Ac225-DOTA-tate conjugates

Abstract

The present disclosure relates to enriched and stable radiopharmaceutical compositions comprising [225Ac]Ac-DOTA-TATE.

Description

[0001] ENRICHED AND STABLE RADIOPHARMACEUTICAL COMPOSITIONS COMPRISING r225AClAC-DOTA-TATE

[0002] RELATED APPLICATIONS

[0003] This application is claims priority to U.S. Provisional Application No. 63 / 550,380 filed on February 6, 2024 and U.S. Provisional Application No. 63 / 727,994 filed on December 4, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] DOTA-TATE is an eight amino acid long peptide with a covalently bonded DOTA bifunctional chelator (Nockel P., et al., Thyroid. 2016, 26 (6): 831-5). DOTA-TATE can be reacted with radionuclides such as actinium-225, gallium-68, lutetium- 177, and copper-64 to form radiopharmaceuticals for positron emission tomography (PET) imaging or radionuclide therapy. Radionuclide therapy with DOTA-TATE targets somatostatin receptors (SSR) (Aktolun, C., et al., Nuclear Medicine Therapy: Principles and Clinical Applications. 2012, Springer, p. 364). Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Because somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs).

[0006] One of the major challenges in the production of radiopharmaceutical drugs is to extend the shelf-life of product to allow treatment of patients at remote locations to the manufacturer site. As a radionuclide, such as Actinium-225, decays a series of highly reactive chemicals are generated. In some cases, they can react with the drug substance, e.g., causing degradation of the radioisotope-containing drug and increasing radioactive impurity over time.

[0007] Most common radionuclide therapy production processes require the use of ICH Class 2 solvents that cannot be injected into humans, which further necessitates additional chemical processing and reformulation steps. However, these added steps often result in degradation of the radioligand therapy in the form of radiolysis. Additionally, because radioactive isotopes have a short half-life, the time between production and administration of the therapy must be minimized. Production of a pure and highly radioactive pharmaceutical that quickly tracks to a tumor will improve the odds of radiation sufficiently reaching the tumor to induce cell death.

[0008] Thus, there remains a need to develop radioligand therapies that are radioactively enriched and have prolonged stability. SUMMARY

[0009] One of the major challenges in the production of radiopharmaceutical drugs is to extend the shelf-life of products to allow for treatment of patients at locations remote from the manufacturing site. As radionuclides (such as Actinium-225) decay, a series of highly reactive chemicals are generated. In some cases, they can react with the drug substance, e.g., causing degradation of the radioisotope-containing drug and increasing radioactive impurity over time. Thus, in one aspect, provided herein are liquid radiopharmaceutical formulations that provide enhanced stability for alpha-emitting radionuclides such as Actinium-225. The present disclosure therefore addresses stability issues by providing radiopharmaceutical compositions comprising [225Ac]Ac-DOTA-TATE that are highly enriched and stable for at least 288 hours.

[0010] Thus, in an aspect, provided herein is a radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 98%, wherein [225Ac]Ac-DOTA-TATE has the structure:

[0011] In another aspect, provided herein is a radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 94%, wherein the RCP is measured by radio-HPLC.

[0012] In yet another aspect, provided herein is a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 99% and 5 pCi / nmol specific activity.

[0013] In still another aspect, provided herein is a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 95% and 5 pCi / nmol specific activity. The radiopharmaceutical compositions of the present disclosure exhibit superior stability over previously developed radiopharmaceutical compositions comprising [225Ac]Ac- DOTA-TATE.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows HPLC separation of DOTATATE and [natLa]La-DOTA-TATE following coinjection.

[0016] FIG. 2 shows HPLC separation of a [225Ac]Ac-DOTA-TATE reaction mixture with collected fractions indicated.

[0017] DETAILED DESCRIPTION

[0018] Provided herein are radiopharmaceutical compositions comprising enriched [225Ac]Ac-DOTA-TATE having high radiochemical purity (RCP) levels over an extended period of time.

[0019] The formulations and compositions disclosed herein are unexpectedly enriched in the desired radiolabeled peptide product, despite the similarity in structure and properties of the desired radiolabeled peptide and the undesired non-radiolabeled peptide starting material. An additional unexpected discovery of the disclosed formulations is that the addition of a surfactant to the formulation improves the stability of the radiolabeled peptide over an extended period of time after isolation.

[0020] Definitions

[0021] Listed below are definitions of various terms used to describe the compositions disclosed herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0022] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0023] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0024] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0025] As used herein, the term “enriched” refers to a radiolabeled peptide composition, in which the ratio of radiolabeled peptide is higher than the ratio of the non-radiolabeled peptide starting material. In an embodiment, the radiolabeled peptide composition is about 90%, 95%, 96%, 97%, 98%, of 99% enriched compared to the non-radiolabeled peptide.

[0026] As used herein, the term “stabilizing solution” refers to a solution comprising a radiolytic stabilizer. Radiolytic stabilizers are substances that prevent or decrease radiolysis, i.e. , the degradation of a target molecule by the energy of radioactive decay.

[0027] As used herein, the terms “quencher” or “quenching agent” refers to a molecule or group of molecules that can scavenge excess amounts of radionuclide starting material in the synthesis of radiolabeled compounds including radiolabeled peptides. In a non-limiting example, the quencher is diethylenetriaminepentaacetic acid (DTPA).

[0028] As used herein, “surfactant” refers to an excipient that preferentially adsorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water / air interface or organic solvent / air interface. Suitable surfactants include but are not limited to fatty alcohols such as polyethylene glycols (PEGs) and cetyl alcohol. In a non-limiting embodiment, the surfactant is a polysorbate. Polysorbates are products of the esterification of ethoxylated sorbitan (a derivative of sorbitol) with fatty acids and include (but are not limited to): polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, and polyoxyethylene (20) sorbitan monooleate. In certain embodiments provided herein, the polysorbate is polyoxyethylene (20) sorbitan monolaurate (Tween 20).

[0029] The term “buffer” refers to a solution where the pH does not change significantly on dilution or on addition of an acid or base at a constant temperature.

[0030] As used herein, the terms “radionuclide” and “radioisotope” are used interchangeably and refer to a nuclide that has excess nuclear energy that is used in one of three ways: emitted from the nucleus as gamma radiation; transferred to one of its electrons to release it as a conversion electron; or used to create and emit a new particle (alpha particle or beta particle) from the nucleus.

[0031] As used herein, the term “radiochemical purity” or “RCP” is defined as the percent of total radioactivity within a composition that corresponds to the radiolabeled drug substance (radiolabeled peptide). In an embodiment, the radiolabeled peptide is [225Ac]Ac-DOTA-TATE.

[0032] As used herein, the term “half-life” or “ti / 2” refers to the time it takes for half of the radioactive atoms of a radionuclide to decay. As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into components as a result of differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.

[0033] As used herein, the phrase “liquid chromatography” or “LC” means a process of selective retardation of one or more components of a fluid solution as the fluid uniformly percolates through a column of a finely divided substance, or through capillary passageways. The retardation results from the distribution of the components of the mixture between one or more stationary phases and the bulk fluid, (i.e. , mobile phase), as this fluid moves relative to the stationary phase(s). Examples of “liquid chromatography” include reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC), and turbulent flow liquid chromatography (TFLC) (sometimes known as high turbulence liquid chromatography (HTLC) or high throughput liquid chromatography).

[0034] The mobile phase composition may be constant (i.e., “isocratic elution” as used herein) or may be changed (i.e., “gradient elution” as used herein) during the separation process. In order to separate compositions comprising components that have very different chemical natures, additional solvents may be introduced to the column, typically by increasing the proportion of solvent in the mobile phase. In a non-limiting example, the stationary phase is C18 bonded to silica. In a non-limiting example the mobile phase includes an aqueous mixture of water and organic solvent, for example ethanol.

[0035] In some embodiments, liquid chromatography is ultra-performance liquid chromatography (LIPLC; the term “ultra high performance liquid chromatography” or LIHPLC may be used interchangeably herein). LIPLC is known in the art as an LC technique that relies upon a column with reduced particle size (e.g., less than 2 pm) and increased flow velocity to improve chromatographic resolution, efficiency, peak capacity, and sensitivity (see, e.g., Plumb, R. et al. (2004) Rapid Commun. Mass Spectrom. 18:2331-2337). In some embodiments, LIPLC refers to the use of a column with a particle size less than 2 pm in liquid chromatography. In some embodiments, LIPLC refers to the use of a high linear solvent velocity (e.g., as observed when operating at 6000 psi or higher) in liquid chromatography. Exemplary LIPLC instruments are commercially available, e.g., Waters ACQUITY Premier LIPLC H Class (Premier QSM, Premier SM-FTN, CM-A, PDA eA detector & SQD 2 mass analyzer).

[0036] As used herein, the phrase “high performance liquid chromatography” or “HPLC” (sometimes known as “high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under pressure through a stationary phase, typically a densely packed column. As used herein, the terms “extraction column” and “column” are used interchangeably to refer to a chromatography column having sufficient chromatographic plates to affect a separation of materials in a sample that elute. The general purpose of an extraction column is for separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis. Such columns are often distinguished from “analytical columns,” which allow for the determination of the presence or amount of an analyte. As used in this context, the term “about” means ±10%. In a preferred embodiment the analytical column contains particles of about 5 pm in diameter.

[0037] As used herein, the term “radiopharmaceutical composition” refers to a composition comprising at least one active ingredient in a form and amount that permits the active ingredient to be therapeutically effective and a pharmaceutically acceptable carrier or excipient.

[0038] The term “pharmaceutically acceptable,” as used herein, refers to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio (e.g., in accordance with the guidelines of government agencies or other regulatory bodies, for example, the U.S. Food and Drug Administration).

[0039] As used herein, the phrase “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0040] As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional nontoxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1 :1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0041] As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0042] As used herein, the terms “patient,” “subject,” and “individual” refer to a subject seeking treatment, in need of treatment, requiring treatment, receiving treatment, expecting treatment, or that are under the care of a trained (e.g., licensed) professional for a particular disease, disorder, or condition. Patients may include any organism. Patient treatments may include, but are not limited to, experimental, diagnostic, prophylactic, and / or therapeutic treatments. Typical patients include, but are not limited to, animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).

[0043] The term “administration” or the like as used herein refers to the providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. As used herein, the term “cancer” refers to a disease characterized by abnormal cell growth and division.

[0044] As used herein, the term “cancer cell” refers to a cell that grows and divides in an abnormal and uncontrolled manner.

[0045] As used herein, the term “tumor” refers to a group of cells forming in solid tissue as a result of abnormal cell growth and division. Benign or “noncancerous” tumors remain isolated while malignant or “cancerous” tumors include cells capable of proliferating to surrounding tissues.

[0046] As used herein, the term “therapeutically effective amount” means an amount of an agent to be delivered that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition.

[0047] As used herein, the term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e. , arresting further development of the pathology and / or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) such as decreasing the severity of the disease.

[0048] The term “prevent,” “preventing,” or “prevention” as used herein, comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

[0049] Enriched Formulations

[0050] In an aspect, provided herein is a radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 98%.

[0051] In an embodiment, the composition is stable for at least 120 hours as indicated by an RCP of greater than 99%. In another embodiment, the composition is stable for at least 168 hours as indicated by an RCP of greater than 98%. In yet another embodiment, the composition is stable for at least 200 hours as indicated by an RCP of greater than 98%. In still another embodiment, the composition is stable for at least 288 hours as indicated by an RCP of greater than 98%.

[0052] In an embodiment, the RCP is measured by radio-TLC (i-TLC).

[0053] In another aspect, provided herein is a radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 94%, wherein the RCP is measured by radio-HPLC. In an embodiment, the composition is stable for at least 120 hours as indicated by an RCP of greater than 94%, i.e. , the composition exhibits an RCP of greater than 94% following storage for 120 hours. In some embodiments, the composition is stored at 2-8 °C. In another embodiment, the composition is stable for at least 168 hours as indicated by an RCP of greater than 94%, i.e., the composition exhibits an RCP of greater than 94% following storage for 168 hours. In some embodiments, the composition is stored at 2-8 °C. In yet another embodiment, the composition is stable for at least 288 hours as indicated by an RCP of greater than 94%, i.e., the composition exhibits an RCP of greater than 94% following storage for 288 hours. In some embodiments, the composition is stored at 2-8 °C.

[0054] Specific Activity Formulations

[0055] As used herein, “specific activity” or “specific molar activity” refers to the measured radioactivity of a composition or formulation comprising [225Ac]Ac-DOTA-TATE per total moles of DOTA-TATE. A composition comprising only [225Ac]Ac-DOTA-TATE will be characterized as having the theoretical maximum specific molar activity. A composition comprising both [225Ac]Ac-labeled and unlabeled DOTA-TATE will be characterized as having a specific molar activity that is less than the theoretical maximum, and the specific molar activity decreases as the ratio of unlabeled compound to radiolabeled compound increases. Compositions that are enriched in radiolabeled compound (e.g., via chromatography, as described herein) are referred to as “high specific activity.” Nonenriched compositions are referred to as “regular specific activity” or “low specific activity.” For purposes of determining specific molar activity, radioactivity of the composition may be measured with a suitable radiodetector as described in the Examples herein. Moles (e.g., represented as millimoles or micromoles) of the compound may be calculated by known methods from measurements such as gravimetric or spectroscopic data. For example, spectroscopic data from a UV absorbance detector may be used to quantify the amount of a compound present in a chromatography eluant. From such measurements, the specific molar activity of the compound is calculated. In the case that the radioactivity of a compound may be quantified but the molar amount of the compound cannot be quantified (e.g., by data from a UV absorbance detector) because the compound is present in a quantity or at a concentration that is below the limit of quantification of the detector, the specific molar activity of the composition may be reported as a “greater than” value (e.g., > 60 pCi / nmol), such value being the quotient of the measured radioactivity divided by the limit of quantification of the device (e.g., UV absorbance detector). The upper bound of such a “greater than” value will be the theoretical maximum specific molar activity. The theoretical maximum specific molar activity of a radiolabeled compound is a function of the activity of the radiolabel and the stoichiometric ratio of the radiolabel to the compound. For example, a mono-radiolabeled compound has a stoichiometric ratio of 1 :1.

[0056] By way of example, the theoretical maximum specific molar activity of a mono-225Ac- labeled compound may be calculated as follows:

[0057] •225Ac half-life = 9.92 day = 14284.8 min

[0058] • Probability of 1 atom to decay every minute = Ln(2) / 14284.8 = 0.693 / 14284.8 = 4.85E-5

[0059] • Atom number in 1 nmol = 6.022E23 / E9 = 6.022E14

[0060] • Decay number of 1 nmol every minute= 6.022E14*4.85E-5 = 2.92E10 DPM (decay per minute)

[0061] • 1 mCi = 2.22E9 DPM (unit conversion)

[0062] • Theoretical specific activity = 2.92E10 DPM / nmol = 2.92E10 / 2.22E9 mCi / nmol = 13.2 mCi / nmol.

[0063] Accordingly, in some embodiments, an enriched radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE is characterized as having a specific molar activity in the range of 60-13200 pCi per nmol compound. In an embodiment, the radiopharmaceutical composition has a specific molar activity in the range of 60-13000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 60-100 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 60-500 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 60- 1000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 100-1000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 100-2000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 2000-3000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 3000-4000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 5000-6000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 6000-7000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 7000-8000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 8000-9000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 9000-10000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 10000-11000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 11000-12000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 12000-13000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 2000-4000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 2000-6000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 4000-6000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 4000-8000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 4000-10000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 6000-8000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 6000-10000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 6000-12000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 8000-10000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 8000-12000 pCi per nmol compound. In some embodiments, the specific molar activity is in the range of 10000-13200 pCi per nmol compound.

[0064] In an aspect, provided herein is a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 99% and 5 pCi / nmol specific activity.

[0065] In an embodiment, the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 99% and 5 pCi / nmol specific activity after addition of a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE with an RCP of about 94%. In another embodiment, the composition is stable for at least 120 hours as indicated by an RCP of greater than 99%. In yet another embodiment, the composition is stable for at least 168 hours as indicated by an RCP of greater than 99%. In still another embodiment, the composition is stable for at least 288 hours as indicated by an RCP of greater than 99%.

[0066] In an embodiment, the RCP is measured by radio-TLC (i-TLC).

[0067] In another aspect, provided herein is a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 95% and 5 pCi / nmol specific activity.

[0068] In an embodiment, the radiopharmaceutical composition has a radiochemical purity (RCP) of greater than 95% and 5 pCi / nmol specific activity after addition of a radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE with an RCP of about 94%. In another embodiment, the composition is stable for at least 120 hours as indicated by an RCP of greater than 96%. In yet another embodiment, the composition is stable for at least 168 hours as indicated by an RCP of greater than 96%. In still another embodiment, the composition is stable for at least 288 hours as indicated by an RCP of greater than 95%. In an embodiment, the RCP is measured by radio-HPLC. Pharmaceutical Compositions

[0069] The pharmaceutical compositions of the disclosure can also comprise additional excipients, including surfactants, polymers, and antioxidants. Surfactants suitable for use in the formulations of the disclosure include surfactants commonly used in the formulation of pharmaceuticals. Examples of surfactants include, but are not limited to, ionic- and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or derivatives thereof, lecithins, phospholipids, combinations thereof, and the like. Additional surfactants include but are not limited to fatty alcohols such as polyethylene glycols (PEGs) and cetyl alcohol.

[0070] Antioxidants suitable for use in the formulations of the disclosure include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassium metabisulfite, tartaric acid, citric acid, citric acid monohydrate, and sodium sulfite.

[0071] Radiopharmaceuticals and radiopharmaceutical compositions are typically prepared at radio-pharmacies or PET Centers, where they also undergo quality control testing. Once a drug product has passed the quality control (QC) process and has been released for administration to a patient, it may be administered to a patient on site, where PET scanning facilities exist, or it may be shipped to a PET scanning facility.

[0072] Regulatory standards for radioligand therapies (RLTs) require that they are sterile, pyrogen-free, safe, and effective. One of the key tests in the QC process is quantifying chemical impurities and the radiochemical purity (RCP) of the drug product. In the United States, the FDA sets the minimum threshold for all radiopharmaceuticals, including RLTs, at 90% RCP. Maintaining a high RCP up to the point of administration is critical.

[0073] RCP analysis is routinely carried out by high pressure liquid chromatography (HPLC). HPLC achieves the separation of the various components of a liquid composition due to the different interactions of the components with the stationary phase (usually a silica-based column) and the mobile phase, or eluent, that passes through the column. The chemical nature of the components determines their affinity for the stationary phase, based on the intermolecular interactions, and the time spent on the column before eluting.

[0074] Also provided herein is a pharmaceutical composition (e.g., a radiopharmaceutical composition) comprising radiolabeled compound that is radiolabeled DOTA-TATE, and a stabilizing solution. In an embodiment, the pharmaceutical composition (which comprises the stabilizing solution) comprises one or more components selected from the group consisting of: ethanol, L-methionine, selenomethionine, histidine, melatonin, a polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol.

[0075] In another embodiment, the pharmaceutical composition comprises one or more components selected from the group consisting of: ethanol, L-methionine, a polysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

[0076] In yet another embodiment, the pharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0077] It has surprisingly been found that the presence of a polysorbate (e.g., Tween 20), even in a small amount, enables the amount of ascorbic acid or a pharmaceutically acceptable salt thereof (i.e., a radiolytic stabilizer) to be reduced significantly without impacting the (high) RCP. As such, in an embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 99% for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2-8 °C. In a particular embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 99% for at least 168 hours at 2-8 °C. In an embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 98% for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2-8 °C. In a particular embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 98% for at least 168 hours at 2-8 °C. In an embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 96% for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2-8 °C. In a particular embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 96% for at least 168 hours at 2-8 °C. In an embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 94% for at least 24 hours, at least 48 hours, at least 120 hours, at least 144 hours, at least 168 hours, or at least 288 hours at 2-8 °C. In a particular embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof and the polysorbate are present in the pharmaceutical composition in amounts sufficient to provide an RCP of at least 94% for at least 168 hours at 2-8 °C.

[0078] In an embodiment, the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the pharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1. In still another embodiment, the ascorbic acid or a pharmaceutically acceptable salt thereof is present in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

[0079] In an embodiment, the polysorbate is present in the pharmaceutical composition in an amount of <0.1% (w / v) (corresponding to < 1 mg / mL), optionally 0.03-0.07% (w / v) (corresponding to 0.3-0.7 mg / mL), optionally 0.04-0.06% (w / v) (corresponding to 0.4-0.6 mg / mL), optionally about 0.05% (w / v) (corresponding to 0.5 mg / mL). In another embodiment, the polysorbate is polyoxyethylene (20) sorbitan monolaurate (Tween 20), optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the pharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

[0080] In yet another embodiment, the pharmaceutical composition further comprises L- methionine, optionally wherein the L-methionine is present in the pharmaceutical composition at a concentration of about 10 mg / mL to about 30 mg / mL.

[0081] In still another embodiment, the pharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of about 0.01 M to about 0.15 M. In an embodiment, the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate. In another embodiment, the pharmaceutical composition further comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition at about 1% v / v to about 15% v / v, optionally wherein the ethanol is present at about 5% v / v to about 10% v / v.

[0082] In yet another embodiment, the pharmaceutical composition comprises ethanol, L- methionine, a polyoxyethylene sorbitan monooleate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof. In still another embodiment, the pharmaceutical composition comprises ethanol, ammonium acetate, sodium ascorbate, L-methionine, and polyoxyethylene (20) sorbitan monolaurate. In an embodiment, the pH of the stabilized solution is about 6 and / or the pH of the pharmaceutical composition is about 6.

[0083] In another embodiment, the DOTA-TATE of the pharmaceutical composition comprises a radioisotope selected from111In,99mTc,94mTc,66Ga,67Ga,68Ga,134Ce,52Fe,169Er,72As,97Ru,203Pb,61Cu,62Cu,64Cu,67Cu,89Sr,186Re,188Re,86Y,90Y,89Zr,51Cr,52Mn,51Mn,177Lu, ,169Yb,175Yb,105Rh,166Dy,166Dy,166Ho,153Sm,149Pm,151Pm,172Tm,121Sn,117mSn,212Bi,213Bi,142Pr,143Pr,198Au,199Au,18F (e.g., [1SF]AIF),149Tb,152Tb,155Tb,161Tb,43Sc,44Sc,47Sc,212Pb,211At,223Ra,227Th,226Th,82Rb,32P,76As,89Zr,111Ag,165Er,225Ac, and227Ac. In still another embodiment, the radiolabeled compound comprises111ln (i.e. , the radioisotope is111ln). In an embodiment, the radiolabeled compound comprises177Lu (i.e., the radioisotope is177Lu). In another embodiment, the radiolabeled compound comprises225Ac (i.e., the radioisotope is225Ac).

[0084] In some embodiments, the radiolabeled compound has an affinity for a cell surface protein. In another embodiment, the affinity in units KD of < 1.0 nM. In other embodiments, the affinity is characterized as: 1.0 nM < KD 10 nM, 10 nM < KD 100 nM, or 100 nM < KD < 300 nM.

[0085] In an embodiment, the pharmaceutical composition has a total activity in the range of 0.01-1000 mCi. In some embodiments, the radioisotope is177Lu and the total activity of the pharmaceutical composition is in the range of 10-1000 mCi, for example, 10-100 mCi, 100- 200 mCi, 200-300 mCi, 300-400 mCi, 400-500 mCi, 500-600 mCi, 600-700 mCi, 700-800 mCi, 800-900 mCi, or 900-1000 mCi. In some embodiments, the radioisotope is225Ac and the total activity of the pharmaceutical composition is in the range of 0.01-5 mCi, for example, 0.1-5 mCi, 1-5 mCi, 2-5 mCi, 3-5 mCi, 4-5 mCi, 0.01-4 mCi. 0.1-4 mCi, 1-4 mCi, 2- 4 mCi, 3-4 mCi, 0.01-3 mCi. 0.1-3 mCi, 1-3 mCi, 2-3 mCi, 0.01-2 mCi. 0.1-2 mCi, 1-2 mCi, 2- 3, 0.01-1 mCi, or 0.1-1 mCi.

[0086] In another embodiment, the pharmaceutical composition has a volume of about 1- 100 mL. In an embodiment, the pharmaceutical composition has a volume of about 1-10 mL. In another embodiment, the pharmaceutical composition has a volume of about 11-20 mL. In yet another embodiment, the pharmaceutical composition has a volume of about 15 mL. In an embodiment, the pharmaceutical composition has a volume of about 21-30 mL. In still another embodiment, the pharmaceutical composition has a volume of about 31-40 mL. In an embodiment, the pharmaceutical composition has a volume of about 41-50 mL. In another embodiment, the pharmaceutical composition has a volume of about 41 mL.

[0087] In yet another embodiment, the pharmaceutical composition has a volume of about 51-60 mL. In still another embodiment, the pharmaceutical composition has a volume of about 61-70 mL. In an embodiment, the pharmaceutical composition has a volume of about 71-80 mL. In another embodiment, the pharmaceutical composition has a volume of about 81-90 mL. In yet another embodiment, the pharmaceutical composition has a volume of about 91-100 mL.

[0088] In another embodiment, the pharmaceutical composition comprises sodium ascorbate, L-methionine, polyoxyethylene (20) sorbitan monolaurate, ethanol, and acetate.

[0089] In still another embodiment, the pharmaceutical composition comprises sodium ascorbate in a concentration of about 40 mg / mL to about 60 mg / mL, L-methionine in a concentration of about 10 mg / mL to about 30 mg / mL, polyoxyethylene (20) sorbitan monolaurate in an amount of from about 0.01% w / v to about 0.1% w / v, ethanol in an amount of from about 1% v / v to about 10% v / v, and acetate in a concentration of about 0.01 M to about 0.1 M.

[0090] Theranostics

[0091] “Theranostics,” a term derived from a combination of therapeutics and diagnostics, is an emerging field of medicine where specific disease-targeting agents, e.g., radiopharmaceuticals, may be used to diagnose and treat medical conditions simultaneously or sequentially. Theranostic techniques have become an important field of research and development in medical physics, where varying the isotope of the radionuclide present in a given disease-targeting agent, e.g., a radioligand therapy, can change the disease-targeting agent from an imaging probe (by, e.g., using p+ or y emitting isotopes to facilitate positron emission tomography (PET) or single photon emission computed tomography (CT) imaging, respectively), to a therapy probe (by, e.g., using a or p- particle or Auger electron emitting isotopes to facilitate targeted radiotherapy). As such, the enriched and stable radioligand formulations of the present disclosure can be used in theranostic methods.

[0092] Methods of Treatment

[0093] In an aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a radiopharmaceutical composition disclosed herein.

[0094] In an embodiment, the cancer is a neuroendocrine tumor. In another embodiment, the cancer is a somatostatin receptor-positive (SSTR+) tumor. In yet another embodiment, the SSTR+tumor is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0095] In another embodiment, the cancer is a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a stomach cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a neuroendocrine cancer, which can optionally be recurrent. In some embodiments, the neuroendocrine cancer is refractory to a radiotherapy that comprises beta-particle emitting radionuclide. In some embodiments, the subject has received a radiotherapy that comprises beta-particle emitting radionuclide prior to the administering of the radiopharmaceutical composition. The neuroendocrine cancer can also be a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a carcinoid tumor in the lungs, gastrointestinal tract, or thymus. In another embodiment, the neuroendocrine cancer is a pancreatic neuroendocrine tumor (e.g., gastrinoma, insulinoma, glucagonoma, VIPoma), medullary thyroid carcinoma, Merkel cell carcinoma, pheochromocytoma of the adrenal gland, adrenal cancer, small cell carcinoma (such as in the lungs), or large cell carcinoid tumor (such as in the lungs).

[0096] In still another embodiment, the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt’s lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor.

[0097] In another embodiment, the cancer is selected from the group consisting of primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi’s sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small-cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous cancer, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancy, triple negative breast cancer, HER2- amplified breast cancer, nasopharageal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinomas of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumor, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomysarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancy.

[0098] In an embodiment, the cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system, chronic myeloid leukemia (CML), and leukemia.

[0099] In another embodiment, the cancer is selected from the group consisting of myeloma, lymphoma, or a cancer selected from gastric, renal, head and neck, oropharangeal, nonsmall cell lung cancer (NSCLC), endometrial, hepatocarcinoma, non-Hodgkin’s lymphoma, and pulmonary.

[0100] In an embodiment, the cancer is selected from the group consisting of prostate cancer, colon cancer, lung cancer, squamous cell cancer of the head and neck, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, breast cancer.

[0101] In an embodiment, the cancer is selected from the group consisting of tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T- cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular), lung cancer (e.g., small-cell and nonsmall cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer which may be treated by the subject compounds include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0102] Additional cancers that the radiopharmaceutical compositions described herein may be useful in treating are, for example, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. Equivalents and scope

[0103] While various disclosure embodiments have been particularly shown and described in the present disclosure, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the spirit and scope of the embodiments disclosed herein and set forth in the appended claims.

[0104] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims.

[0105] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0106] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiments of compositions disclosed herein can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[0107] All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.

[0108] EXAMPLES

[0109] The formulations and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0110] Example 1: Preparation of Enriched and Stable Radiopharmaceutical Compositions

[0111] Chromatographic separation of radiolabeled peptides from non-radiolabeled peptides by chromatography is challenging because the radiolabeled peptide often coelutes with the excess non-radiolabeled peptide starting material. The process outlined below allows for the synthesis and isolation of radioligand therapies enriched in radiolabeled peptide. DOTA-TATE (Peptide 1) can be purchased from commercial sources. The IIIPAC name for [225Ac]Ac-DOTA-TATE is (2,2',2"-(10-(2,4(R)-1-(((4R,7S,10S,13R,16S,19R)-13- ((1 / 7-indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1 S,2R)-1-carboxy-2- hydroxypropyl)carbamoyl)-16-(4-hydroxybenzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18- pentaoxo-1,2-dithia-5,8,11 ,14,17-pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan- 2-yl)amino)-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecane-1 , 4, 7-triy l)triacetate; actinium- 225(3+)), and it has the following structure:

[0112] Synthesis

[0113] Dried Actinium-225 (225Ac(l 11) nitrate or chloride), was reconstituted in weak hydrochloric acid and transferred to a pharmaceutical grade glass or reinforced plastic reaction vessel. Low molarity (0.04-0.1M) hydrochloric acid, sodium acetate buffer, and a solution of Peptide 1 were then prepared.

[0114] The HCI, buffer solution, peptide solution, and reconstituted Actinium-225 were combined in a sealed glass container and heated at 90 °C for 15 minutes in a dry heating block heater. Diethylenetriaminepentaacetic acid (DTPA) was then added to quench the reaction, and the crude reaction mixture was then analyzed by iTLC (Mobile phase 50mM EDTA, pH 5.5). Purification

[0115] A 100 l (small-scale) or a 5.5 mL (large-scale) aliquot of the crude product mixture was manually injected into an HPLC injector-loop large enough to hold the entire volume in a single injection [small scale: Waters XSelect Peptide CSH C18; 130A; 3.5 urn; 4.6x150 mm (PN 186006957) or similar; large scale: Waters XSelect Peptide CSH C18 OBD; 130A 5 urn; 10x250mm (PN 186008267), or similar].

[0116] In the small-scale purification process, an isocratic method with an 80% 1.5 mM ammonium acetate / 20% ethanol mobile phase was used over 45 min; 0.5 mL / min; 100 uL injection was applied. The retention time of the purified radiolabeled peptide was simulated using an analogous method with non-radioactive Lanthanum-based peptide (La-DOTA- TATE) against non-radiolabeled DOTA-TATE. The purified radiolabeled DOTA-TATE drug product, [225Ac]Ac- DOTA-TATE, was then diluted to strength, containing less than 10% v / v of ethanol, methionine, sodium ascorbate, and ammonium acetate buffer to mark the End of Synthesis (EOS).

[0117] In the large-scale purification process, an isocratic method was used with a mobile phase solvent of 1.5 mM ammonium acetate, with 20% v / v ethanol. The retention time of the purified radiolabeled peptide was simulated using an analogous method with non-radioactive Lanthanum-based peptide (La-DOTA-TATE) against non-radiolabeled DOTA-TATE. After elution, Tween-20 was added. The purified radiolabeled DOTA-TATE drug product, [225Ac] Ac- DOTA-TATE, was diluted to strength, containing less than 10% v / v of ethanol, methionine, sodium ascorbate, and Tween-20, in an ammonium acetate buffer to mark the EOS.

[0118] After isolation, the purified radiolabeled DOTA-TATE drug product, [225Ac] Ac- DOTA- TATE, was passed through a Millipore Millex GV sterile filter or equivalent to mark the End of Formulation (EOF). Radiochemical Purity (RCP) analysis of the sterile product is then performed using an analytical HPLC equipped with a fraction collector.

[0119] High performance liquid chromatography (HPLC) purification and RCP analysis was determined using the two high pressure liquid chromatographs below.

[0120] 1. Small Scale a. Agilent 1260 Infinity II HPLC System i. Major Components ii. 1260 Infinity II Quaternary Pump iii. 1260 Infinity II Vialsampler iv. 1260 Infinity II Diode Array Detector WR v. 1260 Infinity II Analytical FC vi. Flow-RAM with Laura for PET vii. PMT / Nal - 1" detector viii. Well type Nal / PMT

[0121] 2. Large Scale a. AUTOMATION MODULE by Optimized Radiochemical Applications, ORA sprl

[0122] 15 rue de la salette 5600 Neuville BELGIUM b. AUTOMATION SYSTEM: NEPTIS Mosaic RS® Synthesizer and NEPTIS control system c. ATTACHED HPLC with AUTOMATION Module by KNAUER Wissenschaftliche Gerate GmbH

[0123] Hegauer Weg 38 14163 Berlin Germany d. Isocratic HPLC SYSTEM: P 4.1S with 10ml pump head and UVD 2.1S e. Gradient HPLC SYSTEM: P 6.1 L Pump P 6.1 L (LPG) with 10 ml pump head.

[0124] Dispensing and Storing Radiopharmaceutical Compositions / Formulations

[0125] Bulk drug product [225Ac]Ac-DOTA-TATE was stored in a seal glass container at low temperature (-20 °C, 2-8 °C, or 25 °C) prior to dose dispensing. Additional RCP analyses were performed prior to dispensing stored purified, enriched product. After RCP analysis, the purified product is dispensed as a unit-dose or a multi-dose into a Final Product Vial (FPV).

[0126] Particular formulations of [225Ac]Ac-DOTA-TATE with corresponding RCP values are shown below in Table 1.

[0127] Table 1 iTLC method: iTLC Mobile Phase: 50 mM EDTA pH 5.5 iTLC Stationary Phase: Agilent Silica Gel Glass Microfiber

[0128] RadioHPLC method:

[0129] A = 0.1 % formic acid water

[0130] B = 0.1 % formic acid acetonitrile 1-15 minutes 20-50% B 15-20 minutes 90% B Formulation 1 comprises: Formulation 2 comprises:

[0131] 0.04 pCi / pL 0.04 pCi / pL

[0132] 50 mg / mL sodium ascorbate 50 mg / mL sodium ascorbate

[0133] 23.6 mg / mL L-methionine 23.6 mg / mL L-methionine

[0134] 0.05% (w / v) Tween-20 (0.5 mg / mL) 0.05% (w / v) Tween-20 (0.5 mg / mL)

[0135] 5% ethanol 5% ethanol

[0136] 75.3 mM ammonium acetate 75.3 mM ammonium acetate DOTA-TATE sufficient to reach 5 pCi / nmol specific activity

[0137] As can be seen in Table 1 above, the radiopharmaceutical compositions of the present disclosure exhibits the ability to spike the cold (nonradioactive) DOTA-TATE precursor to the now enriched [225Ac]Ac- DOTA-TATE product and maintain the same stability trending results equal to the enriched product, and the ability to produce an Actinium-225 [225Ac]Ac-DOTA-TATE product that is stable at high RCP over an extended period of time.

[0138] These compositions therefore extended product shelf-life stability from production to distribution, and clinical applications.

[0139] Furthermore, the present disclosure has demonstrated the enriched process has removed radioactive by-products (resulting from radiolysis) that are not detectable by any conventional analytical methods, by spiking DOTA-TATE precursor that has not gone through the radiosynthesis harsh chemicals and radiolysis, with resulting radioactive product no longer being enriched and yet resulting in equal extended stability.

[0140] Example 2: Radiochemistry Process and Formulation Development of High Specific Activity (HSA) I^AclAc-DOTA-TATE

[0141] DOTA-TATE can be purchased from commercial sources.

[0142] / .25Ac]Ac Radiolabeling of DOTA-TA TE

[0143] Reagents consisted of a 1.0 M sodium acetate buffer pH 5.5-6.0, DOTA-TATE dissolved in metal free water or 0.1 M sodium acetate buffer pH 5.5 to a concentration of 0.4-1.3 nmol / pL, and Actinium-225 (225Ac(l II) nitrate or chloride) dissolved in 0.04-0.1 M hydrochloric acid at a radioconcentration of 24.0-8.2 pCi / pL. The above reagents were mixed in various proportions such that the final concentrations present in the reaction mixture ranged from 0.04-0.15 M sodium acetate, 0.30-0.96 nmol / pL DOTA-TATE, and 1.19- 3.16 pCi / pL Actinium-225. This mixture was incubated at 90 °C for 15 minutes and shaken at 700 RPM. After 15 minutes had elapsed, the reaction was allowed to cool briefly, quenched with a solution of 0.05 mg / mL DTPA, and injected into RP-HPLC for purification as described in section II below, in 100 pL aliquots as needed. See, FIG. 2. Reaction conditions are summarized in Table 2. In Run #1, the injected activity was 74 pCi and the recovered activity was 67 pCi, resulting in a purification yield of 91% and a process yield of 80%. In Run #2, the injected activity was 541 pCi and the recovered activity was 370 pCi, resulting in a purification yield of 68% and a process yield of 58%. In Run #3, the injected activity was 76 pCi and the recovered activity was 55 pCi, resulting in a purification yield of 73% and a process yield of 67%.

[0144] Table 2. Summary of initial [225Ac]Ac-DOTA-TATE radiolabeling reaction conditions

[0145] Run #1 #2 #3

[0146] 0 1

[0147] Net sodium acetate (M) 0.04 0.15

[0148] Reaction activity (pCi) 83.5 632 82.2

[0149] Peptide mass (nmol) 25 191 20.7

[0150] Specific activity (pCi / nmol) 3.3 3.3 4.0

[0151] Reaction volume (pL) 59 200 69 - . . 5.0- 4.5- 5.0-

[0152] Reaction pH K 5.5 5.0 5.5

[0153] Incubation temperature H 90 90 90

[0154] [225AC]AC Incorporation (iTLC, %)

[0155] 99.

[0156] T= 15 min 992>99

[0157] / / . Isocratic RP-HPLC Purification Development

[0158] Isocratic RP-HPLC purification development was performed using an Agilent 1260 Infinity II system equipped with a diode array detector with detection at 220 nm. Separations were performed on a Waters XSelect Peptide CSH C18 column (130A, 3.5 pm, 4.6x150 mm). A single buffer strength was tested, 1.5 mM ammonium acetate, along with two different ethanol concentrations, 20% and 30% at 0.5 mL / min. These solvent compositions yielded buffer strengths on-column of 1.20 and 1.05 mM respectively. Internally produced DOTA-TATE and [natLa]La-DOTA-TATE were dissolved in water to a concentration of 0.47 and 0.36 nmol / uL respectively. Co-injections were performed by mixing the compounds in equivalent volumes for 5 uL injections.

[0159] Initial testing with 20% ethanol yielded very favorable results with good resolution and peak shape of both species. Several co-injections were performed to verify results and a DOTA-TATE injection performed to confirm peak identity. See, FIG. 1. III. Formulation Development

[0160] A formulation buffer consisting of ~50 mg / mL sodium ascorbate, ~24 mg / mL L- methionine, -0.05% Tween-20, and -75 mM ammonium acetate and -5% v / v ethanol was selected using the optimization strategy described above, and was able to maintain an RCP > 90% over 288 hr. During HPLC purification, fractions were collected into 2 mL HPLC vials pre-loaded with 0.75 mL of formulation buffer. Each fraction was collected for 30 seconds, yielding -0.25 mL of collected eluant and -1 mL total fraction volume post-collection.

[0161] A study was conducted to determine stability differences between the high specific activity formulation, and a reduced specific activity (i.e. , “regular specific activity) formulation (5 pCi / nmol). A precise quantification of the specific molar activity of the high specific activity formulation is unavailable due to inability to detect peptide mass at the mass loading used. Post-purification and after secular equilibrium was re-established, an aliquot of high specific activity formulation was diluted with sufficient precursor DOTA-TATE mass to achieve the 5 pCi / nmol specific activity. Samples were taken at the time points indicated in the table below and analyzed via iTLC and RP-HPLC for RCP.

[0162] Both formulations maintained a high RCP of > 90% up to the tested 288 hr. See Table 3 and Table 4.

[0163] Table 3. Summary of Regular Specific Activity (RSA) vs HSA [225Ac]Ac-DOTA-TATE %RCP up to 288 hr via iTLC stored at 2-8°C.

[0164] Run #1 #2

[0165] Regular Specific

[0166] High Specific Activity High Specific Activity

[0167] Activity (5 pCi / nmol)

[0168] Activity Stored (pCi) 58.4 186.2 183.2

[0169] Radioconcentration 0.058 0.037 0.037

[0170] (pCi / pL)

[0171] RCP (iTLC, %)

[0172] T= EOS 99.9 99.9 99.9

[0173] T=24 hr 99.4 99.9 98.8

[0174] T=48 hr - 99.9 99.8

[0175] T=120 hr - 99.7 99.2

[0176] T=144hr 98.5

[0177] T=168 hr 98.7 99.6 98.6

[0178] T=288 hr 98.8 99.3 98.5 Table 4. Summary of RSA vs HSA [225Ac]Ac-DOTA-TATE %RCP up to 288 hr via RP- HPLC stored at 2-8°C.

[0179] Run #1 #2

[0180] Regular Specific

[0181] High Specific Activity High Specific Activity

[0182] Activity (5 pCi / nmol)

[0183] Activity Stored (pCi) 58.4 186.2 183.2

[0184] Radioconcentration 0.058 0.037 0.037

[0185] (pCi / pL)

[0186] RCP (RP-HPLC, %)

[0187] T= EOS 93.4 96.2 96.2

[0188] T=24 hr 95.0 96.3 95.2

[0189] T=48 hr - 96.1 94.7

[0190] T=120 hr - 96.4 94.4

[0191] T=144hr 95.0

[0192] T=168 hr 94.8 96.1 94.4

[0193] T=288 hr 92.9 95.6 94.4 IV. Determination of RCP

[0194] The analytical conditions used for HPLC and iTLC analysis are described below in Table 5 and Table 6, respectively.

[0195] Table 5. Analytical HPLC conditions. Gradient Conditions

[0196] 1DTPA chelated [225Ac]Ac in analyses is representative of unbound [225Ac]Ac in the reaction / formulation mixtures.

[0197] Table 6. Analytical iTLC conditions.

[0198] 1DTPA chelated [225Ac]Ac in analyses is representative of unbound [225Ac]Ac in the reaction / formulation mixtures.

[0199] V. HSA f225Ac] Ac-DOT A-T ATE: Comparison of Formulation and Stability

[0200] A study was conducted to compare the stability profile of a [225Ac]Ac-DOTA-TATE formulation prepared according to the methods described herein with a formulation prepared according to a previously known method. The known method involves the chelation of radioisotope ions with an excess quantity of chelate ligands (e.g., DOTA-peptides) in a buffer with stabilizers / radioprotectants. This method results in a low specific activity radioactive product containing mostly unlabeled chelate ligands and impurities derived from a radiolabeling reaction. In contrast, the methods described herein remove excess unlabeled chelate ligands as well as impurities produced during the radiolabeling reaction conditions.

[0201] The known method is disclosed in Example 13 of United States Patent Number 11 ,819,556 and involves heating a mixture of [225Ac]Ac and DOTA-TATE to yield the product [225Ac]Ac-DOTA-TATE having a targeted specific molar activity of 5 pCi / nmol. The [225Ac]Ac- labeled DOTA-TATE was then mixed with a formulation buffer consisting of sodium ascorbate, DTPA, and saline to provide a product solution having a radioactive concentration of 0.033 pCi / pL, which was then assessed by iTLC at different time points (Table 7). Table 7.

[0202] The comparator formulation of [225Ac]Ac-DOTA-TATE was prepared and formulated in sodium ascorbate, L-methionine, Tween-20, 75 mM ammonium acetate, and ethanol, as described above, to afford a product solution having a specific molar activity of 5 pCi / nmol and a radioactive concentration of 0.033 pCi / pL. The product solution was divided into three portions, the stability of which were assessed by iTLC. See, Table 3.

[0203] EMBODIMENTS

[0204] E1. A radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 98%, wherein [225Ac]Ac-DOTA-TATE has the structure:

[0205] E2. The radiopharmaceutical composition of E1 , wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 99%.

[0206] E3. The radiopharmaceutical composition of E1 or E2, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 98%.

[0207] E4. The radiopharmaceutical composition of any one of E1-E3, wherein the composition is stable for at least 200 hours as indicated by an RCP of greater than 98%. E5. The radiopharmaceutical composition of any one of E1-E4, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 98%.

[0208] E6. The radiopharmaceutical composition of any one of E1-E5, wherein the composition is characterized as having the recited RCP upon storage at a temperature of 2-8 °C for the recited number of hours.

[0209] E7. The radiopharmaceutical composition of any one of E1-E6, wherein the RCP is measured by radio-TLC (i-TLC).

[0210] E8. A radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 94%, wherein the RCP is measured by radio-HPLC.

[0211] E9. The radiopharmaceutical composition of E8, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 94%.

[0212] E10. The radiopharmaceutical composition of E8 or E9, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 94%.

[0213] E11. The radiopharmaceutical composition of any one of E8-E10, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 94%.

[0214] E12. The radiopharmaceutical composition of any one of E1-E11, having a specific activity of at least about 5 pCi / nmol.

[0215] E13. The radiopharmaceutical composition of E12, having a specific activity of about 5 pCi / nmol.

[0216] E14. The radiopharmaceutical composition of E12, having a specific activity of greater than about 5 pCi / nmol.

[0217] E15. The radiopharmaceutical composition of E14, having a specific activity of about 60 to about 13200 pCi per nmol. E16. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a specific activity of about 5 pCi / nmol and a radiochemical purity (RCP) of greater than 99%.

[0218] E17. The radiopharmaceutical composition of E16, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 99%.

[0219] E18. The radiopharmaceutical composition of any one of E16-E17, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 99%.

[0220] E19. The radiopharmaceutical composition of any one of E16-E18, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 99%.

[0221] E20. The radiopharmaceutical composition of any one of E16-E19, wherein the RCP is measured by radio-TLC (i-TLC).

[0222] E21. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a specific activity of about 5 pCi / nmol and a radiochemical purity (RCP) of greater than 95%.

[0223] E22. The radiopharmaceutical composition of E21, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 96%.

[0224] E23. The radiopharmaceutical composition of any one of E21-E22, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 96%.

[0225] E24. The radiopharmaceutical composition of any one of E21-E23, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 95%.

[0226] E25. The radiopharmaceutical composition of any one of E21-2E4, wherein the RCP is measured by radio-HPLC.

[0227] E26. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE and having a specific activity of greater than about 5 pCi / nmol.

[0228] E27. The radiopharmaceutical composition of E26, having a specific activity of about 60 to about 13200 pCi per nmol. E28. The radiopharmaceutical composition of any one of the preceding Embodiments, comprising one or more components selected from the group consisting of ethanol, L- methionine, selenomethionine, histidine, melatonin, a polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol.

[0229] E29. The radiopharmaceutical composition of any one of the preceding Embodiments, comprising one or more components selected from the group consisting of: ethanol, L- methionine, a polysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

[0230] E30. The radiopharmaceutical composition of any one of the preceding Embodiments, wherein the radiopharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0231] E31. The radio pharmaceutical composition of E30, wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1.

[0232] E32. The radiopharmaceutical composition of any one of E30-E31, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

[0233] E33. The radiopharmaceutical composition of any one of E30-E32, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of <1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

[0234] E34. The radiopharmaceutical composition of any one of E30-E33, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL. E35. The radiopharmaceutical composition of any one of E30-E34, wherein the radiopharmaceutical composition comprises L-methionine, optionally wherein the L- methionine is present in the pharmaceutical composition in a concentration of about 10 mg / mL to about 30 mg / mL.

[0235] E36. The radiopharmaceutical composition of any one of E30-E35, wherein the radiopharmaceutical composition comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of about 0.01 M to about 0.15 M.

[0236] E37. The radiopharmaceutical composition of any one of E30-E36, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

[0237] E38. The radiopharmaceutical composition of any one of E30-E37, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

[0238] E39. The radiopharmaceutical composition of any one of any one of the preceding Embodiments, wherein the pH of the radiopharmaceutical composition is about 6.

[0239] E40. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0240] E41. The radiopharmaceutical composition of E40, wherein the ascorbic acid or pharmaceutically acceptable salt thereof, and the polysorbate, are present in amounts sufficient to provide an RCP of at least 94% (as measured by HPLC) for at least 168 hours at 2-8 °C, or an RCP of at least 98% (as measured by radio-HPLC) for at least 168 hours at 2-8 °C.

[0241] E42. The radiopharmaceutical composition of E40 or E41 , wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1 , optionally about 100:1. E43. The radiopharmaceutical composition of any one of E40-E42, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

[0242] E44. The radiopharmaceutical composition of any one of E40-E43, wherein the ascorbic acid or pharmaceutically acceptable salt thereof is sodium ascorbate, optionally wherein the sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 30 mg / mL to about 70 mg / mL.

[0243] E45. The radiopharmaceutical composition of any one of E40-E44, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of <1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

[0244] E46. The radiopharmaceutical composition of any one of E40-E45, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

[0245] E47. The radiopharmaceutical composition of any one of E40-E46, wherein the radiopharmaceutical composition further comprises L-methionine, optionally wherein the L- methionine is present in the pharmaceutical composition in a concentration of about 10 mg / mL to about 30 mg / mL.

[0246] E48. The radiopharmaceutical composition of any one of E40-E47, wherein the radiopharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of about 0.01 M to about 0.15 M.

[0247] E49. The radiopharmaceutical composition of any one of E40-E48, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

[0248] E50. The radiopharmaceutical composition of any one of E40-E49, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

[0249] E51. The radiopharmaceutical composition of any one of E40-E50, wherein the pH of the radiopharmaceutical composition is about 6.

[0250] E52. A method of making a radiopharmaceutical composition comprising [225Ac]Ac-DOTA- TATE, comprising contacting DOTA-TATE with225Ac in the presence of acetic acid or a salt thereof to obtain [225Ac]Ac- DOTA-TATE.

[0251] E53. The method of E52, comprising contacting DOTA-TATE with225Ac in the presence of acetic acid or a salt thereof, and hydrochloric acid.

[0252] E54. The method of any one of E52-E53, wherein said contacting comprises heating.

[0253] E55. The method of any one of E52-E54, wherein the [225Ac]Ac- DOTA-TATE is purified by chromatography.

[0254] E56. The method of any one of E52-E55, wherein the [225Ac]Ac- DOTA-TATE is formulated with a formulation buffer comprising one or more radiostabilizers to obtain the radiopharmaceutical composition comprising [225Ac]Ac- DOTA-TATE.

[0255] E57. The method of E56, wherein the formulation buffer further comprises a surfactant.

[0256] E58. The method of any one of E56-E57, wherein the formulation buffer comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0257] E59. The method of any one of E56-E58, wherein the formulation buffer further comprises L-methionine.

[0258] E60. The method of any one of E56-E59, wherein the formulation buffer further comprises ethanol.

[0259] E61. The method of any one of E56-E60, wherein the radiopharmaceutical composition comprises [225Ac]Ac-DOTA-TATE, sodium ascorbate, polyoxyethylene (20) sorbitan monolaurate, L-methionine, ammonium acetate, ethanol, and water. E62. A radiopharmaceutical composition prepared according to the method of any one of E52-E61.

[0260] E63. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the radiopharmaceutical composition of any one of E1- E51 and E62.

[0261] E64. The method of E63, wherein the cancer is a neuroendocrine tumor.

[0262] E65. The method of E63 or E64, wherein the cancer is a somatostatin receptor-positive (SSTR+) tumor.

[0263] E66. The method of E65, wherein the SSTR+tumor is gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0264] Although the methods and pharmaceutical compositions of the disclosure have been described in some detail by way of illustration and example for purposes of clarity of understanding, one of ordinary skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference, including all of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety, to the extent not inconsistent with the present description. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

CLAIMS1. A radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 98%, wherein [225Ac]Ac-DOTA-TATE has the structure:

2. The radiopharmaceutical composition of claim 1 , wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 98%.

3. The radiopharmaceutical composition of claim 1 or 2, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 98%.

4. The radiopharmaceutical composition of any one of claims 1-3, wherein the composition is stable for at least 200 hours as indicated by an RCP of greater than 98%.

5. The radiopharmaceutical composition of any one of claims 1-4, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 98%.

6. The radiopharmaceutical composition of any one of claims 1-5, wherein the composition is characterized as having the recited RCP upon storage at a temperature of 2-8 °C for the recited number of hours.

7. The radiopharmaceutical composition of any one of claims 1-6, wherein the RCP is measured by radio-TLC (i-TLC).

8. A radiopharmaceutical composition comprising enriched [225Ac]Ac-DOTA-TATE having a radiochemical purity (RCP) of greater than 94%, wherein the RCP is measured by radio-HPLC.

9. The radiopharmaceutical composition of claim 8, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 94%.

10. The radiopharmaceutical composition of claim 8 or 9, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 94%.

11. The radiopharmaceutical composition of any one of claims 8-10, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 94%.

12. The radiopharmaceutical composition of any one of claims 1-11, having a specific activity of at least about 5 pCi / nmol.

13. The radiopharmaceutical composition of claim 12, having a specific activity of about 5 pCi / nmol.

14. The radiopharmaceutical composition of claim 12, having a specific activity of greater than about 5 pCi / nmol.

15. The radiopharmaceutical composition of claim 14, having a specific activity of about 60 to about 13200 pCi per nmol.

16. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a specific activity of about 5 pCi / nmol and a radiochemical purity (RCP) of greater than 99%.

17. The radiopharmaceutical composition of claim 16, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 99%.

18. The radiopharmaceutical composition of any one of claims 16-17, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 99%.

19. The radiopharmaceutical composition of any one of claims 16-18, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 99%.

20. The radiopharmaceutical composition of any one of claims 16-19, wherein the RCP is measured by radio-TLC (i-TLC).

21. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, wherein the radiopharmaceutical composition has a specific activity of about 5 pCi / nmol and a radiochemical purity (RCP) of greater than 95%.

22. The radiopharmaceutical composition of claim 21, wherein the composition is stable for at least 120 hours as indicated by an RCP of greater than 96%.

23. The radiopharmaceutical composition of any one of claims 21-22, wherein the composition is stable for at least 168 hours as indicated by an RCP of greater than 96%.

24. The radiopharmaceutical composition of any one of claims 21-23, wherein the composition is stable for at least 288 hours as indicated by an RCP of greater than 95%.

25. The radiopharmaceutical composition of any one of claims 21-24, wherein the RCP is measured by radio-HPLC.

26. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE and having a specific activity of greater than about 5 pCi / nmol.

27. The radiopharmaceutical composition of claim 26, having a specific activity of about 60 to about 13200 pCi per nmol.

28. The radiopharmaceutical composition of any one of the preceding claims, comprising one or more components selected from the group consisting of ethanol, L-methionine, selenomethionine, histidine, melatonin, a polysorbate, ammonium acetate, ascorbic acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, benzyl alcohol, p-aminobenzoic acid or a pharmaceutically acceptable salt thereof, cysteamine, 5-amino-2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof, nicotinic acid or a pharmaceutically acceptable salt thereof, nicotinamide, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol.

29. The radiopharmaceutical composition of any one of the preceding claims, comprising one or more components selected from the group consisting of: ethanol, L-methionine, apolysorbate, ascorbic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

30. The radiopharmaceutical composition of any one of the preceding claims, wherein the radiopharmaceutical composition comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

31. The radio pharmaceutical composition of claim 30, wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1.

32. The radiopharmaceutical composition of any one of claims 30-31 , wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

33. The radiopharmaceutical composition of any one of claims 30-32, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of <1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

34. The radiopharmaceutical composition of any one of claims 30-33, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

35. The radiopharmaceutical composition of any one of claims 30-34, wherein the radiopharmaceutical composition comprises L-methionine, optionally wherein the L- methionine is present in the pharmaceutical composition in a concentration of about 10 mg / mL to about 30 mg / mL.

36. The radiopharmaceutical composition of any one of claims 30-35, wherein the radiopharmaceutical composition comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of about 0.01 M to about 0.15 M.

37. The radiopharmaceutical composition of any one of claims 30-36, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

38. The radiopharmaceutical composition of any one of claims 30-37, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

39. The radiopharmaceutical composition of any one of any one of the preceding claims, wherein the pH of the radiopharmaceutical composition is about 6.

40. A radiopharmaceutical composition comprising [225Ac]Ac-DOTA-TATE, ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

41. The radiopharmaceutical composition of claim 40, wherein the ascorbic acid or pharmaceutically acceptable salt thereof, and the polysorbate, are present in amounts sufficient to provide an RCP of at least 94% (as measured by HPLC) for at least 168 hours at 2-8 °C, or an RCP of at least 98% (as measured by radio-HPLC) for at least 168 hours at 2-8 °C.

42. The radiopharmaceutical composition of claim 40 or 41, wherein the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the radiopharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1 , optionally about 100:1.

43. The radiopharmaceutical composition of any one of claims 40-42, wherein the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the radiopharmaceutical composition in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

44. The radiopharmaceutical composition of any one of claims 40-43, wherein the ascorbic acid or pharmaceutically acceptable salt thereof is sodium ascorbate, optionally wherein the sodium ascorbate is present in the radiopharmaceutical composition in an amount of about 30 mg / mL to about 70 mg / mL.

45. The radiopharmaceutical composition of any one of claims 40-44, wherein the polysorbate is present in the radiopharmaceutical composition in an amount of <1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5 mg / mL.

46. The radiopharmaceutical composition of any one of claims 40-45, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the radiopharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

47. The radiopharmaceutical composition of any one of claims 40-46, wherein the radiopharmaceutical composition further comprises L-methionine, optionally wherein the L- methionine is present in the pharmaceutical composition in a concentration of about 10 mg / mL to about 30 mg / mL.

48. The radiopharmaceutical composition of any one of claims 40-47, wherein the radiopharmaceutical composition further comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of about 0.01 M to about 0.15 M.

49. The radiopharmaceutical composition of any one of claims 40-48, wherein the acetic acid or a pharmaceutically acceptable salt thereof is ammonium acetate.

50. The radiopharmaceutical composition of any one of claims 40-49, wherein the radiopharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

51. The radiopharmaceutical composition of any one of claims 40-50, wherein the pH of the radiopharmaceutical composition is about 6.

52. A method of making a radiopharmaceutical composition comprising [225Ac]Ac-DOTA- TATE, comprising contacting DOTA-TATE with225Ac in the presence of acetic acid or a salt thereof to obtain [225Ac]Ac- DOTA-TATE.

53. The method of claim 52, comprising contacting DOTA-TATE with225Ac in the presence of acetic acid or a salt thereof, and hydrochloric acid.

54. The method of any one of claims 52-53, wherein said contacting comprises heating.

55. The method of any one of claims 52-54, wherein the [225Ac]Ac- DOTA-TATE is purified by chromatography.

56. The method of any one of claims 52-55, wherein the [225Ac]Ac- DOTA-TATE is formulated with a formulation buffer comprising one or more radiostabilizers to obtain the radiopharmaceutical composition comprising [225Ac]Ac- DOTA-TATE.

57. The method of claim 56, wherein the formulation buffer further comprises a surfactant.

58. The method of any one of claims 56-57, wherein the formulation buffer comprises ascorbic acid or a pharmaceutically acceptable salt thereof, and a polysorbate.

59. The method of any one of claims 56-58, wherein the formulation buffer further comprises L-methionine.

60. The method of any one of claims 56-59, wherein the formulation buffer further comprises ethanol.

61. The method of any one of claims 56-60, wherein the radiopharmaceutical composition comprises [225Ac]Ac- DOTA-TATE, sodium ascorbate, polyoxyethylene (20) sorbitan monolaurate, L-methionine, ammonium acetate, ethanol, and water.

62. A radiopharmaceutical composition prepared according to the method of any one of claims 52-61.

63. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the radiopharmaceutical composition of any one of claims 1-51 and 62.

64. The method of claim 63, wherein the cancer is a neuroendocrine tumor.

65. The method of claim 63 or 64, wherein the cancer is a somatostatin receptor-positive (SSTR+) tumor.

66. The method of claim 64, wherein the SSTR+tumor is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

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