Microspheres and methods of making and use thereof

Abstract

The present disclosure relates to an imageable microsphere comprising one or more radionuclide precursors, and methods of making and using the same in transarterial radioembolizatrion (TARE). The microsphere is a theranostic. The microsphere provides medical imaging capabilities and emits therapeutic radiation.

Description

WSGR Docket No. 66410-702.601MICROSPHERES AND METHODS OF MAKING AND USE THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 746,457, filed January 17, 2025, which is entirely incorporated herein by reference.BACKGROUND

[0002] Transarterial radioembolization (TARE), also known as Selective Internal Radiation Therapy (SIRT) or radioembolic therapy, is a form of brachytherapy intended for the locoregional treatment of hepatic malignancies. More specifically, TARE is an established treatment for patients with chemo-resistant and unresectable primary and secondary liver cancers, such as hepatocellular carcinoma (HCC) and liver-involved metastatic colorectal cancer (mCRC), and is increasingly being examined for other oncology applications. This procedure may offer targeted treatment that may reduce the size of tumors, relieve symptoms, and prolong survival time for liver cancer patients who have limited treatment options.

[0003] TARE therapy may consist of administering microspheres loaded with beta-emitting radionuclides through a microcatheter positioned in the hepatic artery or its branches. The microspheres may have two mechanisms of action: they partially occlude the distal tumor arterioles that supply blood to the tumor and emit ionizing radiation (beta particles) that causes localized damage to the targeted lesion while sparing the surrounding healthy liver parenchyma from damage.SUMMARY

[0004] The present disclosure provides the design of radioactive microspheres that are imageable and therapeutic, and can be used in TARE or other therapies. The radioactive microspheres can be used to treat tumors in the liver and organs or tissues other than liver. The components of the microspheres can be adjusted or personalized to achieve better therapeutic results for the patients receiving the radioactive microspheres. When using the radioactive microspheres the medical doctors have more control of the treatment by successfully evaluating and confirming the radioactive dosage more accurately than other methods for each patient, and adjusting the radiation dosage accordingly. These radioactive microspheres are theranostics.

[0005] In an aspect, provided is a microsphere, comprising: (i) an aluminosilicate; (ii) yttrium oxide, and (iii) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbiumWSGR Docket No. 66410-702.601(Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb). In some embodiments, the microsphere comprises one or more radionuclides.

[0006] In an aspect, provided herein is a microsphere, comprising an aluminum oxide, a silicon oxide, and one or more radionuclide precursors. In some embodiments, the one or more radionuclide precursors have a mole fraction of at least about 15 mol% and the microsphere is radiopaque.

[0007] In another aspect, provided herein is a method comprising: administering to a subject a plurality of microspheres, wherein a microsphere of the plurality of microspheres is any microsphere or glass composition as disclosed herein.

[0008] In still another aspect, provided is a method comprising: (i) in a treatment planning step: administering to a subject, a first plurality of microspheres; and (ii) in a therapeutic treatment step: administering to the subject, a second plurality of microspheres, wherein a microsphere of the first plurality of microspheres and the second plurality of microspheres is any microsphere or glass composition as disclosed herein.

[0009] In another aspect, provided is a method comprising (a) administering to a subject a microsphere comprising (i) alumina and silica, (ii) yttrium oxide, and (iii) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb), and (b) imaging a body of the subject to identify a location of the microsphere within the body of the subject.

[0010] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.WSGR Docket No. 66410-702.601To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0013] FIG. 1 shows the melted frit and crucible for an example glass formulation Bl.

[0014] FIG. 2 shows the X-ray Diffraction (XRD) spectrum of the microspheres of the example glass formulation Bl.

[0015] FIG. 3 shows the Scanning Electron Microscope (SEM) image of the microspheres of the example glass formulation Bl.

[0016] FIG. 4 shows a representative SEM image of Glass No. 12.DETAILED DESCRIPTION

[0017] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.Definitions

[0018] The singular forms “a,” “an,” and “the”, as used herein, include the plural reference unless the context clearly dictates otherwise.

[0019] When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range is encompassed within the scope of the present disclosure. Where the stated range includes upper or lower limits, ranges excluding either of those included limits are also included in the present disclosure.

[0020] When the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series ofWSGR Docket No. 66410-702.601numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0021] When the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0022] As used herein, the term “substantially” generally refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.

[0023] As used herein, the term “substantially depleted” regarding isotope abundance generally refers to a particular isotope having less than 10% or less than 5% or less than 1% of relative to the natural abundance of the same isotope. For example, if the natural abundance of isotope A is 10% weight / weight (wt / wt) of an element B, then a substantially depleted level of isotope A is less than 1% or less than 0.5% or less than 0.1% wt / wt of element B.

[0024] The term “subject,” as used herein, generally refers to an individual who is in need of a therapy. The subject may be a mammal or non-mammal. The subject may be human, nonhuman mammal, animal, ape, monkey, chimpanzee, dog, cat, bird, reptilian, amphibian, avian, or a plant.

[0025] As used herein, the term “radionuclide” generally refers to an atom with excess nuclear energy making it unstable and that undergoes radioactive decay. Radionuclides are also known as radioactive nuclides, radioisotopes, medical isotopes, or radioactive isotopes.Radioactive decay may produce a new stable nuclide, or a new unstable radionuclide, which may undergo further decay. The term “parent radionuclide,” as used herein, refers toa radionuclide that may decay into a new radionuclide, or “daughter radionuclide”. Examples of parent radionuclides and their daughter radionuclides may include Mo-99 / Tc-99m, Ge-68 / Ga-68 and W-188 / Re-188, among other pairs. In some cases, the “radionuclide” may refer to a parent radionuclide. In some cases, the “radionuclide” may refer to a daughter radionuclide.

[0026] As used here, the terms “theranostic,” “theragnostic,” and “theranostics” generally refer to an integration of therapeutics and diagnostics in a single management approach allowing an image-guided therapy and defining of treatment outcome at an early stage. These terms describe a material that combines the modalities of therapy and diagnostic imaging.

[0027] As used herein, the term “microsphere” generally refers to nanospheres (with nanometer dimension(s)), microspheres (with micrometer dimension(s)) and also largerWSGR Docket No. 66410-702.601microsphere-like particles. Nanospheres generally have a diameter of 1000 nanometers (nm) or less. In some embodiments, the microsphere is about 1 micrometer (pm) to 5000 pm, 10 pm to 2000 pm in diameter, or about 100 pm to 4500 pm in diameter, as characterized by electron microscopy, such as scanning electron microscopy (SEM). In some embodiments, the microsphere is from about 40 to about 250 pm in diameter. In some embodiments, the microsphere is about 45 to 100 pm in diameter. In some embodiments, the spheres can be up to about 0.5 millimeters (mm), 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, and 4.5 mm in diameter.

[0028] As used herein, the term “sphere” generally refers to a particle that is substantially, although perhaps not exactly, spherical and further refers to both beads and bubbles.

[0029] As used herein, the term “bead” generally refers to a solid particle that is substantially, although perhaps not exactly, spherical. The microspheres disclosed herein can be beads.

[0030] As used herein, the term “bubble” refers to a hollow particle that is substantially, although perhaps not exactly, spherical. The microspheres disclosed herein can be bubbles.

[0031] As used herein, the term “glass” generally refers to a noncrystalline material exhibiting glass transition behavior, and whose principal phase(s) is primarily amorphous, such as at least 50% amorphous, at least 75% amorphous, at least 90% amorphous, at least 95% amorphous, or at least 97% amorphous by volume. In some examples, a glass according to the present disclosure is substantially free or completely free of identifiable crystalline species. The microspheres disclosed here can be glass microspheres.

[0032] As used herein, the term “glass-ceramic” generally refers to an inorganic, metal oxide formed initially as a glass that is subsequently devitrified or otherwise made a glassceramic by thermal treatment such that it exhibits an at least partially crystalline phase and optionally some residual glass phase. The microspheres disclosed here can be glass-ceramic microspheres.

[0033] As used herein, the term “devitrify” generally refers to converting at least partially from a glassy state to a crystalline state.

[0034] As used herein, the term “mole fraction” or “molar percentage” (mol%) refers to the number of moles of a given component in a composition divided by the total number of moles in the composition, then displayed as a fraction or percentage when appropriate. A formula of a glass composition (e.g., a glass microsphere composition) can be expressed by listing the percentage of each oxide constituent present in the glass composition, usually given as a molarWSGR Docket No. 66410-702.601percentage (mol%) or mole fraction which indicates the relative number of moles of each oxide within the total glass composition.

[0035] As used herein, the term “imageable” generally refers to a property of the microspheres disclosed herein that can be detected by an imagery device. The imagery device can be computerized tomography (CT), cone-beam computed tomography (CBCT), positron emission tomography (PET), intra-procedural angiography, x-ray fluoroscopy, magnetic resonance imaging (MRI), ultrasound, or single-photon emission computed tomography (SPECT), or others.

[0036] As used herein, the term “durable” when describing a microsphere generally refers to a property of the microsphere what is physically robust, stable to temperatures at or more than 500 °C, and does not exhibit damage (e.g., damage is no more than 1% activity leaching) after exposure to high flux neutron irradiation conditions (cp is no less than 1 x 1014n / cm2,s for a duration of time of no less than 24 h) in a nuclear research reactor.Passive Embolization

[0037] Passive embolization is a procedure that attempts to block blood vessels feeding tumors or abnormal tissues. In this approach, blood vessels which nourish a tumor are deliberately blocked by injection of an embolic material into the vessels. The embolic material includes but is not limited to, autologous substances such as fat, blood clot, and chopped muscle fragments, artificial materials such as wool, cotton, steel balls, plastic or glass beads, tantalum powder, silicone compounds, sterile absorbable gelatin sponge, oxidized cellulose, steel coils, alcohol, lyophilized human dura mater, microfibrillar collagen, collagen fibrils, polyvinyl alcohol sponge, barium-impregnated silicon spheres and detachable balloons. The obstruction of tumor blood supply, with the simultaneous disruption in nutrient supply and waste removal, may help the destruction of the tumor cells. After the passive embolization, the size of tumor metastases may be temporarily decreased, but tumors may respond by causing the growth of new blood vessels into the treated tumor. Passive non-radioactive or radioactive embolization can treat conditions such as cancer, uterine fibroids, and chronic prostatitis. In some embodiments, the non-radioactive microspheres and / or radioactive microspheres disclosed herein may be used in passive embolization of blood vessels as microspheres. In some embodiments, the non-radioactive microspheres and / or radioactive microspheres disclosed herein may be used to treat arteriovenous malformations, hypervascular tumors. In some embodiments, the non-radioactive microspheres and / or radioactive microspheres disclosedWSGR Docket No. 66410-702.601herein may be used in prostate artery embolization, uterine fibroid embolization, treatment of meningiomas, or occlusion of vascular anomalies.Active Embolization

[0038] Therapeutic vascular occlusions (or embolization) may treat certain pathological conditions in situ. Catheters may be used, under imagery control, to position particulate occlusion agents (or emboli) in the circulatory system of a subject. In the case of tumors, vascular occlusion can suppress pain, limit blood loss on the surgical intervention to follow embolization or even bring on a tumoral necrosis and avoid the operation.

[0039] Different types of emboli include but are not limited to, liquid agents (e.g., acrylic glues, gels, viscous suspensions), particulate agents (e.g., polymers, dura mater, gelatin sponges, spheres, balloons, spirals). The dual functions of the regional distribution of drugs to and the minimization of loss from the target site can be achieved with microspheres. When introduced via a regional artery, such microspheres can be trapped within the vasculature of tissues, where they may release their drug load. Such dual action is referred to as active embolization.Microspheres may be of either a solid or porous composition, and can be made to contain dispersed drug molecules either in solution or solid form. In some embodiment, both the radioactive microspheres and the non-radioactive microspheres disclosed herein may be used in combination of a therapeutic drug. In some embodiments, the drug may be a chemotherapy drug, a gene therapy drug, a small molecule drug, a biological drug (e.g., an antibody, a cell), a peptide, a hormone or steroid, or a peptide or peptide analog.Radioembolization

[0040] Radioembolization is a minimally invasive treatment that delivers radiation directly to cancerous tumors (e.g., liver cancer) by injecting radioactive beads called microspheres into tumor's blood supply. The microsphere can be as small as about one-third the diameter of a human hair, or other dimensions. Over a period of several days, the microspheres emit high energy radiation to shrink the tumor. This transarterial therapy strategically attacks tumors with localized, high doses of radiation. Radioembolization may also be called intra-arterial brachytherapy, selective internal radiation therapy, targeted radiation therapy, or Y-90 treatment (using yttrium-90 as the radioactive element). In some embodiments, the radioactive microspheres (or beads) and / or the non-radioactive microspheres (or beads) disclosed here may be used in passive embolization of blood vessels.WSGR Docket No. 66410-702.601Commercially available microspheres

[0041] Therapeutic microspheres used in TARE may contain a single radioactive isotope, such as, for example, yttrium-90 or holmium-166. There are two types of therapeutic microspheres commercially available for clinical use in TARE (Table 1).Table 1. Characteristics of example radioactive microspheres used clinically in TARE.

[0042] TheraSphere® and SIR-Spheres® may be some of the examples. TheraSphere® may consist of aluminosilicate glass microspheres impregnated with yttrium oxide; the therapeutic radionuclide yttrium-90 (90Y, t’A = 64.1 h) may be formed by placing the microspheres in a nuclear reactor, where thermal neutrons may elicit the89Y(n,y)90Y nuclear transformation. SIR-Spheres® may be cation exchange resin microspheres wherein90Y is adsorbed onto the surface of the microspheres via ion-exchange.

[0043] Each clinically available TARE microsphere may have unique limitations due to its physical properties and selected radionuclide production process, respectively.

[0044] The therapeutic radionuclide in SIR-Spheres may not be generated in situ via neutron activation; instead, SIR-Spheres may be produced by radiolabeling a polymer substrate with90Y obtained from a90Sr / 90Y radionuclide generator. Due to the nature of the labeling process, a limited amount of90Y can be loaded onto the surface of each microsphere, resulting in very low specific activity microspheres (~50 Bq / sphere). This may limit their clinical use, as a much larger number of microspheres may be required to impart the same radiation dose compared to TheraSphere®. In consequence, SIR-Spheres may be limited to treating patients who require low therapeutic doses (Gy / kg) of radiation, rather than the full spectrum of individuals with hepatic malignancies.

[0045] Glass microspheres may be a good carrier for radionuclides. For example, an aluminosilicate glass matrix may be resistant to thermal and radiation-induced damage, enabling it to withstand neutron bombardment in a high flux environment. This in turn enables microspheres to reach higher specific activities (-2,500 Bq / sphere), with no significant post-WSGR Docket No. 66410-702.601suspension degradation en route to the clinic. Using microspheres with higher specific activity may create a larger utilization window (i.e., shelf-life) compared to the lower specific activity microspheres SIR-Spheres. The higher specific activity may also provide clinicians with more flexibility in dosimetry and mass of material administered, allowing them to fine-tune the treatment to individual patient needs.

[0046] A combination of microspheres having different half-lives and / or different energies can be desirable and beneficial. Firstly, the advantage of having isotopes with extremely short half-lives (e.g., no more than a day or two) may permit the inclusion of elements that may provide CT contrast but may have decayed substantially by the time of administration, thereby allowing for personalized dosimetry. Secondly, another variation is to provide microspheres containing combined isotopes with variable therapeutic half-lives to further allow optimization of procedures. Thirdly, providing a combination of microspheres with variable energies allows treatments to be tailored specifically to different tumor types, sizes, and locations. This tunability of the disclosed microspheres make them a better choice for personalized dosimetry.The need for theranostics

[0047] TARE has traditionally served as a palliative treatment; however, an increasing prevalence of cancer, an increasing demand for minimally invasive treatment options, as well as recent strides in patient-specific dosimetry models and software have raised a demand for its use as a curative treatment therapy across all stages of disease. These “personalized medicine” approaches may facilitate individualized treatment plans tailored to each patient and their unique anatomical measurements and treatment goals. This enhanced precision may enable the administration of maximum tolerable radiation doses (maximum threshold dosimetry) to the tumor while limiting exposure to the surrounding healthy tissue, resulting in improved tumor response and patient outcomes. However, a shift towards personalized dosimetry demands a high level of accuracy in both treatment planning and in microsphere administration. This can be achieved if the biodistribution of the microspheres can be monitored precisely and accurately during administration to the patient.

[0048] The treatment planning procedure can occur 1-3 weeks prior to the treatment and involve the use of an imageable diagnostic surrogate particle, or scout dose, to simulate the treatment. This pre-treatment procedure can be a crucial step in assessing both intra- and extrahepatic microsphere distribution, identifying contraindications for treatment, confirming patient eligibility, and planning the prescribed activity for the subsequent treatment.Traditionally in TARE, treatment planning has been conducted using technetium-99m labelledWSGR Docket No. 66410-702.601macroaggregated albumin (99mTc-MAA). The radionuclide "mTc (ty2= 6.0 h; Ey= 140 keV, 89%) is considered the gold standard for SPECT imaging, with more than 40 million diagnostic procedures conducted worldwide every year due to its low cost, near-ideal nuclear properties, and short half-life, which allows sufficient time for radiopharmaceutical production and imaging without imparting unnecessary radiation dose to the patient. "mTc-MAA is a biodegradable radiotracer comprised of macroaggregated albumin particles intended for use as a diagnostic tool for evaluating pulmonary regional perfusion; however, it is also used off-label as a scout dose for patients prior to TARE, enabling visualization of the intra- and extrahepatic particle distribution. "mTc-MAA particles have a density of 1.1 g / mL and a broad size range of 10-150 pm, with more than 90% of particles falling within 20-70 pm and a mean particle size of approximately 20-40pm. Typically, "mTc-MAA is administered in a dose of approximately 350,000 particles, although this can vary anywhere from 200,000 to 700,000 particles depending on the treatment case. See, A. S. Pasciak et al., “Treatment planning part II: Procedure simulation and prognostication,” Handb. Radioembolization, no. 11822, pp. 53-61, 2016.Synergy Spheres II may permit same-day on-table workup, treatment, intra-procedural feedback, and post-procedural feedback on distribution and dosing.

[0049] When comparing the properties of "mTc-MAA diagnostic / scout dose to the therapeutic microspheres used in TARE, it is evident that despite having a similar mean particle size to the therapeutic microspheres, "mTc-MAA has a different overall particle size range, density, and number of particles administered, rendering it a non-ideal surrogate for treatment planning. For example, "mTc-MAA has been shown to overestimate lung shunting, thereby resulting in erroneous curtailment of prescribed activity to some patients, while excluding others who would benefit from access to this therapy. As such, there is an opportunity for the development of new scout doses capable of providing a more accurate and precise depiction of therapeutic microsphere distribution, a pre-requisite for effective personalized treatment plans.

[0050] "mTc-MAA was the primary surrogate particle used in TARE until recently, when the166HO product Quirem Spheres® received European regulatory approval in 2015.Quirem Spheres® was the first TARE device designed for accurate treatment planning, as the therapeutic radionuclide166Ho has a low-intensity photon (Ey= 80.6 keV, 6.56%) that enables imaging of the microspheres using a standard SPECT camera. The introduction ofQuirem Spheres® was accompanied by QuiremScout®, a new166Ho scout dose, which is simply a smaller dose (250 MBq) of the166Ho therapeutic microspheres. Thus, in166Ho TARE, the microspheres used for both treatment planning and therapy are identical aside from the number of microspheres administered and their specific activity. The166Ho microspheres have a particleWSGR Docket No. 66410-702.601size distribution of 15-60 m (mean diameter of 30 pm), and a density of 1.4 g / mL, such that the approximate number of microspheres administered per GBq is 10 x 106. Accordingly, there are approximately 2.5 x 106microspheres administered in a 250 MBq dose of QuiremScout®, whereas the number of microspheres delivered for treatment varies depending on the desired absorbed dose to the tumor. Although SPECT images obtained from166Ho exhibit inferior spatial resolution, sensitivity, and contrast recovery compared to "mTc scans, the 250 MBq dose of QuiremScout® microspheres may permit imaging of microsphere biodistribution.Additionally,166Ho microspheres can be visualized on magnetic resonance imaging (MRI) due to the highly paramagnetic nature of holmium. The improved dosimetric accuracy that arises from using the same microspheres for simulation and treatment can support more accurate patient screening and increased clinical benefit for patients. For instance, with a true representation of therapeutic microsphere biodistribution, clinicians can be more aggressive with their treatment plans, delivering maximum tolerable doses to the tumor with an enhanced confidence that surrounding tissue will not be harmed. The congruence between scout and therapeutic microspheres is valuable in promoting the use of166Ho TARE; however, Quirem Spheres® are limited by the production challenges.

[0051] The quantitative imaging of TheraSphere® and SIR-Sphere® using conventional imaging techniques is non-trivial. Neither TheraSphere® nor SIR-Spheres® is visible using MRI or CT imaging, as they do not contain paramagnetic components or components with sufficient electron density to create X-ray contrast, respectively. Moreover, unlike166Ho,90Y decays without emitting gamma photons suitable for imaging by SPECT. Nonetheless, it emits high energy beta particles that generate a broad and continuous spectrum of secondary X-ray photons called bremsstrahlung, which can be imaged on SPECT systems. However, due to the continuous energy spectrum and lack of a distinct photopeak, bremsstrahlung SPECT imaging may pose a challenge. Alternatively, a small fraction of the90Y decay results in positron emissions (via pair production) that can be reconstructed by PET detectors, but the low positron yield (1 per 0.003% of disintegrations, ~32 ppm) complicates quantification especially in the presence of high-energy bremsstrahlung emissions. Although advancements in PET scanners over the recent years (e.g., adopting time-of-fhght (TOF) algorithms, hardware, and image reconstruction software developments) may have made post-treatment90Y dosimetry and treatment verification technically possible, the very low count rate may make images prone to deterioration by Poisson noise and accurate detection of small activity levels difficult.WSGR Docket No. 66410-702.601Theranostics comprising90Y and a radiopacifying agent

[0052] A new paradigm for TARE microsphere technology may arise from the development of90Y microspheres comprising a radiopacifying agent. A radiopaque and radioactive microsphere may have the innate capability to act as both a diagnostic marker and a therapeutic agent, permitting real time tracking of microsphere distribution during administration. This may contribute to individualized treatment, improve real-time prediction of response and toxicity, and eliminate costs associated with unnecessary post-treatment diagnostic examinations. These advances in TARE may exhibit both the potential clinical utility and benefit to patients of a fully imageable radioactive microsphere, and the need for a new generation of imageable TARE therapeutics that are specifically designed to meet clinician needs.

[0053] At present, therapeutic TARE microspheres (i.e., radioactive microspheres) can be imaged by positron emission tomography (PET) and / or single-photon emission computed tomography (SPECT), however, neither is the ideal imaging modality for TARE administration. While SPECT has high sensitivity capable of detecting levels of radioactivity that exceed background levels by as little as 2.4- to 1-fold, it also has low resolution and lacks anatomical information compared to alternative imaging techniques such as computerized tomography (CT) or magnetic resonance imaging (MRI). Additionally, because SPECT scan acquisition times are typically in the order of 10-30 minutes, respiratory motion throughout the scan has been reported to result in artifacts and misregistration of activity around the diaphragm.

[0054] MRI has remarkable soft tissue contrast and, at high levels of high temporal and spatial resolution, provides detailed functional and anatomical information. Since MRI relies on differences in susceptibility rather than radioactivity, it can be used to image the biodistribution of decayed microspheres well beyond the time of therapy, unlike SPECT imaging. However, susceptibility artifacts in MRI, particularly around air-containing organs like the lungs and intestines, hinder dose assessment. Furthermore, MRI and PET do not permit intraoperative dosimetry due to long acquisition times and because these scanners are not typically available in-room. Thus, to acquire an interoperative PET or MRI image, the patient must be transported to an imaging suite during administration of the radioactive microspheres, which is far from ideal.

[0055] To optimize accuracy and precision in TARE, further advances in microsphere imaging are desired. For example, real-time tracking of the microsphere administration during both the treatment planning and therapeutic procedures would give the clinician direct and actionable feedback, increased control over the procedure for immediate adjustment of treatment parameters and confirmation of microsphere delivery to optimize and verify dosimetry.WSGR Docket No. 66410-702.601Furthermore, real-time imaging would provide the opportunity to combine the scout and therapeutic dose in one single out-patient procedure, resulting in less stress to patients and costsavings for the healthcare system. Currently, none of the particles used in TARE are imaged in real-time during administration because the scan durations for nuclear imaging and MRI are typically in the order of 15-30 minutes. Although the localized and concentrated deposition of activity characteristic of TARE procedures may permit good quality images after only 5-10 minutes, imaging during treatment would still require a planar scintigraphy, SPECT, SPECT / CT, PET, or MRI scanner to be available in the interventional radiology (IR) suite. This may not be ideal due to the inconvenience of additional bulky equipment in the IR suite, the cost associated with dedicated SPECT, PET, or MRI scanners solely for the IR suite, and potentially limited access to shared equipment used outside the IR suite. As such, having a microsphere that can be visualized using intra-procedural angiography or x-ray fluoroscopy, CT, or cone beam computed tomography (CBCT) would be of extreme value, as this imaging equipment is readily available in the IR suite.Radioactive materials

[0056] In addition to the two radionuclides currently used for TARE (Y-90, Ho- 166), there are several other beta emitting radionuclides that may demonstrate therapeutic abilities. For example, lutetium-177 is already approved by the US FDA and other regulatory bodies for clinical use in two different chemical forms: Lutathera (neuroendocrine tumors) and Pluvicto (prostate cancer), and is under investigation for treating a wide range of other malignancies. Several chelated forms of samarium- 153 may treat bone metastases from common primary tumors; Sm-153 may be used clinically. Rhenium-188 may be used as the cancer therapy Rhenium-SCT (non-melanoma skin cancer) and may be used as the active component in radi opharm aceuti cal s .

[0057] Radiopharmaceuticals containing rhenium-186 may be used in clinical studies.Dysprosium- 166 (t’A = 81.6 h) is a short-range therapeutic itself (Epmax = 0.399 MeV) but may decay spontaneously to Ho- 166; it may be used to increase the effective half-life of Ho- 166 in targeted and colloidal radiopharmaceuticals. Terbium-161 may display similar nuclear properties to Lu-177 with additional emission of Auger electrons which may impart additional therapeutic efficacy. Radionuclides of praseodymium (Pr-142, 143), promethium- 149, and rhodium- 105 may demonstrate therapeutic ability in preclinical studies.

[0058] In some embodiments, the radionuclide may comprise one or more of Y, Ho, Yb, Rh, Pr, Lu, Sm, Dy, Re, and Au.WSGR Docket No. 66410-702.601

[0059] The radionuclide may be administered in a pharmaceutically acceptable form. The form may also be capable of remaining at the site of application for a controlled length of time, in combination with a means for control of local delivery. For example, the radionuclide could be in the form of an element, an inorganic compound, or an organic compound.Radiopacifying agents

[0060] There are several options for the radiopacifying agent accompanying the radioactive materials in the imageable microspheres. For example, neodymium is a chemical element found within the lanthanoid group. Like other elements with an atomic number of about 50 or greater, neodymium is able to impart CT contrast to materials due to its relatively high electron density. Neodymium is a typical lanthanoid element: under ambient conditions it has a preferred oxidation state of +3, exhibits a coordination number ranging from 6-12, and has an affinity for “hard” Lewis Base donor atoms like oxygen. The coordination behavior of neodymium is similar to that of yttrium, which enables neodymium (III) oxide (Nd2Ch) to be incorporated into glasses much like yttrium oxide (Y2O3). However, neodymium’s greater atomic number (60) compared to yttrium (39) is superior for inducing CT contrast in the resulting glass.

[0061] In nature, neodymium is found as a mixture of seven different stable isotopes (Nd-142, 143, 144, 145, 146, 148, and 150) with differing relative abundances. The relative abundances of neodymium isotopes are:142Nd (27.15%),143Nd (12.17%),144Nd (23.80%),145Nd (8.29%),146Nd (17.19%),148Nd (5.76%), and150Nd (5.64%). See Meija, J., et al. (2016) Atomic Weights of the Elements 2013 (IUPAC Technical Report). Pure and Applied Chemistry, 88(3), 265-291. When considering the use of neodymium in a radioembolic microsphere, this may be problematic because several of these isotopes have non-zero neutron capture cross-sections, meaning that when the glass comprising neodymium oxide is exposed to a neutron flux to generate the therapeutic radionuclide (e.g., Y-90), the process may also generate radioisotopes of neodymium.

[0062] The neutron activation byproducts of neodymium are summarized in Table 2. While two of these radionuclides (Nd- 149, Nd-151) are so short-lived that they may decay to background levels before the glass reaches the processing laboratory, their respective decay products (Pm- 149, Pm- 151) will remain as contaminants within the glass matrix. Similarly, the Nd- 146 activation product Nd- 147 and its decay product Pm- 147 will remain present within the glass. However, if these three heavier isotopes (Nd-146, Nd-148, and Nd-150) of neodymium are substantially absent from the neodymium oxide stock material that is used to generate the glass, then the formation of these incidental activation products (e.g., the neutron activationWSGR Docket No. 66410-702.601products ofNd-146, Nd-148, Nd-150 areNd-147, Pm-147, Nd-149, Pm-149, Pm-151, etc.) can be substantially avoided, while retaining the CT contrast capability provided by the neodymium. The second generation of TARE microspheres (“Synergy Spheres II”) may use a radiopacifying agent, and may use selectively enriched neodymium (“light neodymium”) as the radiopacifying agent with substantially depleted levels of the three heavier isotopes. That is, the selectively enriched neodymium comprises substantially lower concentrations ofNd-146, Nd-148, and Nd-150 below their respective natural levels, preferably to no more than 0.5 % of the total neodymium mass (for the total concentration of these three heavier isotopes). The majority of the selectively enriched neodymium is therefore Nd-142, Nd-143, Nd-144, and Nd-145. In some embodiments, Synergy Spheres II may not use a radiopacifying agent.Table 2. Neutron activation products of natural neodymium.

[0063] Neodymium is not the only lanthanoid metal that can be used in this way. Several other neighboring elements with similar chemical properties and electron densities can also be used to induce CT contrast. These lanthanoid metals can also comprise substantially depleted levels of certain natural stable isotopes such that the remaining levels of the isotopes generate substantially lower radioactive impurities during production of the therapeutic Y-90. Some candidates of these lanthanoid metals are shown in Table 3, with details on which naturally occurring isotopes may be substantially depleted or enriched when used in Synergy Spheres II Table 3. Lanthanoid metals as radiopacifying agents: Nd, Sm, Dy, Er, and Yb.WSGR Docket No. 66410-702.601

[0064] Rhodium oxide and lead oxide can be radiopacifying agents as well. They can be imageable by CT.

[0065] For an f-block element, such as neodymium (also including Dy, Sm, Er, etc.), an electromagnetic approach can be used to separate the isotopes of the f-block element. A moving stream of the natural chemical element can be exposed to strong magnetic fields - since Nd- 150 is heavier than Nd-148 (for example), it has more momentum than Nd-148, and its movement path may be less affected by the “pull” of the magnet. This provides a basis for separating isotopes of different masses of the same element. The process is usually called Electromagnetic Isotope Separation (EMIS), or electromagnetic enrichment. For example, a device called “Calutron” may be used to separate isotopes of an element based on their mass. The Calutron works by using electromagnetic fields to deflect the differently-massed ions along different paths, allowing for collection of the desired isotope. See Yergey AL, Yergey AK. Preparative scale mass spectrometry: A brief history of the calutron. Journal of the American Society for Mass Spectrometry 1997, 8 (9), 943-953.

[0066] In some embodiments, the radiopacifying agent may comprise one or more of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb).

[0067] In some embodiments, the radiopacifying agent may comprise one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb). In some embodiments, the radiopacifying agent may comprise one or more oxides, one or more carbonates, and / or one or more chlorides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb), or a combination thereof.

[0068] In some embodiments, the one or more of the radionuclides may be present in the microspheres as non-radioactive radionuclide precursors. In some embodiments, the radionuclide precursor(s) (e.g., oxides of the one or more stable isotopes that generates aWSGR Docket No. 66410-702.601radionuclide after neutron activation) in the glass microspheres may have sufficient radiopacity such that no additional radiopacifying agent may be needed.Radioactive and imageable microspheres

[0069] The present disclosure presents a microsphere matrix comprising one or more radionuclides. The radionuclides include but are not limited to: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au. The microsphere matrix may have multi-modal imaging capabilities. In some embodiments, the one or more of the radionuclides may be present in the microspheres as nonradioactive radionuclide precursors. In some embodiments, a non-radioactive radionuclide precursor may comprise an oxide of the radionuclide. In some embodiments, a non-radioactive radionuclide precursor may comprise a chloride of the radionuclide. In some embodiments, a non-radioactive radionuclide precursor may comprise a carbonate of the radionuclide. In some embodiments, a non-radioactive precursor may become radioactive when activated (e.g., neutron activation).

[0070] In some embodiments, the second generation of TARE microspheres (“Synergy Spheres II”) may possess a unique and powerful set of advantages in the field of TARE as shown in any or combination of the following attributes:

[0071] (1) Synergy Spheres II may be microspheres (including glass microspheres and glassceramic microspheres) comprising a mixture of element oxides, including but not limited to silicon oxide, aluminum oxide, and yttrium oxide. In some embodiments, the microspheres may further comprise a radiopacifying agent as disclosed herein. In some embodiments, the microspheres may not comprise a radiopacifying agent. These element oxides may be physically robust, stable to temperatures > 500 °C, and may not exhibit substantial damage (as used herein, the term “substantial damage,” generally refers to more than 5%, preferably more than 2%, and more preferably more than 1% activity leaching over the duration of one half-life) after exposure to high flux neutron irradiation conditions (as used herein, the term “high flux,” generally refers to (p > 1 x 1014n / cm2»s for a duration of t > 24 h) in a nuclear research reactor. In some embodiments, the microspheres may comprise chemical elements other than silicon, aluminum, yttrium, and oxygen.

[0072] (2) Synergy Spheres II may be a microsphere family designed to enable fully personalized TARE treatments by making a therapeutic radionuclide (or in a radionuclide precursor form) in combination with a radiopacifying agent available to clinicians. Synergy Spheres II may be the first microspheres to contain both a radioactive element for therapy and a non-radioactive but imageable element for diagnostics. Providing a radioactive isotope, such asWSGR Docket No. 66410-702.601yttrium-90, and a non-radioactive but imageable element, such as neodymium oxide or another radioactive element, may provide flexibility in the imaging capabilities of the microspheres. Synergy Spheres II may provide optimal dosimetric flexibility to clinicians, enabling treatment of smaller lesions with less damage to healthy tissue.

[0073] (3) Synergy Spheres II may offer multi-modal imaging capabilities. They can be imaged by CT and CBCT, which may permit real-time imaging and intraoperative dosimetry as CT is the imaging modality already present in the IR suites where TARE administration takes place. This feature may provide clinicians with real-time feedback on microsphere biodistribution during administration, enabling the medical professionals to make informed decisions and adjust the treatment plan as necessary, ensuring accurate and optimal radiation delivery. Real-time imaging may also provide the opportunity to combine the scout and therapeutic dose in one single out-patient procedure, saving on costs and reducing patient stress. Certain Synergy Spheres II formulations may also be imageable using other standard clinical modalities, such as, for example, MRI, ultrasound, and SPECT.

[0074] (4) Synergy Spheres II may be theragnostic microspheres with the capability to act as a diagnostic tool and a therapeutic agent at the same time and / or in the same or similar configuration in terms of chemical composition and physical attributes (except for the radiation intension and capacity). By employing advanced targeting techniques and customized dosimetry models, selective delivery of the maximum tolerable radiation dose to the tumor may be accomplished, while minimizing the impact on healthy parenchyma. This may ensure effective tumor control while reducing potential complications for patients.Synergy Spheres II

[0075] As disclosed here, there are different compositions for Synergy Spheres II. For example, some non-exclusive compositions of Synergy Spheres II include the following designs from which multiple products can be made:

[0076] (1)90Y based therapeutic microsphere or theranostic microsphere in combination with a radiopacifying agent, optionally with the potential inclusion of alternative radionuclides in the same matrix;

[0077] (2) A portfolio of therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au, in combination with a radiopacifying agent.

[0078] (3) Therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Sm, Dy, Re, and Au, with a high radionuclide content;WSGR Docket No. 66410-702.601

[0079] (4) Therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au, with a high radionuclide content, and one or more dopant materials;

[0080] (5) Therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au, and a coating of one or more radiopacifying agent;

[0081] (6) Therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au, and a metallic coating; and

[0082] (7) Therapeutics or theranostics based on one or more of the radionuclides from the following list: Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au, with a high radionuclide content, and a coating of one or more radiopacifying agent.

[0083] In some embodiments, the one or more of the radionuclides may be present in the glass microspheres as non-radioactive radionuclide precursors. In some embodiments, a nonradioactive radionuclide precursor may comprise an oxide of the radionuclide. In some embodiments, a non-radioactive radionuclide precursor may comprise a carbonate of the radionuclide. In some embodiments, a non-radioactive radionuclide precursor may comprise a chloride of the radionuclide. In some embodiments, a non-radioactive radionuclide precursor may comprise an organic compound of the radionuclide (e.g., a polymeric resin, a polymer, e.g., polystyrene, polyester, poly(lactic-co-glycolic acid), gelatin, poly(methyl methacrylate), and / or albumin based compound). In some embodiments, a non-radioactive radionuclide precursor may comprise an inorganic compound of the radionuclide. In some embodiments, a non-radioactive precursor may become radioactive when activated (e.g., by neutron activation).

[0084] Compositions

[0085] In an aspect, the present disclosure provides a glass composition. In some embodiments, the glass composition may comprise an aluminosilicate. In some embodiments, the composition may comprise aluminum oxide. In some embodiments, the composition may comprise silicon oxide. In some embodiments, the composition may comprise one or more radionuclides (e.g., in a radionuclide precursor form as disclosed herein). In some embodiments, the one or more radionuclides may comprise one or more of Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au. In some embodiments, the composition may comprise one or more oxides of Y, Ho, Rh, Pr, Lu, Yb, Sm, Dy, Re, and Au.

[0086] In some embodiments, the glass composition may have a CT radiopacity of at least about 4000 Hounsfield Units (HU), at least about 5000 HU, at least about 6000 HU, at leastWSGR Docket No. 66410-702.601about 7000 HU, at least about 8000 HU, at least about 9000 HU, or at least about 10000 HU at 120 kVp.

[0087] In some embodiments, the glass composition may have the one or more radionuclide precursors with a mole fraction of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, or at least about 50%. In some embodiments, the glass composition may have one or more radionuclide precursors with a mole fraction of at most about 50%, at most about 45%, at most about 40%, at most about 35%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, or at most about 5%. In some embodiments, the glass composition may have a high loading of one or more radionuclides or radionuclide precursors. In some embodiments, the glass composition may be substantially free of any additional radiopacifying agent as disclosed herein. In some embodiments, the one or more radionuclide precursors in the glass composition may have sufficient CT radiopacity such that no additional radiopacifying agent is required.

[0088] In some embodiments, increasing the amount (or percentage, e.g., mole fraction or weight fraction) of the one or more radionuclide precursors in the glass composition may increase the CT radiopacity of the glass composition. In some embodiments, increasing the one or more radionuclide precursors in the glass composition by 10% (e.g., from 10 mol% to 11 mol%, or from 20 mol% to 22 mol%) may increase the CT radiopacity of the glass composition by at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. In some embodiments, increasing the one or more radionuclide precursors in the glass composition by 20% (e.g., from 10 mol% to 12 mol%, or from 20 mol% to 24 mol%) may increase the CT radiopacity of the glass composition by at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%,WSGR Docket No. 66410-702.601at least about 17%, at least about 18%, at least about 19%, or at least about 20%. In some embodiments, increasing the one or more radionuclide precursors in the glass composition by 30% (e.g., from 10 mol% to 13 mol%, or from 20 mol% to 26 mol%) may increase the CT radiopacity of the glass composition by at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, or at least about 30%. In some embodiments, increasing the one or more radionuclide precursors in the glass composition by 40% (e.g., from 10 mol% to 14 mol%, or from 20 mol% to 28 mol%) may increase the CT radiopacity of the glass composition by at least about 8%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, or at least about 40%. In some embodiments, increasing the one or more radionuclide precursors in the glass composition by 50% (e.g., from 10 mol% to 15 mol%, or from 20 mol% to 30 mol%) may increase the CT radi opacity of the glass composition by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.

[0089] In some embodiments, the glass composition may comprise one or more dopants. In some embodiments, the one or more dopants may reduce the required melting temperature in making the glass composition. In some embodiments, the glass composition may comprise at least about 0.1 mol%, at least about 0.2 mol%, at least about 0.5 mol%, at least about 1 mol%, at least about 1.2 mol%, at least about 1.5 mol%, at least about 2 mol%, at least about 2.5 mol%, at least about 3 mol%, at least about 4 mol%, or at least about 5 mol% of the one or more dopants. In some embodiments, the glass composition may comprise at most about 5 mol%, at most about 4 mol%, at most about 3 mol%, at most about 2.5 mol%, at most about 2 mol%, at most about 1.5 mol%, at most about 1 mol%, at most about 0.5 mol%, at most about 0.2 mol%, or at most about 0.1 mol% of the one or more dopants. In some embodiments, the one or more dopants may comprise one or more of titanium oxide, rhodium oxide, zinc or depleted zinc oxide, lead oxide, zirconium oxide, manganese oxide, and vanadium oxide. In some embodiments, the one or more dopants may comprise a carbonate form. In some embodiments, the one or more dopants may comprise a chloride form. In some embodiments, the one or more dopants may reduce the required temperature in making the glass composition, by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, or at least about 20%, in comparison to the composition that does not include the one or more dopants. In some embodiments, the one or more dopants may reduce the required temperature in making the glass composition, by at least about 10 °C, at least about 15 °C, atWSGR Docket No. 66410-702.601least about 20 °C, at least about 25 °C, at least about 30 °C, at least about 35 °C, at least about 40 °C, at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, or at least about 100 °C, in comparison to the composition that does not include the one or more dopants. In some embodiments, the one or more dopants may enhance the processability in making the glass composition. In some embodiments, the one or more dopants may enhance the manufacturability in making the glass composition. In some embodiments, the one or more dopants may reduce the energy needed in making the glass composition (e.g., by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, or at least about 20%). In some embodiments, the one or more dopants may increase the radiopacity of the glass composition (e.g., by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, or at least about 10%). In some embodiments, the one or more dopants may not create unwanted activation byproducts upon undergoing neutron activation. In some embodiments, the one or more dopants may improve the dispersion of the radionuclides in the glass composition. In some embodiments, the one or more dopants may adjust the density (e.g., increasing or reducing the density) of the glass composition. In some embodiments, the one or more dopants may improve the stability of the glass composition. In some embodiments, the one or more dopants may improve the stability of the radionuclides during storage or transportation. In some embodiments, the one or more dopants may improve the radioactivity of the radionuclides upon activation. In some embodiments, the one or more dopants may increase the possible loading of the radionuclide precursor (e.g., yttrium oxide or other radionuclide precursor as disclosed herein), which may impart additional flexibility to radionuclide production logistics and / or increase the achievable specific activity of the microspheres, and improve the clinician’s ability to deliver personalized treatment plans.

[0090] In some embodiments, the glass composition may comprise at least about 30 mol%, at least about 35 mol%, at least about 40 mol%, at least about 45 mol%, at least about 50 mol%, at least about 55 mol%, at least about 60 mol%, at least about 65 mol%, at least about 70 mol%, at least about 75 mol%, or at least about 80 mol% silicon dioxide. In some embodiments, the glass composition may comprise at most about 80 mol%, at most about 75 mol%, at most about 70 mol%, at most about 65 mol%, at most about 60 mol%, at most about 55 mol%, at most about 50 mol%, at most about 45 mol%, at most about 40 mol%, at most about 35 mol%, or at most about 30 mol%, silicon dioxide.

[0091] In some embodiments, the glass composition may comprise at least about 10 mol%, at least about 15 mol%, at least about 20 mol%, at least about 25 mol%, at least about 30 mol%, at least about 35 mol%, or at least about 40 mol% aluminum oxide. In some embodiments, theWSGR Docket No. 66410-702.601glass composition may comprise at most about 40 mol%, at most about 35 mol%, at most about 30 mol%, at most about 25 mol%, at most about 20 mol%, at most about 15 mol%, or at most about 10 mol% aluminum oxide.

[0092] In some embodiments, the glass composition may comprise one or more radiopacifying agents. In some embodiments, the glass composition may comprise one or more of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb). In some embodiments, the glass composition may comprise one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb). In some embodiments, the glass composition may comprise one or more may comprise one or more one or more oxides, one or more carbonates, and / or one or more chlorides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb), or a combination thereof.

[0093] In some embodiments, the glass composition may comprise at least about 0.001 mol%, at least about 0.005 mol%, at least about 0.01 mol%, at least about 0.05 mol%, at least about 0.1 mol%, at least about 0.5 mol%, at least about 1 mol%, at least about 2 mol%, at least about 5 mol%, at least about 10 mol%, at least about 15 mol%, at least about 20 mol%, at least about 25 mol%, or at least about 30 mol% of the one or more radiopacifying agents. In some embodiments, the glass composition may comprise at most about 30 mol%, at most about 25 mol%, at most about 20 mol%, at most about 15 mol%, at most about 10 mol%, at most about 5 mol%, at most about 2 mol%, at most about 1 mol%, at most about 0.5 mol%, at most about 0.1 mol%, at most about 0.05 mol%, at most about 0.01 mol%, at most about 0.005 mol%, or at most about 0.001 mol% of the one or more radiopacifying agents.

[0094] In some embodiments, the glass composition as disclosed herein may comprise a coating of one or more radiopacifying agents as disclosed herein. In some embodiments, the glass composition may comprise a metallic coating (e.g., Au, Pt, Ta, Pd, or other radiopacifying agent disclosed herein in metallic form, or a combination thereof). In some embodiments, theWSGR Docket No. 66410-702.601coating may impart sufficient CT imageability (or radiopacity). In some embodiments, the coating may increase the CT radiopacity of the glass composition by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%. In some embodiments, the coating may increase the CT radiopacity of the glass composition by at most about 100%, at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, at most about 30%, at most about 20%, or at most about 10%. In some embodiments, the coating may comprise a thickness of at least about 10 nanometers (nm), at least about 20 nm, at least about 30 nm, at least about 40 nm, at least about 50 nm, at least about 100 nm, at least about 150 nm, at least about 200 nm, at least about 250 nm, at least about 300 nm, at least about 400 nm, or at least about 500 nm. In some embodiments, the coating may comprise a thickness of at most about 500 nm, at most about 400 nm, at most about 300 nm, at most about 200 nm, at most about 100 nm, at most about 50 nm, at most about 40 nm, at most about 30 nm, at most about 20 nm, or at most about 10 nm. In some embodiments, the glass composition may comprise at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 layers of coatings. In some embodiments, the glass composition may comprise at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, or 1 layer of coatings. In some embodiments, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% surface area of the glass composition may comprise the coating. In some embodiments, at most about 99%, at most about 95%, at most about 90%, at most about 80%, at most about 70%, at most about 60%, at most about 50%, at most about 40%, or at most about 30% surface area of the glass composition may comprise the coating. In some embodiments, when the glass composition has multiple layers of coatings, the layers (e.g., composition, thickness) may be same. In some embodiments, when the glass composition has multiple layers of coatings, the layers (e.g., composition, thickness) may be different. In some embodiments, the coating may be coated onto the glass microspheres by any suitable coating methods, e.g., spray coating, spin coating, vapor deposition, chemical vapor deposition, physical vapor deposition, vacuum deposition, or sputter coating.

[0095] In an aspect, the microsphere comprises: from about 0.60 to about 0.80 mole fraction of silicon dioxide; from about 0.10 to about 0.25 mole fraction of aluminum oxide; and from about 0.001 to about 0.30 mole fraction of neodymium oxide.WSGR Docket No. 66410-702.601

[0096] In some embodiments, the microsphere comprises: from about 0.62 to about 0.75 mole fraction of silicon dioxide; from about 0.14 to about 0.25 mole fraction of aluminum oxide; and from about 0.001 to about 0.20 mole fraction of neodymium oxide.

[0097] In some embodiments, the microsphere comprises: from about 0.64 to about 0.74 mole fraction of silicone dioxide; from about 0.14 to about 0.19 mole fraction of aluminum oxide; and from about 0.001 to about 0.15 mole fraction of neodymium oxide.

[0098] In some embodiments, the microsphere comprises from about 0.001 to about 0.30 mole fraction of neodymium oxide, e.g., about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, or 0.30 mole fraction of neodymium oxide.

[0099] In some embodiments, the microsphere comprises from about 0.001 to about 0.30 mole fraction of neodymium oxide, e.g., from about 0.001 to about 0.002, from about 0.002 to about 0.003, from about 0.003 to about 0.004, from about 0.004 to about 0.005, from about 0.005 to about 0.007, from about 0.007 to about 0.009, from about 0.011 to about 0.015, from about 0.015 to about 0.020, from about 0.020 to about 0.025, from about 0.025 to about 0.030, from about 0.035 to about 0.040, from about 0.04 to about 0.05, from about 0.05 to about 0.07, from about 0.07 to about 0.09, from about 0.09 to about 0.11, from about 0.11 to about 0.12, from about 0.12 to about 0.13, from about 0.13 to about 0.14, from about 0.14 to about 0.15, from about 0.15 to about 0.16, from about 0.16 to about 0.17, from about 0.17 to about 0.18, from about 0.18 to about 0.19, from about 0.19 to about 0.20 mole, from about 0.20 to about 0.21, from about 0.21 to about 0.22, from about 0.22 to about 0.23, from about 0.23 to about 0.24, from about 0.24 to about 0.25, from about 0.25 to about 0.26, from about 0.26 to about 0.27, from about 0.27 to about 0.28, from about 0.28 to about 0.29, from about 0.29 to about 0.30 mole fraction of neodymium oxide.

[0100] In some embodiments, the microsphere comprises Y-90. In some embodiments, the microsphere comprises from about 0.05 to about 0.24 mole fraction of yttrium oxide. In some embodiments, the microsphere comprises Y-90. In some embodiments, the microsphere comprises from about 0.05 to about 0.50 mole fraction of yttrium oxide.

[0101] In some embodiments, the microsphere comprises from about 0.05 to about 0.50 mole fraction of yttrium oxide, e.g., about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.WSGR Docket No. 66410-702.601

[0102] In some embodiments, the microsphere comprises from about 0.05 to about 0.50 mole fraction of yttrium oxide, e.g., from about 0.05 to about 0.07, from about 0.07 to about 0.09, from about 0.09 to about 0.11, from about 0.11 to about 0.12, from about 0.12 to about 0.13, from about 0.13 to about 0.14, from about 0.14 to about 0.15, from about 0.15 to about 0.16, from about 0.16 to about 0.17, from about 0.17 to about 0.18, from about 0.18 to about 0.19, from about 0.19 to about 0.20, from about 0.20 to about 0.21, from about 0.21 to about 0.22, from about 0.22 to about 0.23, from about 0.23 to about 0.24, from about 0.05 to about 0.24, from about 0.15 to about 0.50, from about 0.20 to about 0.45, from about 0.20 to about 0.40, or from about 0.20 to about 0.35 mole fraction of yttrium oxide.

[0103] In some embodiments, the microsphere comprises any combination of (i) the mole fraction of neodymium oxide disclosed above and (ii) the mole fraction of yttrium oxide disclosed above, including both the mole fractions and the range of mole fractions for neodymium oxide and yttrium oxide, respectively.

[0104] In some embodiments, the microsphere comprises about 0.001 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0105] In some embodiments, the microsphere comprises about 0.002 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0106] In some embodiments, the microsphere comprises about 0.003 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0107] In some embodiments, the microsphere comprises about 0.004 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0108] In some embodiments, the microsphere comprises about 0.005 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.WSGR Docket No. 66410-702.601

[0109] In some embodiments, the microsphere comprises about 0.006 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0110] In some embodiments, the microsphere comprises about 0.007 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0111] In some embodiments, the microsphere comprises about 0.008 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0112] In some embodiments, the microsphere comprises about 0.009 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0113] In some embodiments, the microsphere comprises about 0.01 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0114] In some embodiments, the microsphere comprises about 0.02 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0115] In some embodiments, the microsphere comprises about 0.03 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0116] In some embodiments, the microsphere comprises about 0.04 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0117] In some embodiments, the microsphere comprises about 0.05 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16,WSGR Docket No. 66410-702.6010.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0118] In some embodiments, the microsphere comprises about 0.06 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0119] In some embodiments, the microsphere comprises about 0.07 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0120] In some embodiments, the microsphere comprises about 0.08 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0121] In some embodiments, the microsphere comprises about 0.09 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0122] In some embodiments, the microsphere comprises about 0.1 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0123] In some embodiments, the microsphere comprises about 0.11 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0124] In some embodiments, the microsphere comprises about 0.12 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0125] In some embodiments, the microsphere comprises about 0.13 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.WSGR Docket No. 66410-702.601

[0126] In some embodiments, the microsphere comprises about 0.14 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0127] In some embodiments, the microsphere comprises about 0.15 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0128] In some embodiments, the microsphere comprises about 0.16 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0129] In some embodiments, the microsphere comprises about 0.17 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0130] In some embodiments, the microsphere comprises about 0.18 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0131] In some embodiments, the microsphere comprises about 0.19 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0132] In some embodiments, the microsphere comprises about 0.20 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0133] In some embodiments, the microsphere comprises about 0.21 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0134] In some embodiments, the microsphere comprises about 0.22 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16,WSGR Docket No. 66410-702.6010.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0135] In some embodiments, the microsphere comprises about 0.23 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0136] In some embodiments, the microsphere comprises about 0.24 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0137] In some embodiments, the microsphere comprises about 0.25 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0138] In some embodiments, the microsphere comprises about 0.26 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0139] In some embodiments, the microsphere comprises about 0.27 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0140] In some embodiments, the microsphere comprises about 0.28 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0141] In some embodiments, the microsphere comprises about 0.29 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.

[0142] In some embodiments, the microsphere comprises about 0.30 mole fraction of neodymium oxide and about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mole fraction of yttrium oxide.WSGR Docket No. 66410-702.601

[0143] In some embodiments, the microsphere disclosed above further comprise another radionuclide or a metal oxide that can become radioactive other than yttrium. In some embodiments, most beta emissions from the microsphere disclosed above are arising from yttrium-90. In some embodiments, the microspheres are a combination of the microsphere disclosed above, i.e., including microspheres of having two or more different compositions.

[0144] In some embodiments, the microsphere disclosed above comprises at least one radionuclide or a metal oxide that can become radioactive, wherein at least one radiopacifying agent or metal oxide is imageable.

[0145] In some embodiments, the microsphere (or glass composition) as disclosed herein may remain durable following neutron irradiation with a high thermal neutron flux. In some embodiments, the high thermal neutron flux may comprise neutron irradiation conditions having a neutron flux (cp) no less than 1 x 1014 n / cm2»s for a duration of time (t) no less than 24 h in a nuclear reactor.

[0146] In some embodiments, the microsphere may be adjustable in at least one property selected from the group consisting of ratio of different types of radiation, half-life, tissue penetration depth, specific activity per microsphere, and imaging capabilities. In some embodiments, the at least one property may correlate to a ratio of yttrium to the one or more radionuclides in the microsphere. In some embodiments, the specific activity may be from about 50 to about 5000 Bq / microsphere.

[0147] Particle sizes

[0148] In some embodiments, the microsphere disclosed above may have an average diameter from about 5 pm to about 4500 pm. In some embodiments, the microsphere may have an average diameter from about 5 pm to about 4000 pm, from about 5 pm to about 3000 pm, 5 pm to about 2000 pm, from about 5 pm to about 1500 pm, 5 pm to about 1300 pm, from about 5 pm to about 1200 pm, from about 5 pm to about 30 pm, from about 10 pm to about 35 pm; from about 10 pm to about 45 pm; from about 20 pm to about 30 pm; from about 20 pm to about 40 pm; from about 20 pm to about 50 pm; from about 40 pm to about 500 pm; from about 40 pm to about 300 pm; from about 300 pm to about 500 pm; from about 500 pm to about 700 pm; from about 700 pm to about 1200 pm, from about 1200 pm to about 1500 pm, from about 1500 pm to about 2000 pm, from about 2000 pm to about 2500 pm, from about 2500 pm to about 3000 pm, from about 3000 pm to about 3500 pm, from about 3500 pm to about 4000 pm, or from about 4000 pm to about 4500 pm. The ranges described herein include all endpoints and sub-ranges between the end points, and all integer values between the endpoints. In some embodiments, the individual particles of the microspheres are, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,WSGR Docket No. 66410-702.60115, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 85, 90, 95, or 100 pm in diameter. In some embodiments, the particle size comprises: Do=15 pm; Dso=25 pm, D95=35 pm. In some embodiments, the particle size comprises: Do=25 pm; Dso=35 pm, D95=45 pm. In some embodiments, the particle size comprises: Do=35 pm; Dso=45 pm, D95=55 pm. In some embodiments, the particle size comprises: Do=45 pm; Dso=55 pm, D95=65 pm. The particle size can be determined using methods, for example, laser diffraction according to ISO13320 standard (2009).

[0149] Radiopacity

[0150] The microspheres described herein have a radi opacity sufficient to visualize the particulate materials (e.g., beads or bubble or microspheres) during in vivo delivery of the particulate materials to a human or animal subject. In some embodiments, the radi opacity is determined by cone-beam and conventional CT evaluation (see S. Kehoe et al., Effects of y-irradiation and accelerated aging on composition-structure-property relationships for radiopaque embolic microspheres. Journal of Non-Crystalline Solids 402, 2014, 84-90). In some embodiments, the average CT radi opacity is from about 8,000 to about 19,000 Hounsfield Units (HU) at an energy of 70 kVp, and the average CT radiopacity is from about 4,000 to about 16,000 HU at an energy of 120 kVp.

[0151] Irradiated compositions

[0152] The compositions of microspheres described herein can produce radioisotopes when irradiated with neutrons. Neutron activation is a consistent and highly predictable phenomenon. The quantity of radioisotope produced upon irradiation on the microspheres disclosed herein in a neutron flux can be accurately predicted or estimated using the equation shown below. The number of atoms N is determined by the sample mass and composition; the neutron flux cp and irradiation time t are selected by the nuclear scientist; the neutron absorbance cross-section o is a fixed value that is unique to each stable isotope; the decay constant X is a physical property of the radioisotope being formed.• A=activity produced• N=number of atoms(p=neutron fluxo=neutron absorbance cross-sectionWSGR Docket No. 66410-702.601• X=decay constant• t=irradiation time

[0153] For clarity, radioisotope scientists generally differentiate between radionuclidic impurities-radioisotopes that form unexpectedly due to impurities in the sample-and incidental activation products, which are radioisotopes other than the desired species that are expected to form due to the sample composition. Radionuclidic impurities can be minimized (or eliminated) by careful preparation of the sample material, use of high purity reagents, and so on. Neutron Activation Analysis (NAA) can be used to determine whether there are any impurities in the compositions described herein. As disclosed below, impurities, such as certain elements, are to be excluded or to be kept at a threshold level.Methods of production

[0154] The glass compositions according to the present disclosure may be formed by melting a combination of starting materials (reagents) at a temperature of at least about 1400 °C, at least about 1450 °C, at least about 1500 °C, at least about 1550 °C, at least about 1600 °C, at least about 1650 °C, or at least about 1700 °C. The glass compositions according to the present disclosure may be formed by melting a combination of starting materials at a temperature of at most about 1700 °C, at most about 1650 °C, at most about 1600 °C, at most about 1550 °C, at most about 1500 °C, at most about 1450 °C, or at most about 1400 °C. In some embodiments, the starting materials may be homogenized for at least about 10 min, at least about 20 min, at least about 30 min, at least about 40 min, at least about 50 min, at least about 60 min, at least about 90 min, or at least about 120 min before the melting process. In some embodiments, the starting materials may be homogenized for at most about 120 min, at most about 90 min, at most about 60 min, at most about 50 min, at most about 40 min, at most about 30 min, at most about 20 min, or at most about 10 min before the melting process. In some embodiments, the melting process may take at least about 10 min, at least about 20 min, at least about 30 min, at least about 40 min, at least about 50 min, at least about 60 min, at least about 90 min, at least about 120 min, at least about 3 hours (h), at least about 4 h, at least about 5 h, at least about 6 h, at least about 7 h, or at least about 8 h. In some embodiments, the melting process may take at most about 8 h, at most about 7 h, at most about 6 h, at most about 5 h, at most about 4 h, at most about 3 h, at most about 120 min, at most about 90 min, at most about 60 min, at most about 50 min, at most about 40 min, at most about 30 min, at most about 20 min, or at most about 10 min. In some embodiments, the melted composition may be maintained at the temperature for an additional period time to further homogenize the composition. In someWSGR Docket No. 66410-702.601embodiments, the additional period time may be at least about 10 min, at least about 20 min, at least about 30 min, at least about 40 min, at least about 50 min, or at least about 60 min. In some embodiments, the additional period time may be at most about 60 min, at most about 50 min, at most about 40 min, at most about 30 min, at most about 20 min, or at most about 10 min. The composition may be stirred during the melting process.

[0155] In some embodiments, the melted composition may be quenched. In some embodiments, the melted composition may be quenched with water. In some embodiments, the melted composition may be quenched with other cool or cold medium or surface (e.g., air, inert gas, oil, stainless steel).

[0156] In some embodiments, the quenched composition may be dried (e.g., in an oven), e.g., at a temperature from 60 °C to about 100 °C. In some embodiments, the dried composition may be milled and sieved. In some embodiments, the sieved composition may be subjected to a spheroidization process to generate microspheres. In some embodiments, the spheroidization process may comprise a flame spheroidization or plasma spheroidization. In some embodiments, spheroidization may comprise using a propane oxygen flame to transform the morphology of particulates to microspheres. In some embodiments, after spheroidization, the microspheres may be sieved for the desired diameter size range. In some embodiments, fine particulates may be separated from the resulting microspheres, e.g., by floating in distilled water, air classification (using an upward airstream to lift lighter fine particulates while allowing denser microspheres to fall), mechanical sieving, or air jet sieving. In some embodiments, the microspheres may be dried (e.g., in an oven), e.g., at a temperature from 60 °C to about 100 °C. In some embodiments, the microspheres may be stored in a sealed container (e.g., high density polyethylene (HDPE) container). In some embodiments, the microspheres may be stored in a desiccator (e.g., a vacuum desiccator).Methods of using

[0157] In an aspect, the present disclosure provides a method comprising: administering to a subject, a plurality of microspheres disclosed herein. In some embodiments, a microsphere of the plurality of microspheres may be any microsphere (or glass composition as disclosed herein).

[0158] In some embodiments, the method may further comprise imaging at least a section of the plurality of microspheres at or near an organ of the subject. In some embodiments, the organ may comprise a liver. In some embodiments, the organ may comprise anus, arteries, appendix, adrenal gland, brain, bones, bronchi, bladder, bone marrow, bulbourethral gland, colon, cervix,WSGR Docket No. 66410-702.601clitoris, cerebellum, diaphragm, ear, eye, fallopian tube, genital, gallbladder, heart, hypothalamus, interstitium, kidney, joint, lung, larynx, ligament, lymph node, large intestine, lymphatic vessel, mouth, mesentery, mammary glands, nose, nerve, nasal cavity, ovaries, esophagus, penis, pancreas, pharynx, placenta, prostate, pineal gland, pituitary gland, parathyroid gland, rectum, skin, spleen, scrotum, stomach, spinal cord, small intestine, salivary gland, skeletal muscles, seminal vesicles, subcutaneous tissue, testes, tendons, tongue, thyroid, trachea, thymus gland, ureters, urethra, uterus, vulva, veins, vagina, vas deferens, or vestigial organ.

[0159] In some embodiments, the imaging may comprise computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging. In some embodiments, the imaging may comprise computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof. In some embodiments, the plurality of microspheres may be radioactive. In some embodiments, the plurality of microspheres may be non-radioactive before an activation. In some embodiments, the plurality of microspheres may be radioactive upon activation (e.g., neutron activation). In some embodiments, the microsphere may comprise a theranostic. In some embodiments, the microsphere may provide radionuclide imaging and emit therapeutic radiation. In some embodiments, the administering may be via intra-arterial or intravenous delivery.

[0160] In an aspect, the present disclosure provides a method comprising in a treatment planning step, administering to a subject, a first plurality of microspheres. In some embodiments, the method may comprise in a therapeutic treatment step, administering to the subject a second plurality of microspheres. In some embodiments, a microsphere of the first plurality of microspheres and / or the second plurality of microspheres may comprise any microsphere or glass composition as disclosed herein. In some embodiments, the method may further comprise in the treatment planning step, imaging at least a section of the first plurality of microspheres at or near an organ of the subject. In some embodiments, the method may further comprise in the therapeutic treatment step, imaging at least a section of the second plurality of microspheres at or near an organ of the subject. In some embodiments, the imaging may be in real-time. In some embodiments, the imaging may be conducted in an interventional radiology (IR) suite in which the subject is being treated. In some embodiments, the first plurality of microspheres may be substantially the same as the second plurality of microspheres in terms ofWSGR Docket No. 66410-702.601chemical composition and / or physical characteristics. In some embodiments, imaging may comprise computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging. In some embodiments, the imaging in (i) and the imaging in (ii) may comprise computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof. In some embodiments, the administering of the first plurality of microspheres and / or the second plurality of microspheres may be via intra-arterial or intravenous delivery. In some embodiments, the microsphere may provide radionuclide imaging and emit therapeutic radiation.Numerated Embodiments

[0161] Embodiment 1. A microsphere, comprising:(i) an aluminosilicate;(ii) one or more radionuclides;(iii) yttrium oxide, and(iv) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb).

[0162] Embodiment 2. The microsphere of Embodiment 1, wherein the microsphere is imageable.

[0163] Embodiment 3. The microsphere of Embodiment 1, wherein the microsphere is radioactive.

[0164] Embodiment 4. The microsphere of Embodiment 1, wherein the microsphere is imageable and radioactive.

[0165] Embodiment 5. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is neodymium oxide.

[0166] Embodiment 6. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is rhodium oxide.WSGR Docket No. 66410-702.601

[0167] Embodiment 7. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is samarium oxide.

[0168] Embodiment 8. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is dysprosium oxide.

[0169] Embodiment 9. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is erbium oxide.

[0170] Embodiment 10. The microsphere of any one of Embodiments 1-4, wherein the radiopacifying agent is ytterbium oxide.

[0171] Embodiment 11. The microsphere of any one of Embodiments 1-10, wherein the microsphere is imageable by computerized tomography (CT) or cone-beam computed tomography (CBCT).

[0172] Embodiment 12. The microsphere of Embodiment 11, wherein the microsphere is imageable by neodymium or a product of irradiated neodymium.

[0173] Embodiment 13. The microsphere of any one of Embodiments 1-12, wherein the microsphere is imageable by intra-procedural angiography, x-ray fluoroscopy, CT, CBCT, magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET), or singlephoton emission computed tomography (SPECT), or a combination thereof.

[0174] Embodiment 14. The microsphere of any one of Embodiments 1-13, wherein the microsphere comprises:from about 0.60 to about 0.80 mole fraction of silicon dioxide;from about 0.10 to about 0.25 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.30 mole fraction of neodymium oxide.

[0175] Embodiment 15. The microsphere of Embodiment 14, wherein the microsphere comprises:from about 0.62 to about 0.75 mole fraction of silicon dioxide;from about 0.14 to about 0.25 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.20 mole fraction of neodymium oxide.

[0176] Embodiment 16. The microsphere of Embodiment 15, wherein the microsphere comprises:from about 0.64 to about 0.74 mole fraction of silicon dioxide;from about 0.14 to about 0.19 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.15 mole fraction of neodymium oxide.

[0177] Embodiment 17. The microsphere of any one of Embodiments 14-16, wherein the microsphere comprises from about 0.05 to about 0.50 mole fraction of yttrium oxide.WSGR Docket No. 66410-702.601

[0178] Embodiments 18. The microsphere of Embodiment 17, wherein the microsphere comprises from about 0.05 to about 0.30 mole fraction of yttrium oxide.

[0179] Embodiment 19. The microsphere of Embodiment 17, wherein the microsphere comprises from about 0.05 to about 0.17 mole fraction of yttrium oxide.

[0180] Embodiment 20. The microsphere of any one of Embodiments 1-19, wherein the microsphere has an average diameter from about 5 pm to about 4500 pm.

[0181] Embodiment 21. The microsphere of Embodiment 20, wherein the microsphere has an average diameter from about 5 pm to about 1300 pm, from about 5 pm to about 1200 pm, from about 5 pm to about 30 pm, from about 10 pm to about 35 pm, from about 10 pm to about 45 pm, from about 20 pm to about 30 pm, from about 20 pm to about 40 pm, from about 20 pm to about 50 pm, from about 40 pm to about 500 pm, from about 40 pm to about 300 pm, from about 300 pm to about 500 pm, from about 500 pm to about 700 pm, from about 700 pm to about 1200 pm, from about 1200 pm to about 1500 pm, from about 1500 pm to about 2000 pm, from about 2000 pm to about 2500 pm, from about 2500 pm to about 3000 pm, from about 3000 pm to about 3500 pm, from about 3500 pm to about 4000 pm, or from about 4000 pm to about 4500 pm.

[0182] Embodiment 22. The microsphere of any one of Embodiments 1-21, wherein the microsphere remains durable following neutron irradiation with a high thermal neutron flux.

[0183] Embodiment 23. The microsphere of Embodiment 22, wherein the high thermal neutron flux is neutron irradiation conditions having a neutron flux (cp) no less than 1 x 1014n / cm2»s for a duration of time (t) no less than 24 h in a nuclear reactor (or a nuclear research reactor).

[0184] Embodiment 24. The microsphere of any one of Embodiments 1-23, wherein the microsphere is adjustable in at least one property selected from the group consisting of ratio of different types of radiation, half-life, tissue penetration depth, specific activity per microsphere, and imaging capabilities.

[0185] Embodiment 25. The microsphere of Embodiment 24, wherein the at least one property correlates to a ratio of yttrium to the one or more radionuclides in the microsphere.

[0186] Embodiment 26. The microsphere of Embodiment 24 or 25, wherein the specific activity is from about 50 to about 5000 Bq / microsphere.

[0187] Embodiment 27. The microsphere of any one of Embodiments 1-26, wherein the microsphere is a theranostic.

[0188] Embodiment 28. The microsphere of any one of Embodiments 1-27, wherein the microsphere comprises a radionuclide that is imageable and emitting therapeutic radiation.WSGR Docket No. 66410-702.601

[0189] Embodiment 29. The microsphere of any one of Embodiments 1-28, wherein the microsphere is glass.

[0190] Embodiment 30. The microsphere of any one of Embodiments 1-29, wherein the radiopacifying agent comprises one or more enriched isotopes of a lanthanoid metal.

[0191] Embodiment 31. The microsphere of Embodiment 30, wherein the radiopacifying agent comprises one or more substantially depleted isotopes of the lanthanoid metal.

[0192] Embodiment 32. The microsphere of Embodiment 30 or 31, wherein the one or more enriched isotopes areNd-142, Nd-143, Nd-144, orNd-145.

[0193] Embodiment 33. The microsphere of Embodiment 32, wherein the one or more substantially depleted isotopes areNd-146, Nd-148, orNd-150.

[0194] Embodiment 34. The microsphere of Embodiment 30 or 31, wherein the one or more enriched isotopes are Sm-147, Sm-148, Sm-149, or Sm-154.

[0195] Embodiment 35. The microsphere of Embodiment 34, wherein the one or more substantially depleted isotopes are Sm-144, Sm-150, or Sm-152.

[0196] Embodiment 36. The microsphere of Embodiment 30 or 31, wherein the one or more enriched isotopes are Dy-160, Dy-161, Dy-162, or Dy-163.

[0197] Embodiment 37. The microsphere of Embodiment 36, wherein the one or more substantially depleted isotopes are Dy-156, Dy-158, or Dy-164.

[0198] Embodiment 38. The microsphere of Embodiment 30 or 31, wherein the one or more enriched isotopes are Er-166 or Er-167.

[0199] Embodiment 39. The microsphere of Embodiment 38, wherein the one or more substantially depleted isotopes are Er-162, Er-164, Er-168, or Er-170.

[0200] Embodiment 40. The microsphere of Embodiment 30 or 31, wherein the one or more enriched isotopes are Yb-170, Yb-171, Yb-172, or Yb-173.

[0201] Embodiment 41. The microsphere of Embodiment 40, wherein the one or more substantially depleted isotopes are Yb-168, Yb-174, or Yb-176.

[0202] Embodiment 42. The microsphere of any one of Embodiments 1-41, wherein the radionuclide comprises Y-90.

[0203] Embodiment 43. A microsphere, comprising: (i) an aluminum oxide; (ii) a silicon oxide; and (iii) one or more radionuclide precursors, wherein the one or more radionuclide precursors have a mole fraction of at least about 15 mol% and the microsphere is radiopaque.

[0204] Embodiment 44. The microsphere of Embodiment 43, wherein the microsphere is imageable.WSGR Docket No. 66410-702.601

[0205] Embodiment 45. The microsphere of Embodiment 43, wherein the microsphere is radioactive.

[0206] Embodiment 46. The microsphere of Embodiment 43, wherein the microsphere is imageable and radioactive.

[0207] Embodiment 47. The microsphere of any one of Embodiments 43-46, wherein the microsphere has a CT radiopacity of at least about 6,000 Hounsfield Units (HU) at 120 kVp.

[0208] Embodiment 48. The microsphere of any one of Embodiments 43-47, wherein the microsphere comprises one or more of Y, Ho, Yb, Rh, Pr, Lu, Sm, Dy, Re, and Au.

[0209] Embodiment 49. The microsphere of any one of Embodiments 43-47, wherein the microsphere comprises one or more oxides of Y, Ho, Yb, Rh, Pr, Lu, Sm, Dy, Re, and Au.

[0210] Embodiment 50. The microsphere of any one of Embodiments 43-49, wherein the one or more radionuclide precursors have a mole fraction of at least about 20 mol%.

[0211] Embodiment 51. The microsphere of any one of Embodiments 43-49, wherein the one or more radionuclide precursors have a mole fraction of at least about 25 mol%.

[0212] Embodiment 52. The microsphere of any one of Embodiments 43-49, wherein the one or more radionuclide precursors have a mole fraction of at least about 30 mol%.

[0213] Embodiment 53. The microsphere of any one of Embodiments 43-49, wherein the one or more radionuclide precursors have a mole fraction of at least about 35 mol%.

[0214] Embodiment 54. The microsphere of any one of Embodiments 43-53, wherein the microsphere is substantially free of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb).

[0215] Embodiment 55. The microsphere of any one of Embodiments 43-54, wherein the aluminum oxide is from about 10 mol% to about 40 mol%.

[0216] Embodiment 56. The microsphere of any one of Embodiments 43-55, wherein the silicon oxide is from about 40 mol% to about 80 mol%.

[0217] Embodiment 57. The microsphere of any one of Embodiments 43-56, wherein a radiopacity of the microsphere increases at least about 5% by an increase of an amount of the one or more radionuclide precursors by about 10%.

[0218] Embodiment 58. The microsphere of any one of Embodiments 43-56, wherein the radiopacity of the microsphere increases at least about 6% by an increase of an amount of the one or more radionuclide precursors by about 10%.WSGR Docket No. 66410-702.601

[0219] Embodiment 59. The microsphere of any one of Embodiments 43-58, wherein the microsphere is imageable by intra-procedural angiography, x-ray fluoroscopy, computed tomography (CT), cone-beam computed tomography (CBCT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET), or single-photon emission computed tomography (SPECT), or a combination thereof.

[0220] Embodiment 60. The microsphere of any one of Embodiments 43-59, wherein the microsphere comprises a metallic coating.

[0221] Embodiment 61. The microsphere of Embodiment 60, wherein the coating comprises one or more of Au, Pt, Ta, and Pd.

[0222] Embodiment 62. The microsphere of any one of Embodiments 43-61, wherein the microsphere comprises one or more dopants.

[0223] Embodiment 63. The microsphere of Embodiment 62, wherein the one or more dopants comprise one or more of titanium oxide, rhodium oxide, zinc or depleted zinc oxide, lead oxide, zirconium oxide, molybdenum oxide, manganese oxide, and vanadium oxide.

[0224] Embodiment 64. The microsphere of Embodiment 62, wherein the microsphere comprises the one or more dopants with a mole fraction from about 0.1% to about 5%.

[0225] Embodiment 65. A method comprising: administering to a subject, a plurality of microspheres, wherein a microsphere of the plurality of microspheres is as in any one of Embodiments 1-64.

[0226] Embodiment 66. The method of Embodiment 65, further comprising: imaging at least a section of the plurality of microspheres at or near an organ of the subject.

[0227] Embodiment 67. The method of Embodiment 66, wherein the organ is a liver.

[0228] Embodiment 68. The method of Embodiment 66, wherein the organ is anus, arteries, appendix, adrenal gland, brain, bones, bronchi, bladder, bone marrow, bulbourethral gland, colon, cervix, clitoris, cerebellum, diaphragm, ear, eye, fallopian tube, genital, gallbladder, heart, hypothalamus, interstitium, kidney, joint, lung, larynx, ligament, lymph node, large intestine, lymphatic vessel, mouth, mesentery, mammary glands, nose, nerve, nasal cavity, ovaries, esophagus, penis, pancreas, pharynx, placenta, prostate, pineal gland, pituitary gland, parathyroid gland, rectum, skin, spleen, scrotum, stomach, spinal cord, small intestine, salivary gland, skeletal muscles, seminal vesicles, subcutaneous tissue, testes, tendons, tongue, thyroid, trachea, thymus gland, ureters, urethra, uterus, vulva, veins, vagina, vas deferens, or vestigial organ.WSGR Docket No. 66410-702.601

[0229] Embodiment 69. The method of any one of Embodiments 66-68, wherein the imaging is computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging.

[0230] Embodiment 70. The method of any one of Embodiments 66-68, wherein the imaging is computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof.

[0231] Embodiment 7E The method of any one of Embodiments 65-70, wherein the plurality of microspheres are radioactive.

[0232] Embodiment 72. The method of any one of Embodiments 65-71, wherein the microsphere is a theranostic.

[0233] Embodiment 73. The method of any one of Embodiments 65-71, wherein the microsphere provides radionuclide imaging and emits therapeutic radiation.

[0234] Embodiment 74. The method of any one of Embodiments 65-73, wherein the microsphere is glass.

[0235] Embodiment 75. The method of any one of Embodiments 65-74, wherein the administering is via intra-arterial or intravenous delivery.

[0236] Embodiment 76. A method comprising: (i) in a treatment planning step: administering to a subject, a first plurality of microspheres; and (ii) in a therapeutic treatment step: administering to the subject a second plurality of microspheres, wherein a microsphere of the first plurality of microspheres and the second plurality of microspheres is as in any one of Embodiments 1-64.

[0237] Embodiment 77. The method of Embodiment 76, further comprising: (i) in the treatment planning step: imaging at least a section of the first plurality of microspheres at or near an organ of the subject; and (ii) in the therapeutic treatment step: imaging at least a section of the second plurality of microspheres at or near an organ of the subject.

[0238] Embodiment 78. The method of Embodiment 77, wherein the imaging in (i) and the imaging in (ii) are in real-time.

[0239] Embodiment 79. The method of any one of Embodiments 76-78, wherein the imaging in (i) and the imaging in (ii) are conducted in an interventional radiology (IR) suite in which the subject is being treated.WSGR Docket No. 66410-702.601

[0240] Embodiment 80. The method of any one of Embodiments 76-79, wherein the first plurality of microspheres is substantially the same as the second plurality of microspheres in terms of chemical composition and / or physical characteristics.

[0241] Embodiment 81. The method of any one of Embodiments 76-80, the imaging in (i) and the imaging in (ii) are computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging.

[0242] Embodiment 82. The method of any one of Embodiments 76-80, wherein the imaging in (i) and the imaging in (ii) are computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof.

[0243] Embodiment 83. The method of any one of Embodiments 76-80, wherein the administering in (i) is via intra-arterial or intravenous delivery.

[0244] Embodiment 84. The method of any one of Embodiments 76-83, wherein the administering in (ii) is via intra-arterial or intravenous delivery.

[0245] Embodiment 85. The method of any one of Embodiments 76-84, wherein the subject is a human.

[0246] Embodiment 86. A method comprising (a) administering to a subject a microsphere comprising (i) alumina and silica, (ii) yttrium oxide, and (iii) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb), and (b) imaging a body of the subject to identify a location of the microsphere within the body of the subject.

[0247] Embodiment 87. The method of Embodiment 86, wherein the microsphere is a theranostic.

[0248] Embodiment 88. The method of Embodiment 86 or 87, wherein the microsphere provides radionuclide imaging and emits therapeutic radiation.

[0249] Embodiment 89. The method of any one of Embodiments 86-88, wherein the microsphere is glass.

[0250] Embodiment 90. The method of any one of Embodiments 86-89, wherein the radiopacifying agent is neodymium oxide.WSGR Docket No. 66410-702.601

[0251] Certain examples of the following examples illustrate various methods of making the microspheres or compositions thereof described herein. It is understood that one skilled in the art may be able to make these microspheres by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make other microspheres in a similar manner as described below by using the appropriate starting materials and modifying synthetic routes as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.EXAMPLESExample 1: Microsphere Compositions Design

[0252] The design of Synergy Spheres II compositions is based on a Design of Mixtures (DoM) statistical modelling approach. The DoM approach is employed to allow for unambiguous, systematic evaluations of the individual and interaction effects associated with various mixture components. This approach allows for the development of polynomial equations which indicate the relative influences of components on a given response (e.g., density, glass transition temperature, etc.), and ultimately support optimization of materials to a wide variety of properties via response surface regression methodologies. This form of predictive modelling stands in contrast to traditional trial and error style approaches for glass materials discovery and has the potential to accelerate the design of glass materials via simultaneous use of experimental methods and advanced modelling. Specifically, this disclosure is the first to employ the Design of Mixtures approach to produce statistical models relating to the composition-structure-property -function relationships of aluminosilicate glasses modified with various therapeutic radionuclides.Example 2: Synergy Spheres II

[0253] Three example glass formulations (Table 4; Benchmark 1 (Bl), Benchmark 2 (B2), Benchmark 3 (B3)) were first prepared as test melts and manufactured into microspheres, characterized to inform the compositional constraints of the Design of Mixtures (DoM) for the Synergy Spheres II. The mol% for the starting components of Bl, B2, and B2 are shown in Table 4.WSGR Docket No. 66410-702.601Table 4. Compositions of example microspheres.

[0254] The three test melts (formulations Bl -B3) were conducted to investigate the compositional limits of glass constituents in the glass network (SiCh, Y2O3, ISfcbCh, and AI2O3). Based on the results of the test melts, the minimum and maximum compositional limit was defined for each glass constituent.

[0255] The design constraints based on mol% for each component are provided in Table 5. Table 5. Mixture of starting components and design constraint summary.> > >> >

[0256] Based on the defined compositional limits, the compositions for the starting materials for the glass microspheres are established using Design-Expert Software (Version 13.0.15) from Stat-Ease™. A design of mixtures I-optimal quadratic model is utilized based on four components (SiCh, Y2O3, ISkbCE, and AI2O3).

[0257] This model yields a total of 16 glass formulations, as shown in Table 6, consisting of 10 model points, 3 lack of fit points, and 3 replicates. Replicate compositions are included to verify reproducibility in glass microsphere synthesis and characterization processes, to validate the robustness of the experimental design, and to increase the predictive power of the model. Table 6. Glass compositions based on the mol% of each starting component. Replicate compositions denoted by asterisks.WSGR Docket No. 66410-702.601*Glass compositions Nos. 15 and 16, 2 and 7, and 3 and 13 are replicates.Example 3: Glass Synthesis for DoM - Methods

[0258] Glasses were synthesized (MOSCI Corporation, Missouri, USA) via the traditional melt quench technique. Succinctly, high purity silicon dioxide (>99.9% purity), yttrium (III) oxide (99.99% purity), neodymium oxide (99.5% purity), and aluminum oxide (99.99% purity) reagents were weighed out in accordance with compositions listed in Table 5. The reagents may be homogenized for 1 hour prior to being transferred to platinum crucibles for melting. Glasses were melted in an electric furnace at a temperature of 1650 °C. Once the glasses were observed to be fully melted, they were stirred with a quartz rod and held at the melting temperature for an additional 15-minute dwell time to allow homogenization and release of air bubbles. The total melting time for the glasses (including the dwell time) was 45 minutes, except for formulations Bl, B2 and B3, wherein the melting time was 1 hour. Each melt was water quenched in distilled water and subsequently dried in the oven (90 °C). The dried glass was then ball milled and sieved. Finally, the particles were subjected to flame spheroidization using a propane oxygen flame to transform the morphology of the glass particulate to a microsphere. After spheroidization, the microspheres were sieved for the <45 pm diameter size range. Fine particulate was separated from the resulting microspheres by floating in distilled water. The microspheres were then dried in the oven again (65 °C). Glasses were stored in sealed high density polyethylene (HDPE) containers and housed in vacuum desiccators for subsequent analysis.Example 4: Glass Microsphere Characterization

[0259] Particle Size Analysis (PSA)

[0260] A Malvern Mastersizer 3000 laser diffraction particle size analyzer was used as per the manufacturer’s instructions. Samples of each glass, sieved to less than 45 pm, wereWSGR Docket No. 66410-702.601suspended in deionized water to obtain an obscuration value for the suspension from about 5% to about 8%. The glass suspension was then measured using both a blue (X = 470 nm) and red (X = 632.8 nm) laser. Each glass suspension was measured five times (n= 5) and particle size distribution data is reported as the mean diameter Dx90, Dx50 and DxlO (particle diameters at 90%, 50% and 10% cumulative size, respectively).

[0261] X-ray Diffraction (XRD)

[0262] X-ray diffraction (XRD) analysis was performed using a Malvern Panalytical Aeris XRD system equipped with a PIXcel ID detector. Samples of each glass microsphere were loaded into a hollow steel wafer and analyzed in the region of 20 from about 5° to about 60° with a step size 20 about 0.02° and a step time of about 40 s. XRD spectra were analyzed to determine the relative fraction of crystalline material in each sample.

[0263] Helium pycnometry

[0264] An AccuPyc 1340 helium pycnometer (Micromeritics, USA) equipped with a 1 cm3insert chamber was used to determine the density of each glass composition. From about 1 g to about 1.5 g of glass microspheres were used for each measurement, and each measurement comprises of about 10 fill and purge cycles (run in triplicates). The results are reported as the average ± standard deviation (SD) of three replicate measurements.

[0265] Differential Scanning Calorimetry

[0266] A simultaneous thermal analysis STA 449F5 Jupiter with Auto-Sampler (Netzsch-Geratebau-GMBH, USA) was used to analyze each glass composition. Approximately 30-60 mg of glass microspheres were weighed out, placed into Pt-Rh crucibles, and heated at 10 °C / min from 25 °C to 1400 °C. Proteus Thermal Analysis software (Version 8.0.3) was used to determine the extrapolated onset (Tf), inflection (T0, and end (Te) glass transition temperatures.

[0267] Radiopacity Evaluation (CT)

[0268] To evaluate for CT radiopacity, quantitative measurments were acquired by taking axial CT scans of each sample through glass vials. Images were taken at 70 and 120 kVp (400 mAs, a pitch of 0.5, and a 1 mm reconstructed slice thickness) using a clinical CT scanner (Somatom Definition AS+ (Siemens Healthineers, Erlangen, Germany)). The reported Hounsfield Unit (HU) values were determined from six distinct measurements.

[0269] Scanning Electron Microscopy (SEM)

[0270] A sample of each glass composition was deposited onto a carbon tab adhered to an aluminum SEM stub. Samples were coated with Gold / Palladium for 180s and subsequently examined using a Hitachi TM4000Plus II Tabletop Scanning Electron Microscope (SEM), operating at an accelerating voltage of 15 kV with a backscattered electron detector. SEMWSGR Docket No. 66410-702.601images were acquired at variable magnifications or at a 500x magnification to examine the surface morphology of the microspheres.

[0271] Cytotoxicity

[0272] Prior to cytotoxicity testing, 1 g of each glass microsphere composition was steam sterilized at 121±2 °C for 30±2 minutes. A positive control (Natural Rubber) article, negative control (Negative Control Plastic) article, and untreated control (blank) were prepared to verify the proper functioning of the test system. In accordance with ISO 10993-12: Biological evaluation of medical devices-Part 12: Sample preparation and reference materials, glass test articles and controls were extracted at a ratio of 0.2 g / mL in serum-supplemented (complete) Minimum Essential Medium (MEM) for 72±2 hours at 37±1 °C.

[0273] The biological reactivity of a mammalian monolayer, L929 mouse fibroblast cell culture, in response to the test article extract was determined (Labcorp, MA, USA). The test article or control article extracts were used to replace the maintenance medium of the cell culture. The test article extract was tested at the 100%, 50%, 25%, and 12.5% concentrations. All cultures were incubated in at least 6 replicates for 24 to 26 hours, at 37±1 °C, in a humidified atmosphere containing 5%±1% carbon dioxide (CO2). The viability of cells following the exposure to the extracts was measured via their metabolic activity. Yellow water-soluble MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide) was added to the cells. It was metabolically reduced in viable cells to a blue-violet insoluble formazan. The number of viable cells correlates to the color intensity determined by photometric measurements at 570 nm after extraction. The percent viability for the test article and controls was calculated using the following equation:Percent Viability = Mean Test Article OD / Mean Untreated Control OD * 100%

[0274] A sample with a mean percent viability of less than 70% of the untreated control was deemed to have cytotoxic potential in accordance with ISO 10,993-5: Biological evaluation of medical devices- Part 5: Tests for in vitro cytotoxicity.

[0275] Genotoxicity

[0276] Test articles (1.5 g ± 0.1 g samples of glass microspheres B, E, and DoM2-13) and negative control articles (extraction vehicle without the test article) were extracted at a ratio of 0.2 g / mL in dimethyl sulfoxide (DMSO) and in 0.9% sodium chloride (saline) for 72±2 hours at 50 ± 1 °C under continuous agitation, in accordance with ISO 10993-12. Extracts were clear, colorless, and free of particulates following preparation.

[0277] Bacterial reverse mutation testing (Ames assay) was conducted (NAMSA, OH, USA) based on ISO 10993-3 Biological evaluation of medical devices- Part 3: Tests for genotoxicity,WSGR Docket No. 66410-702.601carcinogenicity and reproductive toxicity. Salmonella typhimurium tester strains TA98, TAI 00, TA1535, and TA1537, and Escherichia coli tester strain WP2uvrA were used for the test.Testing was performed both in the presence and absence of an exogenous metabolic activation system (S9), consisting of phenobarbital and benzoflavone-induced rat liver homogenate. Each test condition was plated in triplicate using the standard plate incorporation method.

[0278] Molten top agar supplemented with histidine-biotin or tryptophan was inoculated with 0.1 mL of tester strain culture, 0.1 mL of the DMSO or saline test extract, and 0.5 mL of sterile water or S9 mix. The mixtures were poured onto minimal agar plates and incubated at 37±1 °C for 48±2 hours. Parallel assays were performed with negative controls (extraction vehicles only) and strain-appropriate positive controls, including sodium azide, 2-nitrofluorene, methyl methanesulfonate, benzo[a]pyrene, 2-aminoanthracene, and ICR-191.

[0279] Following incubation, the mean number of revertant colonies was recorded for each plate. The test article was considered to show mutagenic potential if a >2-fold increase in mean revertants (for TA98, TA100, or WP2uvrA) or a >3-fold increase (for TA1535 or TA1537) was observed relative to the corresponding negative control.

[0280] Post-firing compositional analysis

[0281] Inductively coupled plasma optical emission spectroscopy (ICP-OES) was performed to verify the actual glass compositions after melting and spheroidization to compare against the intended theoretical compositions.

[0282] Leaching Analysis

[0283] The chemical durability of the glasses was assessed in triplicate at time points of 1 d, 3 d, 7 d, and 14 d. For each glass sample, 0.5 g of glass microspheres (< 45 pm) was added to a pre-weighed 15 mL centrifuge tube with 10 mL of deionized water solution. Tubes were then capped and placed at an approximate 45-degree angle on a shaking incubator at 120 RPM and 50 °C. At each timepoint, samples were removed from the shaking incubator and centrifuged (3.0 RCF, 4.4 RPM) for 15 minutes. Supernatants were decanted from the pellets into a separate 15 mL centrifuge tubes and stored at 4 °C for elemental analysis. 10 ml of fresh deionized water was replaced in the original sample tube and samples were placed back on the shaking incubator until the subsequent time point.

[0284] For elemental analysis of the leaching extracts, samples were analyzed by inductively coupled plasma-optical emission spectroscopy (ICP-OES) for Si, Y, Nd and Al content. The mean concentration of each element in the extract was reported in ppm.WSGR Docket No. 66410-702.601

[0285] The above leaching protocol was then repeated on glass microspheres B, D and E in phosphate buffered saline (PBS). Elemental analysis of the leaching extracts was conducted by ICP-OES.

[0286] Results

[0287] FIG. 1 shows the melted frit (left) and crucible (right) for formulation Bl in Table 4. The material characterization results of example glass microspheres made from compositions Bl, B2, and B3 are shown in Table 7. The table presents key properties including particle size distribution, density, CT imageability (70 kVp, 120 kVp), and Tg(onset, inflection and final). All glasses were confirmed to be amorphous and free from identifiable crystalline species.Table 7. Physical and chemical characteristics of example microspheres.

[0288] The XRD spectrum of the microsphere according to Formula B 1 is shown in FIG. 2.No identifiable peaks are found for crystalline solids according to FIG. 2. The SEM image of the microspheres according to Formula Bl is shown in FIG. 3. The shapes shown are consistent with those for microspheres. The Hounsfield Unit (HU) values for example microspheres made from formulations Bl, B2, and B3 suggest that these microspheres may be imageable via CT or CBCT in a clinical setting. FIG. 4 shows a representative SEM image of Glass No. 12. The shapes shown are consistent with those for microspheres.

[0289] Table 8 summarizes the glass characterization results for the developed glasses. The table represents key properties including density, glass transition temperature (Tg), particle size distribution, and CT radiopacity at 70 and 120 kVp. The density of the glasses ranged from 3.04 to 3.82 g / cm3. Glasses had glass transition temperatures ranging from 873.0 to 897.2 °C. The Hounsfield Units (HU) of the glass microspheres, measured at 70 kVp and 120 kVp, ranged from 8030 to 18,023 HU and 4,505 to 14,371 HU, respectively.

[0290] Generally, higher Nd2Ch content resulted in higher CT imageability. When the Nd2Ch content of two glasses were comparable, increasing the Y2O3 content increased the CT imageability. Comparing glass #11 and #12 with no NdiCh, the CT imageability (at 70 kVp) increased 25.2% when Y2O3 increased 40.2%. Comparing glass #B2 and #5 with comparable Nd2C>3, (6.72% and 7.00%), the CT imageability (at 70 kVp) increased 18.2% when Y2O3WSGR Docket No. 66410-702.601increased 32.8%. Comparing glass #6 and #B3 with comparable ISfcbCh, (1.95% and 2.00%), the CT imageability (at 70 kVp) increased 36.5% when Y2O3 increased 26.8%. Comparing glass #6 and #14 with comparable ISfcbCh, (1.95% and 2.18%), the CT imageability (at 70 kVp) increased 6.7% when Y2O3 increased 9.1%.

[0291] Table 9 summarizes the biocompatibility test results for developed glasses. All glass formulations exhibited no cytotoxic potential. Formulations Bl, B2, and B3 were also assessed for genotoxicity and it was demonstrated that these tested samples exhibited no genotoxic potential. Table 10 summarizes the average cumulative concentration (ppm) of Y, Al, Si, and Nd released from glasses 1-16 after incubation in deionized (DI) water for up to 14 d (50 °C, 120 RPM). Table 11 summarizes the average cumulative concentration (ppm) of Y, Al, Si, and Nd released from glasses Bl, B2, and B3 after incubation in phosphate buffered saline (PBS) for up to 14 d (50 °C, 120 RPM). The glasses demonstrated high chemical durability in both DI water and PBS. The measured concentrations of Y released from all glasses in DI water were below 0.18 ppm. The measured concentrations of Y released from glasses Bl, B2, and B3 in PBS were below 0.24 ppm. These values correspond to approximately 0.001 % of total Y released from the glasses.Table 8. Glass characterization results for the developed glasses.WSGR Docket No. 66410-702.601Table 9. Biocompatibility test results for developed glasses.Table 10. Cumulative concentration (ppm) of Y, Al, Si, and Nd released from glasses in deionized (DI) water. Values are reported as mean ± SD (n = 3).WSGR Docket No. 66410-702.601*Calculated based on n=2Table 11. Cumulative concentration (ppm) of Y, Al, Si, and Nd released from glasses in phosphate buffered saline (PBS). Values are reported as mean ± SD (n = 3).

[0292] Table 12 summarizes expected (theoretical) and actual glass compositions (wt%) of glass frit (before spheroidization) and microspheres (MS) (after spheroidization), as measured by ICP-OES. Table 13 summarizes % change of glass composition when comparing the theoretical value and final microspheres, and when glass was transformed from frit to microspheres. Percent change values indicate the change in glass composition as a result of the thermal events involved in the glass synthesis process. There were minimal changes to theoretical glass composition of the thermal processes during glass synthesis.Table 12. Intended and actual glass compositions (wt%) of glass frits and microspheres (MS).WSGR Docket No. 66410-702.601< <<Table 13. Change of glass composition (%).WSGR Docket No. 66410-702.601Example 5: Neutron Activation Calculations

[0293] Neutron activation calculations were conducted for each microsphere composition listed in Table 6 to assess the amount of therapeutic radionuclide formed under high neutron flux activation conditions (cp > 2 * 1014n / cm2»s; tin-adiation = 5 d). The activity of each radionuclide is estimated following the 5 day activation period, and again after a 3 -day cool-down period postactivation. For each composition, a sample size of 1.0 gram is assumed. Table 14 shows Y-90 activation yields in example glasses.Table 14. Yttrium-90 activation yields in example glasses (see Table 6 for compositions).Example 6: YAS glasses with alternative radiopacifying agents

[0294] An additional suite of yttrium aluminosilicate glass formulations with alternative potential radiopacifying agents have been synthesized and tested in terms of their density and CT imageability at 70 kVp and 120 kVp. The glass formulations and testing results (density and CT imageability) are listed below in Table 15.WSGR Docket No. 66410-702.601Table 15. Glass compositions (mol%) and characterization results.

[0295] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No. 66410-702.601CLAIMS1. A microsphere, comprising:(i) an aluminosilicate;(ii) yttrium oxide, and(iii) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb).

2. The microsphere of claim 1, wherein the microsphere is imageable.

3. The microsphere of claim 1, wherein the microsphere is radioactive.

4. The microsphere of claim 1, wherein the microsphere is imageable and radioactive.

5. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is neodymium oxide.

6. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is rhodium oxide.

7. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is samarium oxide.

8. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is dysprosium oxide.

9. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is erbium oxide.

10. The microsphere of any one of claims 1-4, wherein the radiopacifying agent is ytterbium oxide.

11. The microsphere of any one of claims 1-10, wherein the microsphere is imageable by computerized tomography (CT) or cone-beam computed tomography (CBCT).

12. The microsphere of claim 11, wherein the microsphere is imageable by neodymium or a product of irradiated neodymium.

13. The microsphere of any one of claims 1-12, wherein the microsphere is imageable by intra-procedural angiography, x-ray fluoroscopy, CT, CBCT, magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET), or single-photon emission computed tomography (SPECT), or a combination thereof.

14. The microsphere of any one of claims 1-13, wherein the microsphere comprises:WSGR Docket No. 66410-702.601from about 0.60 to about 0.80 mole fraction of silicon dioxide;from about 0.10 to about 0.25 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.30 mole fraction of neodymium oxide.

15. The microsphere of claim 14, wherein the microsphere comprises:from about 0.62 to about 0.75 mole fraction of silicon dioxide;from about 0.14 to about 0.25 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.20 mole fraction of neodymium oxide.

16. The microsphere of claim 15, wherein the microsphere comprises:from about 0.64 to about 0.74 mole fraction of silicon dioxide;from about 0.14 to about 0.19 mole fraction of aluminum oxide; andfrom about 0.001 to about 0.15 mole fraction of neodymium oxide.

17. The microsphere of any one of claims 14-16, wherein the microsphere comprises from about 0.05 to about 0.50 mole fraction of yttrium oxide.

18. The microsphere of claim 17, wherein the microsphere comprises from about 0.05 to about 0.30 mole fraction of yttrium oxide.

19. The microsphere of claim 17, wherein the microsphere comprises from about 0.05 to about 0.17 mole fraction of yttrium oxide.

20. The microsphere of any one of claims 1-19, wherein the microsphere has an average diameter from about 5 pm to about 4500 pm.

21. The microsphere of claim 20, wherein the microsphere has an average diameter from about 5 pm to about 1300 pm, from about 5 pm to about 1200 pm, from about 5 pm to about 30 pm, from about 10 pm to about 35 pm, from about 10 pm to about 45 pm, from about 20 pm to about 30 pm, from about 20 pm to about 40 pm, from about 20 pm to about 50 pm, from about 40 pm to about 500 pm, from about 40 pm to about 300 pm, from about 300 pm to about 500 pm, from about 500 pm to about 700 pm, from about 700 pm to about 1200 pm, from about 1200 pm to about 1500 pm, from about 1500 pm to about 2000 pm, from about 2000 pm to about 2500 pm, from about 2500 pm to about 3000 pm, from about 3000 pm to about 3500 pm, from about 3500 pm to about 4000 pm, or from about 4000 pm to about 4500 pm.

22. The microsphere of any one of claims 1-21, wherein the microsphere remains durable following neutron irradiation with a high thermal neutron flux.

23. The microsphere of claim 22, wherein the high thermal neutron flux is neutron irradiation conditions having a neutron flux (cp) no less than 1 x 1014n / cm2»s for a duration of time (t) no less than 24 h in a nuclear research reactor.WSGR Docket No. 66410-702.60124. The microsphere of any one of claims 1-23, wherein the microsphere is adjustable in at least one property selected from the group consisting of ratio of different types of radiation, halflife, tissue penetration depth, specific activity per microsphere, and imaging capabilities.

25. The microsphere of claim 24, wherein at least one property correlates to a ratio of yttrium to the one or more radionuclides in the microsphere.

26. The microsphere of claim 24 or 25, wherein the specific activity is from about 50 to about 5000 Bq / microsphere.

27. The microsphere of any one of claims 1-26, wherein the microsphere is a theranostic.

28. The microsphere of any one of claims 1-27, wherein the microsphere comprises a radionuclide that is imageable and emitting therapeutic radiation.

29. The microsphere of any one of claims 1-28, wherein the microsphere is glass.

30. The microsphere of any one of claims 1-29, wherein the radiopacifying agent comprises one or more enriched isotopes of a lanthanoid metal.

31. The microsphere of claim 30, wherein the radiopacifying agent comprises one or more substantially depleted isotopes of the lanthanoid metal.

32. The microsphere of claim 30 or 31, wherein the one or more enriched isotopes are Nd-142, Nd- 143, Nd- 144, or Nd- 145.

33. The microsphere of claim 32, wherein the one or more substantially depleted isotopes are Nd-146, Nd-148, orNd-150.

34. The microsphere of claim 30 or 31, wherein the one or more enriched isotopes are Sm-147, Sm-148, Sm-149, or Sm-154.

35. The microsphere of claim 34, wherein the one or more substantially depleted isotopes are Sm-144, Sm-150, or Sm-152.

36. The microsphere of claim 30 or 31, wherein the one or more enriched isotopes are Dy-160, Dy-161, Dy-162, or Dy-163.

37. The microsphere of claim 36, wherein the one or more substantially depleted isotopes are Dy-156, Dy-158, or Dy-164.

38. The microsphere of claim 30 or 31, wherein the one or more enriched isotopes are Er-166 or Er- 167.

39. The microsphere of claim 38, wherein the one or more substantially depleted isotopes are Er-162, Er-164, Er-168, orEr-170.

40. The microsphere of claim 30 or 31, wherein the one or more enriched isotopes are Yb-170, Yb-171, Yb-172, or Yb-173.WSGR Docket No. 66410-702.60141. The microsphere of claim 40, wherein the one or more substantially depleted isotopes are Yb-168, Yb-174, or Yb-176.

42. The microsphere of any one of claims 1-41, wherein the microsphere comprises Y-90.

43. A microsphere, comprising:(i) an aluminum oxide;(ii) a silicon oxide; and(ii) one or more radionuclide precursors,wherein the one or more radionuclide precursors have a mole fraction of at least about 15 mol% and the microsphere is radiopaque.

44. The microsphere of claim 43, wherein the microsphere is imageable.

45. The microsphere of claim 43, wherein the microsphere is radioactive.

46. The microsphere of claim 43, wherein the microsphere is imageable and radioactive.

47. The microsphere of claim 43, wherein the microsphere has a CT radiopacity of at least about 6,000 Hounsfield Units (HU) at 120 kVp.

48. The microsphere of claim 43, wherein the microsphere comprises one or more of Y, Ho, Yb, Rh, Pr, Lu, Sm, Dy, Re, and Au.

49. The microsphere of claim 43, wherein the microsphere comprises one or more oxides of Y, Ho, Yb, Rh, Pr, Lu, Sm, Dy, Re, and Au.

50. The microsphere of claim 43, wherein the one or more radionuclide precursors have a mole fraction of at least about 20 mol%.

51. The microsphere of claim 43, wherein the one or more radionuclide precursors have a mole fraction of at least about 25 mol%.

52. The microsphere of claim 43, wherein the one or more radionuclide precursors have a mole fraction of at least about 30 mol%.

53. The microsphere of claim 43, wherein the one or more radionuclide precursors have a mole fraction of at least about 35 mol%.

54. The microsphere of claim 43, wherein the microsphere is substantially free of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), iodine (I), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb).

55. The microsphere of claim 43, wherein the aluminum oxide is from about 10 mol% to about 40 mol%.WSGR Docket No. 66410-702.60156. The microsphere of claim 43, wherein the silicon oxide is from about 40 mol% to about 80 mol%.

57. The microsphere of claim 43, wherein a radiopacity of the microsphere increases at least about 5% by an increase of an amount of the one or more radionuclide precursors by about 10%.

58. The microsphere of claim 57, wherein the radiopacity of the microsphere increases at least about 6% by an increase of an amount of the one or more radionuclide precursors by about 10%.

59. The microsphere of claim 43, wherein the microsphere is imageable by intra-procedural angiography, x-ray fluoroscopy, computed tomography (CT), cone-beam computed tomography (CBCT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET), or single-photon emission computed tomography (SPECT), or a combination thereof.

60. The microsphere of claim 43, wherein the microsphere comprises a metallic coating.

61. The microsphere of claim 60, wherein the coating comprises one or more of Au, Pt, Ta, and Pd.

62. The microsphere of claim 43, wherein the microsphere comprises one or more dopants.

63. The microsphere of claim 62, wherein the one or more dopants comprise one or more of titanium oxide, rhodium oxide, zinc or depleted zinc oxide, lead oxide, zirconium oxide, molybdenum oxide, manganese oxide, and vanadium oxide.

64. The microsphere of claim 62, wherein the microsphere comprises the one or more dopants with a mole fraction from about 0.1% to about 5%.

65. A method comprising: administering to a subject, a plurality of microspheres, wherein a microsphere of the plurality of microspheres is as in any one of claims 1-64.

66. The method of claim 65, further comprising: imaging at least a section of the plurality of microspheres at or near an organ of the subject.

67. The method of claim 66, wherein the organ is a liver.

68. The method of claim 66, wherein the organ is anus, arteries, appendix, adrenal gland, brain, bones, bronchi, bladder, bone marrow, bulbourethral gland, colon, cervix, clitoris, cerebellum, diaphragm, ear, eye, fallopian tube, genital, gallbladder, heart, hypothalamus, interstitium, kidney, joint, lung, larynx, ligament, lymph node, large intestine, lymphatic vessel, mouth, mesentery, mammary glands, nose, nerve, nasal cavity, ovaries, esophagus, penis, pancreas, pharynx, placenta, prostate, pineal gland, pituitary gland, parathyroid gland, rectum, skin, spleen, scrotum, stomach, spinal cord, small intestine, salivary gland, skeletal muscles, seminal vesicles, subcutaneous tissue, testes, tendons, tongue, thyroid, trachea, thymus gland, ureters, urethra, uterus, vulva, veins, vagina, vas deferens, or vestigial organ.WSGR Docket No. 66410-702.60169. The method of any one of claims 66-68, wherein the imaging is computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging.

70. The method of any one of claims 66-68, wherein the imaging is computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof.

71. The method of any one of claims 65-70, wherein the plurality of microspheres are radioactive.

72. The method of any one of claims 65-71, wherein the microsphere is a theranostic.

73. The method of any one of claims 65-71, wherein the microsphere provides radionuclide imaging and emits therapeutic radiation.

74. The method of any one of claims 65-73, wherein the microsphere is glass.

75. The method of any one of claims 65-74, wherein the administering is via intra-arterial or intravenous delivery.

76. A method comprising:(i) in a treatment planning step: administering to a subject, a first plurality of microspheres; and(ii) in a therapeutic treatment step: administering to the subject a second plurality of microspheres,wherein a microsphere of the first plurality of microspheres and the second plurality of microspheres is as in any one of claims 1-64.

77. The method of claim 76, further comprising:(i) in the treatment planning step: imaging at least a section of the first plurality of microspheres at or near an organ of the subject; and(ii) in the therapeutic treatment step: imaging at least a section of the second plurality of microspheres at or near an organ of the subject.

78. The method of claim 77, wherein the imaging in (i) and the imaging in (ii) are in realtime.

79. The method of any one of claims 76-78, wherein the imaging in (i) and the imaging in (ii) are conducted in an interventional radiology (IR) suite in which the subject is being treated.WSGR Docket No. 66410-702.60180. The method of any one of claims 76-79, wherein the first plurality of microspheres is substantially the same as the second plurality of microspheres in terms of chemical composition and / or physical characteristics.

81. The method of any one of claims 76-80, the imaging in (i) and the imaging in (ii) are computerized tomography (CT) imaging or cone-beam computed tomography (CBCT) imaging.

82. The method of any one of claims 76-80, wherein the imaging in (i) and the imaging in (ii) are computerized tomography (CT) imaging, cone-beam computed tomography (CBCT) imaging, positron emission tomography (PET) imaging, radiographic imaging, intra-procedural angiography imaging, x-ray fluoroscopy imaging, magnetic resonance imaging (MRI) imaging, ultrasound imaging, or single-photon emission computed tomography (SPECT) imaging, or a combination thereof.

83. The method of any one of claims 76-80, wherein the administering in (i) is via intraarterial or intravenous delivery.

84. The method of any one of claims 76-83, wherein the administering in (ii) is via intraarterial or intravenous delivery.

85. The method of any one of claims 76-84, wherein the subject is a human.

86. A method comprising (a) administering to a subject a microsphere comprising (i) alumina and silica, (ii) yttrium oxide, and (iii) a radiopacifying agent, wherein the radiopacifying agent comprises one or more oxides of zirconium (Zr), strontium (Sr), zinc (Zn), titanium (Ti), gadolinium (Gd), barium (Ba), tantalum (Ta), tungsten (W), platinum (Pt), bismuth (Bi), gallium (Ga), neodymium (Nd), rhodium (Rh), molybdenum (Mo), samarium (Sm), dysprosium (Dy), erbium (Er), ytterbium (Yb), palladium (Pd), cadmium (Cd), indium (In), osmium (Os), and lead (Pb), and (b) imaging a body of the subject to identify a location of the microsphere within the body of the subject.

87. The method of claim 86, wherein the microsphere is a theranostic.

88. The method of claim 86 or 87, wherein the microsphere provides radionuclide imaging and emits therapeutic radiation.

89. The method of any one of claims 86-88, wherein the microsphere is glass.

90. The method of any one of claims 86-89, wherein the radiopacifying agent is neodymium oxide.

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