RT dose enhancement is about 0.125 mg • g'1for typical ranges of RT dosage amount, e.g., fractionalized dosage of 1 to 6 Gray per day. That is, about 0.125 milligrams of cerium oxide is administered per 1 gram of cancerous tissue. For a 20% cerium oxide in water dispersion mixed with LIFE hydrogel according to above ratios, 2.4 milligrams of hydrogel is injected per 1 gram of cancerous tissue.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02

[0053] Performance and toxicity of any drug or other material introduced into biological tissue, including cerium oxide nanoparticles, is highly dependent on the route of administration. SRBs were originally designed to perform two purposes: (i) to provide imagecontrast important for ensuring geometric accuracy and precision during image-guided radiotherapy for cancer patients and (ii) to allow sustained release of the payloads. In the application of radiation therapy, these payloads may include chemotherapeutics and immunotherapeutics. In an embodiment presented herein, SRBs comprise a payload that includes cerium oxide nanoparticles to provide additional selective radioprotection in addition to separating the pancreas from the surrounding healthy tissue.

[0054] The effectiveness of SRBs and similar biomaterials highly depends on the accuracy of smart material placement procedures. Inaccurate placement of biomaterials can lead to infection, inflammation, soft-tissue wall infiltration, and patient discomfort due to misplacement or over-injections. More specifically, in the case of pancreatic cancer, the duodenum's hard-to-reach location and the endoscopic procedure's complexity make the outcome highly uncertain. Ultrasound (US) and endoscopic US (EUS) are widely used image modalities to guide intra-operative procedures including interventional oncology procedures. EUS is not, however, optimized for interventional oncology due to three limitations: (i) the success of the procedure greatly depends on the operator’s skills; (ii) it mainly provides only 2D images which lack information about volume and 3D spatial location; and (iii) smart materials such as hydrogel spacers may have very low visibility. While CT and MRI are the optimal feedback for image-guided placement of SRBs, they are not practical for intraoperative image guidance. Because the procedure is done in the operation room with no 3D scanner, CT and MRI would require relocation of the patient to a separate imaging room. With the patient under anesthesia and connected to many monitoring systems, relocation of the patient to the imaging room is not feasible unless absolutely necessary. Further, such relocation can induce anatomical variations that negate the whole point of using this kind of intraoperative feedback.

[0055] An embodiment of an X-ray intra-operative spacer injection system (XIOSIS) is herein presented along with a deep learning system. The XIOSIS system may include multiple mobile C-arm X-ray units to provide three-dimensional (3D) comprehensive image guidance to the physician. Such guidance would significantly enhance the accuracy and success of SRB placement procedure and drug delivery. The novel deep learning (DL) system is designed to track and monitor the placement of the SRB spacer intra-operatively.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02

[0056] XIOSIS is designed for robust image-guided duodenal hydrogel spacer placement. A top priority XIOSIS is clinical practicability. It uses multiple X-ray projections acquired by a portable C-arm scanner. Portable C-arm imaging devices have long been used for image-guided surgery such as fluoroscopy imaging and are used in some endoscopic procedures as the standard of care. One challenge with C-arm projections in image-guided surgery and, more specifically, spacer placement is the small field of view (FOV) of the resulting X-ray images. Another challenge is the 2D nature of X-ray images not providing direct feedback about the 3D structure of region of interest and location and volume of inj ected spacer. XIOSIS recreates the on-demand 3D CT scan from multiple, e.g., three projections to provide on-demand 3D guidance to the physician during the procedure. XIOSIS-guided corrective injection reduces the effect of these uncertainties and improves the effectiveness of the spacer placement. It may be determined, using various models with inputs regarding the actual placement of spacers, that the duodenal volume receiving high dose radiation may be reduced by an average of 70 percent. Also, cadaver studies suggest that synthesized CT provides a comprehensive evaluation of the spacer location and volume.

[0057] FIG. 3 generally illustrates the architecture of XIOSIS is composed of two back-to-back networks where one fuses the small FOV X-ray images with large FOV images of prior digitally reconstructed radiographs (DRRs) and the other uses the high-dimension features to synthesize the patient body and hydrogel spacer. The limitation of intra-operative X-ray images, namely their small field of view (SFOV), was addressed by fusing them with the large FOV (LFOV) digitally reconstructed radiographs (DRRs). LFOV DRRs were created from a prior patient’s diagnostic CT scan. This approach offered two advantages: (i) incorporating patient-specific information for CT synthesis, and (ii) allowing better alignment of the SFOV to LFOV images to provide better localization of the spacer relative to various proximal structures. To compensate for the 2D nature of X-ray images, XIOSIS uses three intra-operative X-ray projections to synthesize the intraoperative CT scan of the patient together with smart material distribution.

[0058] The generator component of XIOSIS comprises two back-to-back networks shown in FIG. 3 as well as the fusion network architecture and the 3D CT shown in FIG. 4. FIG. 4 shows the fusion network architecture wherein a seven-step encoder-decoder architecture is used. The fusion network is a 2D network with a seven-step encoder-decoder architecture. Each step consists of multiple convolutional layers with batch normalization and ReLU activation followed by max pooling. The input 26 to the network is 6 channels ofAttorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 128x128 images, 3 SFOV, and 3 LFOV concatenated together, and the output 28 is 3 channels of 128x128 high-level features. Unlike a biplanar model, the model has three parallel encoderdecoders for the three X-ray projections. The middle network of 3D CT includes 3D blocks that fuse the information from the three parallel encoder-decoders. Each parallel encoderdecoder may be supplied with its expansion module 30.

[0059] In one configuration, 3D CT for CT synthesis was trained using the six projections (3 LFOV and 3 SFOV). A one-by-one configuration may also be used, wherein each network was trained separately on the designated task. The fusion network was trained as a conditional GAN (out-painting network) to out-paint the SFOV X-ray images using the six projections. The 3D CT network was trained separately as a GAN to synthesize 3D CT from three LFOV DRRs generated previously using deep DRR. A third configuration was trained in an “end-to-end” fashion. The fusion network plus 3D CT was trained as a single model which received six projections as the input and generated the 3D CT scan as the final output. This approach enabled the model to come up with high-level feature maps extracted by the fusion network, which is then used by the 3D CT network for CT generation.

[0060] Comparing XIOSIS to the commonly used systems that need at least 36 projections (suggested by studies) to create a 3D reconstruction of the region of interest with decent quality, the third method only needs three projections to create an acceptable reconstruction of the patient body and region of interest for intra-operative feedback. This is of great importance, because it minimizes the image acquisition time and makes the system viable to be used in real-time, image-guided procedures. As a result, the application of XIOSIS is not limited to SRB placement but to a broad array of procedures that use portable C-arm or fluoroscopy imaging devices for image-guided surgery.

[0061] Figure 3 shows an example of XIOSIS performance on CT and biomaterial 3D reconstruction. The pre-inj ection scan 22 illustrates the region of interest with no spacer, a first injection scan 24 illustrates the region of interest after injection of the SRB and subsequent scan 26 illustrates the region of interest some time after injection. XIOSIS synthesizes the 3D CT scan while detecting the spacer using these three X-ray projections.

[0062] The SRB material disclosed herein provides a transformative solution for current IGRT practice. Radio SHIELD enhances the IGRT by using SRBs for normal tissue protection and drug delivery. Combined with a 3D CT real-time imaging solution, e.g., XIOSIS, the disclosed SRB may ensure the accurate placement of SRBs for maximum effectiveness, Radio SHIELD may offer particularly valuable results to patients.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 EXAMPLES

[0063] The top two images of FIG. 5 are a post-injection and pre-inj ection axial, MRI scans of a human cadaver showing the placement of hydrogel spacer 46 in the post-injection scan. The bottom two images of FIG. 5 are a post-injection and pre-inj ection sagittal, CT scans of the same human cadaver showing the placement of hydrogel spacer 46 in the post-injection scan. Pre-inj ection images are taken to display that there is no visible contrast prior to injecting the SRBs. Once the SRB hydrogel 46 is injected, post-injection images are taken to detect the bright contrast provided by the SRBs.

[0064] The FIG. 5 images illustrating Radio SHIELD hydrogel 46 in human cadaveric specimen may be used in the methods, software and / or cloud-based platform of FIG. 3 and FIG. 4 to achieve near real time intra-operative image guidance system for smart biomaterial delivery procedures. Even the number of images shown in FIG. 5 could be sufficient to prepare such intra-operative 3D spatial image guidance and, since C-arm machines, cone-beam CT scanner and similar imaging equipment are available in a procedure room, the methods and software of FIG. 3 and FIG. 4 may be implemented in a real-time manner.

[0065] FIG. 6 presents the initial steps in a mouse model to illustrate the efficacy of using Radio SHIELD in the treatment of cancerous tumors in mice. 300,000 cervical cancer cells (TCI) are injected in both flanks of C57BL6 mice and palpable tumors were confirmed 10 days later. SRB hydrogel, in this example loaded with, is injected in two SRB subsets of mice. One SRB + Ab-CD40 subset of mice is subsequently treated with 6 Gy of radiation. The other SRB + Ab-CD40 subset receives no radiation treatment. Two other ‘no-SRB’ control groups are also studied, i.e., no SRB / no radiation treatment and no SRB / 6 Gy radiation treatment. The data presented in FIGS. 7 A and 7B shows tumor growth in the four mouse subgroups over about 23 days. Little to no tumor growth was observed for the groups treated with LIFE Biomaterial SRB loaded anti-CD40 antibody. In addition, FIG. 8 shows significantly (* p < 0.05) longer mice survival being observed for up to 5 months post-treatment for the groups treated with LIFE Biomaterial SRB + Ab-CD40, with slightly better results for the unirradiated group.Another study adds a group of SRB + anti-CD40 mice that receives a separate, i.e., second, injection of 20 pg of anti-CD40 antibodies, a group of SRB + anti-CD40 mice that receives an intraperitoneal injection of 200 pg of anti-PDl and a group of non-SRB + anti-CD40 that receives only the andi-CD40 intratum orally. Trends relating to slowed tumor growth are presented in FIGS. 9A and 9B. Significantly (* p< 0.05 and ** p < 0.01)) longer survival post-Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 treatment for mice receiving SRB prior to radiation. See also, Moreau, M., Investigating the Use of a Liquid Immunogenic Fiducial Eluter Biomaterial in Cervical Cancer Treatment, Cancers, vol. 16, no. 6, 20 March 2024.

[0066] The embodiments presented in this disclosure are to help explain the concepts described herein. This description is not exhaustive and does not limit the claims to the precise embodiments disclosed. Modifications and variations from the exact embodiments in this disclosure may still be within the scope of the claims.

[0067] Likewise, the components and steps described need not be disposed or performed as presented herein. Various components and steps may be omitted, repeated, shifted, combined, or divided, as appropriate. Accordingly, the present disclosure is not limited to the above-described embodiments, but instead is defined by the appended claims in light of their full scope of equivalents.

[0068] The claims that follow do not invoke 35 U.S.C. §112(f) unless the phrase “means for” is expressly used together with an associated function.

Claims

Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 CLAIMS WHAT IS CLAIMED IS:

1. A radiation therapy biomaterial composition comprising cerium oxide nanoparticles dispersed within a polymer matrix wherein the polymer matrix is a biodegradable hydrogel adapted to be injected in a space between a cancerous tissue and an organ at risk.

2. The composition of claim 1, wherein the cerium oxide nanoparticles are adapted to catalytically reduce reactive oxygen species including hydroxyl radicals, hydroxide ions, superoxide anions and hydrogen peroxides.

3. The composition of claim 1 further comprising a pharmaceutical compound dispersed within the polymer matrix, the pharmaceutical compound comprising a chemotherapy agent or an agent for treating a condition related to radiation therapy or chemotherapy.

4. The composition of claim 3, wherein the pharmaceutical compound is an immunoadjuvant and may include an antigen.

5. The composition of claim 1, wherein the hydrogel comprises 2% (w / v) chitosan and 4% (w / v) sodium alginate at a 1 : 1 ratio and 20% (wt) cerium oxide nanoparticles in water dispersion, the hydrogel and cerium oxide dispersion is mixed at ratio of 4: 1 of hydrogel of nanoparticle dispersion.

6. The composition of claim 1 further comprising an antibody dispersed within the polymer matrix.

7. The composition of claim 1, wherein the nanoparticles have a size from about 2 nm to about 15 nm.

8. The composition of claim 1, wherein the biodegradable hydrogel comprises chitosan or sodium alginate, or combinations thereof and the cerium oxide nanoparticles are adapted to reduce reactive oxygen species catalytically.

9. The composition of claim 1, including about 0.125 mg of cerium oxide per 2.4 mg of hydrogel.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 10. A method of treating cancer comprising:a. determining a base radiation therapy plan for a patient that includes a base radiation dosage determined to achieve a maximum benefit to the patient; b. implanting in the patient a biomaterial composition in one or more spaces between a cancerous tissue and an organ at risk achieving one or more spacer distances, the biomaterial composition comprising cerium oxide nanoparticles dispersed within a polymer matrix, wherein the polymer matrix includes a biodegradable hydrogel and the cerium oxide nanoparticles are adapted to catalytically reduce reactive oxygen molecules;c. determining an aggressive radiation therapy plan that includes an increased radiation dosage that is greater than the base plan radiation dosage, the aggressive plan is based on an expected reduced exposure to radiation of organs at risk considering factors including:i. the one or more spacer distances between the cancerous tissue and the organ at risk achieved with the biomaterial composition;ii. the interaction of the biomaterial composition, the radiation dosage, the cancerous tissue, and the organ at risk, resulting in generation of one of more reactive oxygen species; andd. catalytically reducing the reactive oxygen species by the cerium oxide nanoparticles.

11. The method of claim 10, further comprising:a. generating one or more three-dimensional (3D) image of the biomaterial composition that has been implanted in the spaces between the cancerous tissue and the organs at risk.

12. The method of claim 11, wherein the one or more 3D images are generated from a plurality of images from one of more medical imaging techniques selected from the group consisting of x-ray, computed tomography (CT), magnetic resonance, and ultrasound.

13. The method of claim 10, wherein the biodegradable hydrogel includes chitosan and sodium alginate.Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 14. The method of claim 10, wherein the reactive oxygen species include one or more of the group consisting of hydroxyl radicals, hydroxide ions, superoxide anions, and hydrogen peroxides.

15. The method of claim 10, wherein the biomaterial composition includes an additional agent dispersed within the polymer matrix, the agent including one or more of the group consisting of an antibody, a chemotherapy agent, an agent for treating a condition related to radiation therapy, an agent for treating a condition related to chemotherapy, an immunoadjuvant and an antigen.

16. The method of claim 10, wherein implanting the biomaterial composition is performed using an endoscope.

17. The method of claim 10, wherein the biomaterial composition includes about 0.125 mg of cerium oxide per 2.4 mg of hydrogel and the biomaterial composition administered is about 2.4 mg of hydrogel per 1 gm of the cancerous tissue.

18. A method of treating cancer in a patient comprising:a. generating one or more three-dimensional (3D) representations of a cancerous tissue and one or more organs at risk;b. implanting in the patient a biomaterial composition in one or more spaces between the cancerous tissue and the organs at risk, wherein the biomaterial composition comprising cerium oxide nanoparticles dispersed within a polymer matrix, wherein the polymer matrix includes a biodegradable hydrogel and the cerium oxide nanoparticles are adapted to catalytically reduce reactive oxygen molecules;c. assessing the placement of the biomaterial composition, including quantifying one or more spacer distances achieved by the biomaterial composition; d. determining a base radiation therapy plan for a patient that includes a base radiation dosage; ande. determining an aggressive radiation therapy plan of radiation dosage greater than the base plan radiation dosage, the aggressive plan is based on an expected reduced exposure to radiation of organs at risk considering factors including:i. the spacer distances between the cancerous tissue and the organ at risk;Attorney Docket No. : 0184.0307-PCT Client Reference No.: Pl 8608-02 ii. the interaction of the biomaterial composition, the radiation dosage, the cancerous tissue and the organs at risk.

19. The method of claim 18, wherein a first interaction of the radiation dosage and the patient includes a generation of one of more reactive oxygen species and a second interaction includes a catalytic reduction of the reactive oxygen species by the cerium oxide nanoparticles.

20. The method of claim 18, wherein the one or more 3D images are generated from a plurality of images from one of more medical imaging techniques selected from the group consisting of x-ray, computed tomography (CT), magnetic resonance, and ultrasound.

Images