Radiative shear thinning biomaterial compositions and methods of use

Abstract

The present invention is a method and device for treating solid tumors utilizing a shear-thinning biomaterial composition containing a beta or alpha emitting radiation source, a polymer matrix, and / or a radiopaque agent. The novel radioactive composition disclosed herein can be injected into the target environment percutaneously or via a transcatheter vascular route for locoregional treatment. The present invention is comprised of a shear-thinning biomaterial that, when combined with a radioisotope source, can provide a therapeutic dose of radiation locally to the tumor site with minimal risk of damage to surrounding tissues. The device can be used either as a primary tumor treatment or for the treatment of residual cancer cells following resection of the primary tumor. The present invention provides a method for making the shear-thinning radioactive biomaterial composition, as well as a method for utilizing the composition as part of a treatment method.

Description

[Technical field]

[0001] The present disclosure relates to therapeutic radiation and cancer treatment. More specifically, the present disclosure relates to shear-thinning biomaterials that include radioactive materials. [Background technology]

[0002] Radiation therapy has become one of the most important and effective methods for cancer treatment, and can be used alone or in combination with surgery, chemotherapy, and immunotherapy, and is the standard treatment in approximately half of all cancer cases worldwide. Although there are various forms of radiation therapy, treatment generally relies on the use of radioisotopes (also referred to herein as radioisotopes, radionuclides, and radiopharmaceuticals) that serve as ionizing radiation sources. Ionizing radiation delivered to cancerous targets from either external or internal sources causes damage to DNA that can induce apoptosis.

[0003] Depending on the type of cancer, radiation therapy can be used to treat localized cancer, either as a palliative treatment to reduce symptoms, or to limit disease progression in incurable cases. Radiation therapy can also be used as an adjuvant therapy during and after surgery to help eliminate any residual tumor cells.

[0004] External beam radiation therapy is the most widespread form of radiation therapy used in clinical practice and involves the delivery of high energy rays in the form of photon (e.g., X-rays, gamma rays), protons, or particle radiation from outside the body to a specific tumor site. One major drawback of this therapy is the risk of damaging off-target healthy tissue, given the difficulty of directly targeting cancerous tumors via external administration. Furthermore, external beam radiation has limited efficacy for larger tumors and is unacceptable for deep tumors, as external radiation imparts undesirable tissue absorption around the tumor area. As expected, the use of external radiation requires careful attention, as the patient should be positioned in a precise position and the radiation dose should be precise to minimize irradiation and tissue damage to unintended areas of the body. Even with this caution, external radiation can induce skin damage and still result in undesirable tissue absorption around the tumor area.

[0005] To ameliorate these concerns, internal radiotherapy exists as a technique that allows for more localized administration of therapeutic radiation to the tumor, usually using short-range radionuclides placed within the body, adjacent to or directly within the tumor itself.

[0006] Brachytherapy is a type of internal radiation therapy that involves placing a sealed radioactive source adjacent to or within the cancerous tissue. The location where the radioactive source is placed is used to classify the type of treatment, e.g., intracavitary brachytherapy, interstitial brachytherapy, intraluminal / endovascular brachytherapy, or superficial brachytherapy. Brachytherapy delivers radiation at doses of 0.4 to 2 Gray per hour (Gy.h -1 ) is a low dose rate (LDR) with a dose of 2-12 Gy.h -1 is the medium dose rate (MDR) and the high dose rate (HDR) is 12Gy.h -1It can be further classified according to the dose rate applied, using the International Commission on Radiation Units, which states that HDR brachytherapy typically involves temporary placement of a radioactive source, whereas LDR usually involves permanent implantation. In many cases, brachytherapy facilitates the delivery of highly localized radiation doses that cannot be achieved using conventional external beam radiotherapy.

[0007] Some brachytherapy devices and seeds are radionuclides sealed with metal to provide easier handling and delivery. One major drawback of this class of radioactive seeds is that the encapsulated metal absorbs a significant portion of the low energy beta and photon radiation emitted by the contained radionuclides. Thus, the current practice of brachytherapy based on the use of individual encapsulated sources is limited. One problem with permanent brachytherapy seeds is that in certain instances, they may require surgical implantation and removal. In other cases, the metal encapsulation material may remain permanently in the body, with the potential for migration to other parts of the tissue. Strategies to deliver radioactive seeds minimally invasively while preventing migration could improve the practice of this therapy.

[0008] Radioembolization is one method that has been explored for localized, minimally invasive treatment of tumors without migration of the therapeutic vehicle. Radioembolization generally provides a minimally invasive form of internal radiation therapy that involves the delivery of radioactive microspheres as emboli to tumor vasculature to selectively irradiate the tumor. The proximity of the microspheres to the tumor results in the localized delivery of a lethal dose of radiation to the tumor. At the same time, the microspheres cause some degree of embolization by occluding blood vessels and impeding the flow of blood and nutrients to the tumor. However, while radioactive microspheres are the most common mechanism of radioembolization, they face their own drawbacks. For one, radioembolization with microspheres requires vascular access to the tumor, which is not the case in all cases. Also, if vasculature exists in and outside the tumor, there is the possibility of migration of the microspheres to other parts of the body, including backflow to non-target tissues and organs. Furthermore, because the microspheres are delivered in an aqueous medium, the microspheres may settle and / or result in uneven delivery of radioactivity.

[0009] Thus, the two main limitations of current radioembolization strategies are the possibility of radioactive microspheres migrating away from the tumor site or the spheres settling in the liquid dispersion, causing non-uniform irradiation. This disclosure describes the immobilization of radionuclides within a biomaterial. Whether used as an embolus or delivered percutaneously, the radionuclides are immobilized due to the hydrogel mesh size, which prevents the release of the encapsulated particles and the interaction between the radionuclides and the silicate nanoparticles. Furthermore, the viscosity of the material prevents settling, enhancing the homogeneity of the radionuclides throughout the device.

[0010] In other words, embodiments of the present disclosure overcome the limitations of current radioembolization strategies by incorporating a radioactive source into an injectable semi-solid biomaterial. The compositions herein are delivered to the tumor site via intravascular catheters or percutaneous injection, but once extruded into the tumor, have shear-thinning properties that allow them to remain in place in close proximity to the tumor. Furthermore, the biomaterial can function as an embolism that enhances the antitumor effects of radiation, even by restricting blood flow to the tumor. The polymeric composition of the biomaterial is highly stable to radiation, and the incorporation of radioisotopes can enhance current methods of radiation delivery. Summary of the Invention

[0011] The present disclosure describes methods and devices for treating solid tumors utilizing shear-thinning biomaterial compositions that include a beta or alpha emitter radiation source, a polymer matrix, and / or a radiopaque material. The present disclosure relates to biomaterial compositions that include a radioisotope that is delivered to a vascular site via a catheter or injected percutaneously into a tumor site. In one embodiment, the biomaterial composition is used in a novel method for embolizing blood vessels that supply blood to a solid tumor and for providing therapeutic levels of radiation to the blood vessels and / or tissue. In another embodiment, the biomaterial is injected percutaneously into tissue to transfer the radioisotope.

[0012] The present disclosure relates to devices and methods for the treatment of cancer, including liver cancer, kidney cancer, prostate cancer, brain cancer, and breast cancer.Other types of cancer, including lung cancer, bladder cancer, colon cancer, kidney cancer, pancreatic cancer, thyroid cancer, glioblastoma, head and neck cancer, and soft tissue sarcoma, can be treated using the methods and devices described herein.More specifically, the present disclosure relates in some embodiments to devices and methods for the treatment of solid tumors.

[0013] The present disclosure provides various additional advantages. A high energy radiation source combined with a shear thinning biomaterial with favorable viscosity delivers radiation preferentially via catheter or percutaneous injection. Incorporation of radiation via either high energy beta or alpha emitters focuses the zone of radiation exposure in the vicinity of the tumor, reducing radiation levels and risk of damage to healthy tissue. The slow absorption rate of the composition greatly exceeds the half-life of the radionuclide of interest, which advantageously reduces the risk of leakage to other organs and tissues. The slow degradation rate may allow for repeated treatments once the radionuclide has completely decayed.

[0014] The shear thinning biomaterial composition can be injected and remain intact under physiological conditions, confining radiation close to the point of injection. The radionuclide is, in some embodiments, homogeneously mixed in the composition. The composition does not undergo precipitation or rapid decomposition. The presence of silicate and / or tantalum nanoparticles can increase the radiation potential, as described below.

[0015] Advantages of the present disclosure include, but are not limited to, a better therapeutic index given direct local delivery to the tumor target area, higher radiation doses while limiting damage to surrounding tissues, radiosensitization and immobilization of the radionuclide, and more uniform distribution of the radionuclide at the treatment site. The present disclosure provides a method that allows for the treatment of otherwise inoperable tumors by catheter delivery, percutaneous injection, or another suitable delivery mechanism of such embolic compositions.

[0016] Although this disclosure refers to yttrium-90 as the radionuclide, other embodiments of the disclosure may include a variety of radionuclides including, but not limited to, other beta emitters such as phosphorus-32, copper-64, copper-67, iodine-131, lutetium-177, samarium-153, holmium-166, rhenium-186, and rhenium-188. The disclosure also encompasses embodiments that include alpha emitters including, but not limited to, actinium-225, bismuth-213, bismuth-212, thorium-227, radium-223, astatine-211, and terbium-149.

[0017] The present disclosure may contain imaging agents such as contrast agents or speckles. Various examples of imaging materials may be utilized. Radioactive compositions are space-filling semi-solids that retain the radioactive material at the delivery site and prevent migration to healthy tissue. The embodiments of the present disclosure may be used alone as a palliative or curative treatment or in combination with other modalities of cancer treatment. The compositions of the present disclosure may be used with contrast agents, alone or in combination with radiosensitizers to increase the potential of radiation. [Brief description of the drawings]

[0018] [Figure 1A] 1 shows a radioactivity signal of a radioactive shear thinning biomaterial according to an exemplary embodiment, where the shear thinning biomaterial is mixed with a radionuclide. [Figure 1B] 1 shows a photograph of a syringe containing lutetium-177 as a radionuclide after mixing with a shear-thinning polymer composition according to an exemplary embodiment. [Figure 2A] 1 shows a radioactive shear-thinning biomaterial according to an exemplary embodiment in a rabbit liver under ultrasound, where lutetium-177 was incorporated into the shear-thinning biomaterial and delivered percutaneously to the rabbit liver under ultrasound. [Figure 2B]1 shows SPECT / CT images of localized radioactivity of a radioactive shear-thinning biomaterial according to an exemplary embodiment in rabbit liver, where lutetium-177 was incorporated into the shear-thinning biomaterial and delivered percutaneously under ultrasound to the rabbit liver. [Diagram 3] 1 is a whole body image of a radioactive shear thinning biomaterial according to an exemplary embodiment in a rabbit liver under SPECT / CT. The SPECT / CT image shows isolated radioactivity of the shear thinning biomaterial in the delivery area (i.e., the liver). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition The term "a" or "an" may refer to one or more of that entity, i.e., it may refer to a plurality of referents. Thus, the terms "a", "an", "one or more", and "at least one" are used interchangeably herein. In addition, reference to "an element" by the indefinite article "a" or "an" does not exclude the possibility that there is more than one of that element, unless the context clearly requires that there is only one of that element.

[0020] Throughout this application, the term "about" is used to indicate that a value includes the variation of error inherent in the device or method used to determine the value, or the variation that exists between samples measured. Unless otherwise stated or clear from the context, the term "about" means within 10% above or below the reported numerical value (except when such number is greater than 100% or less than 0% of possible values). When used in conjunction with a range or series of values, the term "about" applies to the endpoints of the range or each of the values ​​recited in the series, unless otherwise indicated. As used in this application, the terms "about" and "approximately" are used interchangeably.

[0021] Regarding microsphere therapy, yttrium-90 ( 90Y) Microsphere radioembolization has emerged for the management of patients with liver cancer. This radioembolization procedure has two components: embolization and brachytherapy. 90 Y is a beta emitter with a physical half-life of 64.2 hours or 2.7 days; 90 Up to 94% of the Y-microsphere radiation dose can be delivered during the first 11 days after treatment, after which it decays into stable zirconium. The clinical advantage of beta radiation is the oncologist's ability to prescribe and deliver relatively high doses to the tumor while minimizing dose to adjacent (non-target) healthy tissue. 90 Y is a high energy beta with no primary gamma emission - It is an emitting radionuclide. 90 Yβ - The maximum energy of the particle spectrum is about 2.3 MeV. According to the principle of medical internal radiation dose (MIRD), 90 One gigabecquerel (GBq) of Y provides an absorbed dose of approximately 50 Gy. Based on the stage of the cancer, size and type of tumor, the amount of radiation delivered varies.

[0022] Radioembolization is currently indicated for the treatment of both locally advanced primary and metastatic cancers with the goal of improving survival while preserving quality of life. There are currently two commercially available FDA-approved drugs for use in radioembolization: 90 Y-containing products exist, but such approaches may increase the risk of migration from the treatment area to non-target tissues and organs, may increase the risk of reflux into non-target tissues and organs, and may require delivery to the vascular system to be effective, as outlined above.

[0023] Biomaterials have been developed to allow for more precise targeting of radiation therapy to reduce toxicity to surrounding healthy tissues and increase the efficacy of treatment. These unique biomaterials have been developed from polymers, glasses, and ceramics. Utilizing biomaterials for radiation therapy to either achieve radiosensitization of surrounding tissues resulting in a radiation boost or to deliver nanoparticles that can act as radioprotectors continues to be an area of ​​interest. The incorporation of radionuclides on or within the structure of various biomaterials can facilitate the targeted and sustained delivery of radiation therapy to cancerous tissues. Each radionuclide has its own characteristic energy spectrum and particle emission. Biomaterials can be used to augment current methods of radiation delivery, and in many cases, their use can be integrated into current treatment protocols.

[0024] Of course, a major challenge in radiation therapy is that tumors are often located near normal tissues and organs at risk of radiation damage, limiting the amount of radiation that can be safely delivered to the target tissue. Thus, agents that preferentially sensitize tumors to ionizing radiation, called radiosensitizers, have attracted great interest in radiation oncology. Tantalum-based nanoparticles can play a role in radiosensitization or synergistic cell killing effects for radiation therapy. Tantalum has shown a high ability to attenuate ionizing radiation, such as X-rays, and can enhance the radiation capacity delivered directly to the tumor. Also, silicate nanoparticles can be beneficial as radiosensitizers and radioactivity trapping to limit the radiation dose outside the target tissue. Additionally, silicate nanoparticles provide a means of radionuclide immobilization due to interactions with oxygen atoms of the silicate, which may enhance the ability of our shear-thinning biomaterials to retain radioactivity in the treatment area.

[0025] In view of the above, the present disclosure relates to compositions for delivery to vascular solid tumors via transcatheter administration, percutaneous injection, and the like. The present disclosure relies on the ability of shear-thinning biomaterials to deliver radiation to tumor tissue or vascular sites while remaining intact in the area of ​​placement with a uniform distribution of the radionuclide. For transcatheter delivery of the material, the shear-thinning biomaterials also function as embolic agents, limiting blood flow to the tumor being treated for greater therapeutic efficacy. The composition can be introduced into the tumor or other lesion by needle or catheter system. The composition can fill the cavity or resection site of the tumor or lesion, or embolize the vasculature tumor, or be delivered directly to solid tissue. The slow absorption over the half-life or full effective life of the radioisotope allows for the continuous delivery of radioactivity. The present disclosure allows for the incorporation of chemotherapy / immunotherapy drugs, sensitizing materials, and different delivery methods while preventing leaching of the radioactive source into non-target tissues.

[0026] The present disclosure provides a method of internal radiation therapy that combines a high energy radiation source combined with a shear thinning biomaterial with a preferred viscosity, thereby delivering radiation preferentially via catheters, percutaneous injection, and / or other suitable delivery routes. The incorporation of radiation via either high energy beta or alpha emitters focuses the zone of radiation exposure in the vicinity of the tumor, reducing radiation levels and the risk of damage to surrounding healthy tissue. The slow absorption of the composition greatly exceeds the half-lives of the various radionuclides of interest, which advantageously reduces the risk of leakage to other organs and tissues. The slow degradation may allow for repeated treatments once the radionuclides have completely decayed.

[0027] As shown, the shear-thinning biomaterial composition of the present disclosure can be injected and remain intact under physiological conditions, confining radiation to the injection point. The radionuclide can be mixed homogeneously in the composition. The composition does not prematurely precipitate or decompose. The presence of silicate and / or tantalum nanoparticles can increase the radiation potential. Advantages of the present invention include, but are not limited to, a better therapeutic index given local delivery directly to the tumor target area, higher radiation doses while limiting damage to surrounding tissues, radiosensitization and immobilization of the radionuclide, and more uniform distribution of the radionuclide at the treatment site.

[0028] In one embodiment, the relative location of the radioactive material within the shear-thinning biomaterial composition after mixing with the shear-thinning biomaterial remains unchanged before, during and after flowing (e.g., injecting) the shear-thinning biomaterial. In other words, a uniform distribution of the radioactive material within the shear-thinning biomaterial composition exists before and after implantation and / or during injection into a treatment site.

[0029] According to one embodiment, the compositions of the present disclosure can be tailored by: (1) varying the radionuclide for radiation therapy delivery, including alpha- or beta-emitting radionuclides; (2) controlling viscosity to modulate diffusion into tissues for transdermal delivery and to concentrate the radionuclide and allow retention in the tumor; and (3) incorporating other drugs (e.g., chemotherapeutic and immunotherapeutic compounds) and releasing them in a controlled manner within the target tissue (e.g., tumor).

[0030] In one embodiment, the shear thinning compositions disclosed herein comprise: (1) a high energy pure beta emitter ( 90The therapeutic ratio can be optimized by (1) using a radioactive material (such as β-radioactive β-emitters) such as β-radioactive ...

[0031] The compositions according to the present disclosure are highly stable to radiation, and the incorporation of radioisotopes can enhance current methods of radiation delivery. Additionally, the compositions can incorporate chemotherapeutic or immunotherapeutic agents.

[0032] According to one embodiment, the present disclosure relates to a method for preparing a radioactive shear thinning biomaterial, comprising the steps of: 1) preparing a biomaterial; and 2) mixing the resulting composition with a radioisotope. Thus, the composition of the present disclosure may comprise a biocompatible polymer, synthetic silicate nanoparticles, a biocompatible solvent, and about 0.1 weight percent to about 25 weight percent of a radioisotope having a radioactivity content of about 0.5 microcuries to about 100 millicuries. In one embodiment, the composition may further comprise a non-radioactive imaging agent.

[0033] The biomaterial of the composition may be a mixture of a biocompatible polymer, synthetic silicate nanoparticles, and a biocompatible solvent. The mixture may, for example, contain silicate nanoparticles in a concentration range of 0.1% to 50%, a biocompatible polymer in a concentration range of 0.5% to 20%, and the remainder solvent. Unless otherwise indicated, percentages (%) expressed herein are percent by weight. The mixture may contain silicate nanoparticles in an amount ranging from 0.1% to 0.2% to 0.5% to 1% to 2% to 5% to 10% to 15% to 20% (in other words, a range between any two of the aforementioned values). The mixture may contain biocompatible polymer in an amount ranging from 0.5% to 1% to 2% to 5% to 10% to 15% to 20%.

[0034] The radioactive shear thinning biomaterial may include a mixture of a biocompatible polymer, synthetic silicate nanoparticles, a radionuclide, and a biocompatible solvent. The radioactive shear thinning biomaterial may include, for example, silicate nanoparticles in a concentration range of 0.1% to 50%, a biocompatible polymer in a concentration range of 0.5% to 20%, a radionuclide in a concentration range of 0.1% to 40%, and a solvent as the remainder. The radioactive shear thinning biomaterial may include silicate nanoparticles in an amount ranging from 0.1% to 0.2% to 0.5% to 1% to 2% to 5% to 10% to 15% to 20%. The radioactive shear thinning biomaterial may include, for example, a biocompatible polymer in an amount ranging from 0.5% to 1% to 2% to 5% to 10% to 15% to 20%. The radioactive shear thinning biomaterial may contain, for example, a radioactive nuclide in an amount ranging from 0.1% to 0.2% to 0.5% to 1% to 2% to 5% to 10% to 15% to 20% to 30% to 40%.

[0035] In a preferred embodiment, the amount and radioactivity content of the radioisotope is sufficient to provide a cumulative ionizing radiation dose at the implantation site of about 200 to about 100,000 rads [2 to 1000 Gray (Gy)].

[0036] In a preferred embodiment, the compositions described herein are used to effect necrosis of at least a portion of a solid tumor, such that the compositions are delivered, for example, directly to the solid tumor or to a vascular site selected to be in or near a solid mass tumor, and the amount and radioactivity content of the radioisotope used in the compositions is sufficient to effect such necrosis.

[0037] In one embodiment, the method of the present invention for making a radioisotope composition comprises mixing a shear-thinning biomaterial with a water-insoluble or entrapped radioisotope. In one embodiment, an already activated radioisotope is incorporated into the biomaterial for administration based on a desired dose. In another embodiment, a radionuclide precursor is incorporated into the biomaterial and subsequently activated by neutron bombardment. In another embodiment, the radioactive content is a naturally emitting radioactive content.

[0038] The term radioisotope refers to, e.g. 90 yttrium, 192 iridium, 198 gold, 125 Iodine, 137 cesium, 60 cobalt, 32 Phosphorescence, 52 magnesium, 55 iron, 90 Refers to natural or unnatural radioisotopes conventionally used in nuclear medicine, including only strontium, different cobalt. Other radionuclides currently produced for use in nuclear medicine include, for example: 81 rubidium, 206 Bismuth, 67 gallium, 77 bromine, 129 cesium, 73 selenium, 72 selenium, 72 Arsenic, 103 palladium, 203 lead, 111 indium, 52 iron, 167 thulium, 57 nickel, 62zinc, 61 copper, 123 Contains iodine.

[0039] The biocompatible polymer used in these compositions and methods can be either biodegradable or non-biodegradable, but is preferably biodegradable.Biodegradable polymers have been disclosed in the art.For example, linear polymers such as gelatin, collagen, protein, alginate, agar, polysaccharide, chitosan, polyvinyl alcohol, polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyethylene glycol, and their copolymers, terpolymers and combinations.

[0040] The term contrast agent refers to a biocompatible radiopaque material that can be monitored during injection, e.g., X-ray. Examples of contrast agents include tantalum, tantalum oxide, gold, tungsten, platinum powder, barium sulfate, and Omnipaque® (iohexol).

[0041] In one embodiment, the radioisotope acts as an imaging agent to allow visualization of the composition during catheter delivery. Alternatively, a non-radioactive imaging agent is used in combination with the radioisotope to ensure visualization.

[0042] In one embodiment, a radioisotope with an atomic number high enough to be radiopaque can be used to function as both a radiation source and an imaging agent for detection under fluoroscopy.

[0043] In another embodiment, a separate non-radioactive imaging agent is used in combination with the radioisotope. According to one embodiment, the radioactive composition is a shear thinning composition. Shear thinning is the non-Newtonian behavior of a fluid whose viscosity decreases under strain. In other words, when a certain force (i.e., shear) is applied to such a shear thinning fluid, the fluid flows more easily. This allows the shear thinning composition to be more easily delivered, such as through a catheter, transdermally, etc.

[0044] Additionally, the composition may have mechanical properties similar to those of the tissue adjacent to the composition upon implantation. For example, the storage modulus (G') of the composition may be between 1 kPa and 1 MPa. In some embodiments, the storage modulus (G') of the composition may be between 1 kPa and 100 kPa. In some embodiments, the storage modulus (G') of the composition is between 1 kPa and 40 kPa. As can be appreciated, the mechanical properties of the composition are determined, in part, by the expected mechanical properties of the tissue expected to be adjacent to the implanted composition.

[0045] In embodiments, the composition has a yield stress of about 1 Pa to about 200 Pa. In some embodiments, the composition has a yield stress of about 1 Pa to about 100 Pa. In embodiments, the composition has a yield stress of about 2 Pa to about 50 Pa. In embodiments, the composition has a yield stress of about 1 Pa to about 25 Pa. In embodiments, the composition has a yield stress of about 1 Pa to about 10 Pa. In embodiments, the composition has a yield stress of about 1 Pa to about 5 Pa. In embodiments, the composition flows upon application of a pressure greater than the yield stress.

[0046] In one embodiment, the phase transition properties of the composition are determined by, among other things, the ratio of components in the composition and / or the total solid content of the composition.The ratio of components (e.g., the ratio of oppositely charged polymer and nanoparticle) can affect electrostatic interaction.At the same time, the ratio of components and the total solid content determine the viscoelastic properties of the composition (e.g., how viscosity changes under shear rate and the degree of recovery / reversibility).

[0047] In embodiments in which the composition is integrated with a chemotherapeutic or other drug or biological treatment, the preferred composition may be mixed with the treatment, for example, the composition may be mixed with doxorubicin.

[0048] According to one embodiment, the above compositions can be used in the treatment of solid tumors. In one such treatment, these compositions are used in a method for needle or catheter-assisted embolization of blood vessels. The injection of the shear-thinning composition may be performed intraoperatively or percutaneously. In such a method, a quantity of the composition is introduced into a selected blood vessel via needle or catheter delivery under fluoroscopic guidance, so that the blood vessel is embolized in the case of catheter delivery. In another embodiment, the composition is injected directly into a solid tumor.

[0049] According to one embodiment, the compositions described herein are useful in necrosis of solid tumors, for example, by embolization of blood vessels leading to or within the solid tumor mass. When used to embolize blood vessels, it is preferred that the level of radiation used in the composition is also sufficient to ablate at least a portion of the tumor. Alternatively, the composition can be delivered directly to the solid tumor mass, and the radiation contained therein can be used to effect necrosis of the tumor.

[0050] The compositions described herein can be used as carriers for chemotherapeutic or immunotherapeutic agents that are intended to be delivered for subsequent release to solid tumors.

[0051] In one embodiment of the present disclosure, the shear-thinning biomaterial is suitable for syringe injection through a needle, allowing the hydrogel to infiltrate and deliver a radiation dose to the tumor site, thereby enabling percutaneous delivery of the radionuclide to the tumor site. The high viscosity of the compositions described herein ensures uniformity of the radionuclide delivered throughout the tumor tissue, while keeping the radioactive source confined to the delivery site. This minimizes the chance of radiation affecting surrounding healthy tissue via migration of the radionuclide. EXAMPLES

[0052] Example 1 The purpose of this example is to demonstrate the preparation of a composition according to the present invention. The composition comprises (a) gelatin, (b) silicate nanoparticles, and (c) water. After all the components are mixed, the composition is added to the contrast agent, and the resulting composition is thoroughly mixed by a speed mixer and then allowed to harden. The hardened composition is mixed with a radioisotope.

[0053] Example 2 The purpose of this example is to demonstrate the preparation of a composition according to the present invention. The composition includes (a) gelatin, (b) silicate nanoparticles, and (c) water. After all the components are mixed, the composition is allowed to harden. The hardened composition is mixed with a radioisotope, i.e., lutetium-177. Example 2 is illustrated in Figures 1A-3.

[0054] For example, Figures 1A and 1B show an example of mixing lutetium-177 radionuclide with a biocompatible polymer of the present disclosure as an injectable solid. Figure 1A shows the radioactivity signal of the radioactive shear-thinning biomaterial. Figure 1B shows a photograph of a syringe containing lutetium-177 after mixing.

[0055] Figures 2A and 2B show the radioactive shear-thinning composition in rabbit liver under ultrasound (Figure 2A) or SPECT / CT (Figure 2B). In this figure, lutetium-177 was incorporated into the shear-thinning biomaterial and delivered percutaneously to the liver under ultrasound.

[0056] Figure 3 shows the radioactive shear thinning composition in rabbit liver under SPECT imaging in the context of an intact rabbit. SPECT / CT imaging shows that the radioactivity is sequestered in the area of ​​delivery (i.e., the liver) and does not migrate away from the treatment site.

[0057] Example 3 The purpose of this example is to demonstrate the preparation of a composition according to the present invention. The composition comprises (a) gelatin, (b) silicate nanoparticles, and (c) water. After all components are mixed, the composition is mixed with non-radioactive seeds and the mixture is bombarded to activate it (e.g., by neutron bombardment), activating the radioisotope.

Claims

1. a biocompatible polymer; silicate nanoparticles; Water, A radionuclide, 16. A composition suitable for treating a solid tumor comprising:

2. 2. The composition of claim 1, wherein the biocompatible polymer is selected from the group consisting of gelatin, collagen, alginate, silk, agar, polysaccharides, cellulose, hydroxypropyl methylcellulose, chitosan, polyvinyl alcohol, polylactide, polyglycolide, polycaprolactone, polyanhydrides, polyamides, polyurethanes, polyethylene glycol (PEG), polyhydroxycellulose, polytetrafluoroethylene (PTFE), polylactic acid (PLA), poly-(l)-lactic acid (PLLA), poly(d)-lactic acid (PLDA), agarose, starch, lignin, keratin, polyvinyl alcohol (PVA), and copolymers, terpolymers, and combinations thereof.

3. The composition of claim 1 or 2, wherein the composition comprises from about 0.5% to about 20% (w / w) of one or more of the biocompatible polymers.

4. 4. The composition according to claim 1, wherein the silicate nanoparticles are selected from the group consisting of synthetic silicate nanoparticles (laponite) and natural silicate nanoparticles (phyllosilicates, bentonite, kaolinite, montmorillonite-smectite).

5. The composition of any one of claims 1 to 4, further comprising an imaging agent.

6. The composition of claim 5, wherein the contrast agent is present in an amount of about 10 to about 40% by weight of the contrast agent.

7. 7. The composition of claim 5 or claim 6, wherein the contrast agent is selected from the group consisting of tantalum, tungsten, platinum, gold, and iohexol.

8. The composition of any one of claims 1 to 7, wherein the composition comprises the radionuclide in an amount of about 0.1 to 40 percent by weight.

9. The composition of any one of claims 1 to 8, wherein the radiation dose is adjustable to the particular tumor and patient condition as determined by the physician.

10. The radionuclide is ９０ Y. １７７ Lu, ３２ P. １９８ Au, １２５ I, １３１ I, ６０ Co, １３７ Ce, and １６６ The composition according to any one of claims 1 to 9, wherein the radionuclide is selected from the group of radionuclides comprising Ho.

11. The composition according to any one of claims 1 to 10, wherein the silicate nanoparticles function as a radiosensitizer for the composition.

12. A composition according to any one of claims 1 to 11, comprising a plurality of different radionuclides.

13. A method in which the composition of any one of claims 1 to 12 is delivered into a blood vessel via a catheter to both embolize the blood vessel and cause tumor necrosis.

14. A method, wherein the composition of any one of claims 1 to 12 is delivered transdermally directly to the site of the tumor.

15. A method, wherein the composition according to any one of claims 1 to 12 is used to fill the residual space in a surgically debulked tumor.

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