PSMA-targeted radiopharmaceuticals for treatment of cancer

Abstract

A treatment for patients having cancer expressing Prostate Cancer Specific Membrane Antigen (PSMA) is disclosed. Said treatment involves the use of an 225Ac-radioconjugate, in particular 225Ac-PSMA-I&T. A dosage regimen that entails more frequent administration of the 225Ac-radioconjugate at lower dose level may be employed. This involves the use of a dosage of 50-75 kBq / kg of body weight on a dosing schedule of every 4-6 weeks. A flat dosing may also be employed where the dose does not depend on the body weight of the subject. Such dosing improve the benefit / risk profile with fewer adverse events and less discontinuations, dosing interruptions and reductions in dose. Of particular importance is a reduction in salivary gland toxicity and xerostomia.

Description

Medicines radioactive Targets PSMA Treatment cancer Technical background of the invention As a transmembrane glycoprotein antigen, prostate-specific membrane antigen (PSMA) is highly expressed in high-grade and advanced-stage prostate cancer, making it an attractive target for diagnostic and therapeutic approaches. PSMA has also become one of the most promising molecular targets in nuclear medicine. Several PSMA-targeted radiopharmaceuticals, such as radiolabeled imaging and radiolabeled therapy, have been developed and translated into clinical applications. Among these, PSMA genes labeled with [missing information - likely "Psma"] are considered promising. 225 Ac is more effective in treating prostate cancers due to its higher alpha emission energy, shorter range, and stronger lethal effect on tumor cells, compared to beta-emitting agents such as 177 However, there are some toxicities and side effects associated with PSMA-tagged genes. 225 Ac. For example, dry mouth (or severe dry mouth) was the predominant side effect of the genes 225 Ac-PSMA in clinical studies, which may have a negative impact on gene use 225 Ac-PSMA. Therefore, there is a need for improved treatment for PSMA-expressing cancers without the major side effects mentioned above. Invention Disclosure Current research includes the understanding that genes 225 Ac-PSMA, such as 225 Ac-PSMA-I&T, in a specific dosing regimen, may provide a less toxic treatment with improved efficacy. Radioactive decay can cause direct physical damage (such as single- or double-stranded DNA fractures) or indirect damage (such as effects on neighboring cells or cross-linking effects) to the biomolecules that make up the cell. Drugs that deliver radionuclides to cancer cells, i.e., radiopharmaceuticals or radioconjugates, provide a mechanism for generating DNA damage with a therapeutic anticancer effect. Current research offers the potential for using a radioconjugate. 225 Ac, which targets PSMA-positive tumors and uses actinium-225 to target cancer cells, in a specific dosing regimen to treat or improve cancer, such as prostate cancer. More specifically, methods are provided to treat a patient with cancer expressing PSMA, where the method involves giving the patient a therapeutically effective amount of the radioactive conjugate. 225 Ac, Where the radioactive conjugate is included 225 Ac on 225 Ac chelated with a compound of formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof: (I)، Where the radioactive conjugate is given 225 AC at a dose of approximately 50 kBc / kg to approximately 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 4-6 weeks. In some incarnations, the radioactive conjugate is included 225 Ac on 225 Ac chelated with the following structure, i.e. 225 Ac-PSMA-I&T: In some incarnations, the radioactive conjugate is given 225 AC at a dose of 50-75 kBc / kg of the aforementioned patient's body weight. In some incarnations, the radioactive conjugate is given 225 AC according to a dosing schedule every 4 or 6 weeks. In some incarnations, the radioactive conjugate is given 225 AC at a dose of 50 kBc / kg of the patient’s body weight according to a dosing schedule every 4 weeks, or a dose of 75 kBc / kg of the patient’s body weight according to a dosing schedule every 6 weeks. In some incarnations, the radioactive conjugate is given 225 Ac for the aforementioned patient for a minimum of 4 cycles. In some incarnations, the radioactive conjugate is included 225 Ac on 225 Ac is chelated to the following structure: Where the radioactive conjugate is given 225 AC at a dose of 50 kBc / kg of the patient’s body weight according to a dosing schedule every 4 weeks, or a dose of 75 kBc / kg of the patient’s body weight according to a dosing schedule every 6 weeks. In some embodiments, administration results in an absorbed dose of at least 10 Gy per cycle in a tumor in the aforementioned patient. In some embodiments, administration results in a cumulative absorbed dose of at least 30 Gy in a tumor in the aforementioned patient. In some embodiments, administration results in an absorbed dose of no more than 25 Gy per cycle in the salivary gland of the aforementioned patient. In some embodiments, administration results in a cumulative absorbed dose of no more than 100 Gy in the salivary gland of the aforementioned patient. In some incarnations, the PSMA-expressing cancer is selected from a group that includes prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, testicular cancer, neuroendocrine cancer, and brain tumors. In certain incarnations, the PSMA-expressing cancer is prostate cancer, such as metastatic castration-resistant prostate cancer (mCRPC). Brief description of the drawings Figure 1: Spider diagram showing the initial change in prostate-specific antigen (PSA) in group 1 as illustrated in Example 6. Figure 2: A spider diagram showing the initial change in prostate-specific antigen (PSA) in group 2 as illustrated in Example 6. Figure 3: A spider diagram showing the initial change in prostate-specific antigen (PSA) in group 3 as illustrated in Example 6. Detailed description of the invention The current detection involves the use of a radioactive conjugate. 225 Ac, like 225 Ac-PSMA-I&T, in a specific dosing regimen, is used to treat PSMA-expressing cancer without significant toxicity or side effects associated with 225 Ac. Radiation-labeled targeted clefts (also known as radiopharmaceuticals or radiolabeled conjugates) are designed to target a protein or receptor (such as PSMA) that is highly expressed in the disease state and / or is specific to the affected cells (such as tumor cells) to deliver a radioactive payload to damage and kill the target cells. It was used 225 Ac-PSMA-I&T has been used in clinical trials for the treatment of advanced metastatic castration-resistant prostate cancer (mCRPC). However, significant side effects such as dry mouth have been observed in patients. Dry mouth can be a life-threatening event. Administering this medication may lead to... 225 Ac-PSMA-I&T, when administered in a specific dosing regimen—such as a lower dose and more frequent schedule—improves the benefit-risk ratio for patients while reducing adverse events attributable to salivary gland toxicity. This may lead to fewer treatment discontinuations, dose interruptions, and dose reductions due to xerostomia. Improved safety characteristics may also enable the administration of more treatment cycles, which would translate into better long-term outcomes in terms of disease progression-free survival and overall survival in patients previously treated with PSMA-targeted beta-emitting radiotherapy. The dosing system provides administration 225 Ac-PSMA-I&T, administered more frequently and at lower dose levels, offers the theoretical advantage of a higher cumulative radiation dose to the target tissue / tumor lesion while reducing secondary toxicity from non-specific binding (e.g., to the salivary glands) of the radiopharmaceutical. The primary reason for using multiple low-dose treatments (or so-called "dose segmentation") is to exploit the difference between fast-responding and slow-responding tissues. The effect of radiation on fast-responding tissues can be reduced by extending the treatment time and segmenting the dose (e.g., a single dose over fewer sessions). The effect of radiation on slow-responding tissues will not change significantly if the total cumulative dose remains unchanged. By using 225 Ac-PSMA-I&T in a specific dosing regimen, such as a dose of approximately 50 kBc / kg to approximately 75 kBc / kg of the patient’s body weight according to a dosing schedule every 4-6 weeks, may reduce the dose absorbed in each administration to the salivary glands, resulting in a lower incidence of dry mouth. Definitions Terminology Chemical The term "isomer," as used here, refers to any chemical isomer, stereoisomer, homolog, or diisomer of a compound. It is generally accepted that a compound with the first formula contains one or more chiral centers and can therefore exist as stereoisomers, such as diisomers (i.e., isomers (+ or -)). Unless otherwise stated, the chemical structures described here include all corresponding stereoisomers, i.e., both the stereopure form (i.e., geometrically, stereoisomerally, or stereoisomerically pure) and stereoisomer-stereomixtures, such as racemes. Stereoisomer-stereomixtures of compounds can usually be separated into their stereoisomer or stereoisomer components by well-established methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers and stereoisomers can also be obtained from stereotactically or stereotactically pure reaction media, reagents, or catalysts by well-known asymmetric synthetic methods. The term "stereoisomer," as used here, refers to all the different isomerization and conformational forms that a compound (such as a compound of any formula shown here) may possess, and in particular all the stereoisomers, conformations, and / or isomers of the basic molecular structure. Some compounds may exist in different chemical analogs, all of which fall within the scope of the current investigation. The term "double isomer," as used here, refers to spatial isomers that are not mirror images of each other and cannot be superimposed onto each other. The term “isomer,” as used here, means every optically active form of a compound, possessing an optical purity or isomer excess (as determined by standard field methods) of not less than 80% (i.e., not less than 90% of one isomer and not more than 10% of the other isomer), preferably not less than 90% and ideally not less than 98%. Terminology Other As used here, the term “approximately” or “about” refers to a variation of ±10% of the stated quantified value (including the stated quantified value itself) unless otherwise stated or inferred from the context. For example, unless otherwise stated or inferred from the context, a dose of approximately 75 kBc / kg refers to a dose range of 75 ± 10% kBc / kg, i.e., from 67.5 kBc / kg to 82.5 kBc / kg, including the two limiting values. As used here, "administering" an active substance to a patient involves contact of the patient's cells with the active substance. The term "cancer" refers to any cancer resulting from the proliferation of malignant tumor cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. "Solid tumor cancer" is cancer that consists of an abnormal mass of tissue, such as sarcomas, carcinomas, and lymphomas. "Hematological cancer" or "liquid cancer," as they are sometimes used interchangeably here, is cancer that occurs in the body's fluids, such as lymphomas and leukemias. The term "chelate," as used here, refers to an organic compound or part thereof that can be attached to a central metal or radioactive atom at two or more points. The term "conjugate," as used here, refers to a molecule containing a chelating group or a metal complex thereof, a bonding group, and may optionally contain a therapeutic moiety or a targeted cleft. As used here, the term "compound" means all stereoisomers, geometric isomers, and chemical isomers of the structures shown. The compounds described here may be asymmetric (i.e., contain one or more stereocenters). All stereoisomers, such as isomers and diisomers, are intended unless otherwise stated. The compounds identified here, which contain asymmetrically substituted carbon atoms in optically active or racemic forms, may be isolated. Methods for preparing optically active forms from optically active precursors are well-established in the field, such as the separation of racemic mixtures or stereoselective synthesis. Several geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described here, and all such stable isomers are described in the present identification. The cis and trans geometric isomers of the compounds identified here are described and may be isolated as mixtures of isomers or as separate isomer forms. Current detection compounds also include chemical isomers. Chemical isomers arise from the substitution of a single bond with an adjacent double bond and the accompanying migration of a proton. Chemical isomers include protonated isomers, which are isomerized protonated (added proton) states that have the same empirical formula and net charge. Examples of protonated isomers include ketone-enol pairs, amide-imide pairs, lactam-lactim pairs, amide-imide pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Chemical isomers can be in equilibrium or stereolocked in a single form by appropriate substitution. As used here, the terms “decrease,” “increase,” or “decrease” (e.g., in reference to therapeutic outcomes or effects) refer to relative meanings of a reference level. In some embodiments, the reference level is a level determined using the method described with a control group in an experimental animal model or clinical trial. In some embodiments, the reference level is a level in the same patient before or at the start of treatment. In some embodiments, the reference level is the average level in a group not receiving the treatment described. The term “effective amount” of an active substance (e.g., any of the above-mentioned conjugates), as used here, refers to the amount sufficient to achieve beneficial or desirable results, such as clinical outcomes. Thus, the “effective amount” depends on the context in which it is applied. The term "pharmaceutical formulation," as used here, refers to a formulation containing the compound described herein formulated with a pharmacologically acceptable excipient. In some formulations, the pharmaceutical formulation is manufactured or sold with the approval of a government regulatory agency as part of a treatment regimen for disease in mammals. Pharmaceutical formulations may be formulated, for example, for oral administration as a unit-dose form (e.g., tablet, capsule, microcapsule, gel capsule, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile embolic particle solution in a solvent suitable for intravenous use); or in any other formulation described herein. The term "pharmaceuticalally acceptable excipient," as used here, refers to any component other than the compounds described herein (e.g., a substance capable of suspending or dissolving the active compound) that has non-toxic and non-inflammatory properties in the patient. Excipients may include, for example: anti-adhesives, antioxidants, binders, coatings, pressure modifiers, dispersants, dyes (colors), emulsifiers, fillers (thinning agents), or coatings, flavorings, perfumes, slip agents (flow enhancers), lubricants, preservatives, printing inks, radiation shielding agents, absorbents, suspending or dispersing agents, sweeteners, or humidifying water.Examples of excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer solution, butylhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, precrystalline starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc. Titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The term "pharmaceuticalally acceptable salt," as used here, refers to salts of the compounds described herein that are, within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic response. Pharmaceuticalally acceptable salts are well-established in the field. For example, pharmacologically acceptable salts have been described in: Berge et al. J. Pharmaceutical Sciences 66:1-19, 1977 And in Pharmaceutical Salts: Properties Selection, and Use (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared on-site during the final isolation and purification of the compounds described here or separately by reacting the free base group with a suitable organic acid. Compounds may contain ionizable groups, enabling them to be prepared as pharmacologically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of acidic forms of the compounds, they may be prepared from inorganic or organic bases. Compounds are often prepared or used as pharmacologically acceptable salts as addition products of pharmacologically acceptable acids or bases. Suitable pharmacologically acceptable bases and acids are well-known in the field, such as hydrochloric, sulfuric, hydroporic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, and various amines for forming basic salts. Methods for preparing suitable salts are well-established in the field. Typical acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzisulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecylsulfate, ethansulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethansulfonate, lactopionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, bivalate, propionate, stearate, succinate, sulfate. Tartrates, thiocyanates, toluenesulfonates, undecylenates, valerates, among other salts.Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, tetraammonium, and amine ions, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. The term “radiotherapy” or “radioconjugate,” as used here, refers to any compound or conjugate containing a radioactive isotope or radionuclide, such as the radioactive isotope or radionuclide described here. The term "prodrug," as used here, refers to a pharmaceutically inactive compound or drug that is given in its inactive form and is converted into a pharmaceutically active drug within the body through metabolism or other chemical reactions. As used here, and as is well understood in the field, “treating” or “treating” a condition (e.g., the conditions described here, such as cancer) means an approach to obtaining beneficial or desirable outcomes, such as clinical results. Beneficial or desirable outcomes may include, but are not limited to, the relief or improvement of one or more symptoms or conditions; a reduction in the extent of the disease, disorder, or condition; stabilization (i.e., no worsening) of the disease, disorder, or condition; prevention of the spread of the disease, disorder, or condition; delay or slow the progression of the disease, disorder, or condition; improvement or relief of the disease, disorder, or condition; and a cure (either partial or complete), whether detectable or undetectable. In the context of cancer treatment, “improvement” may include, for example, a reduction in the incidence of metastases, a reduction in tumor size, a reduction in tumor angiogenesis, and / or a reduction in the rate of tumor growth. “Relief” of a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are reduced and / or its progression is slowed or prolonged, compared to the extent or progression in the absence of treatment. Subjects Treatment In the methods revealed here, the radioactive conjugate is given 225 Ac for a patient with cancer who expresses PSMA or is at risk of developing this cancer. In some incarnations, the patient may have been diagnosed with cancer. The cancer may be primary or metastatic. The patient may have any stage of cancer, such as stage I, stage II, stage III, or stage IV, with or without lymph node involvement and with or without metastases. The approaches presented may prevent or reduce further cancer growth and / or otherwise improve the cancer (e.g., prevent or reduce metastases). In other incarnations, the patient does not have cancer but has been identified as being at risk for developing a PSMA-expressing cancer, for example, due to one or more risk factors such as environmental exposure, the presence of one or more genetic mutations or variants, family history, etc. In some incarnations, the PSMA-expressing cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, testicular cancer, neuroendocrine cancer, and brain tumors. In some incarnations, the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer (mCRPC). Giving and the dose Doses Effective or Therapeutically effective In some incarnations, the radioactive conjugate is given 225 Ac, or a pharmaceutical formulation containing it, as described here, is given to a patient in a manner (e.g., dosage and timing) sufficient to treat or at least partially halt the symptoms and complications of the disorder. In the context of monotherapy (“monotherapy”), the amount sufficient to achieve this purpose is defined as the “therapeutically effective amount,” which is the amount of the compound sufficient to significantly improve one or more of the symptoms associated with the disease or medical condition. The therapeutically effective amount typically varies depending on the treatment. For well-known treatments, the relevant therapeutically effective amounts may be known or readily identifiable by an expert in the field. For example, in cancer treatment, any substance or compound that reduces, prevents, delays, inhibits, or stops any symptom of the disease or condition is considered therapeutically effective. A therapeutically effective amount of a substance or compound does not need to cure the disease or condition, but it will provide treatment for the disease or condition such that its onset is delayed, impeded, or prevented; its symptoms are improved; its course is altered; or, for example, it is less severe or the individual's recovery is accelerated. For instance, a treatment may be therapeutically effective if it causes the cancer to regress or slow its growth. The effective dosing regimen (e.g., the amount of each treatment, the relative timing of treatments, etc.) for these uses may depend on the severity of the disease or condition, the patient's weight, and their overall health. For example, the effective therapeutic dose of a given formulation containing a therapeutic agent applied to mammals (e.g., humans) may be determined by an experienced practitioner, taking into account individual differences in age, weight, and condition of the mammal. Since some of the conjugates mentioned in this disclosure exhibit enhanced ability to target and deposition within cancer cells, the dose of these compounds may be less than (e.g., less than or equal to approximately 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of) the equivalent dose required to achieve a therapeutic effect of the unconjugate substance. Effective and / or optimal therapeutic amounts can also be determined experimentally by an expert in the field. Single or multiple administrations of a radioconjugate can be performed. 225 AC or a combination (e.g., a pharmaceutical formulation containing a therapeutic agent or radiopaque conjugate) 225 Ac) with dosage levels and patterns determined by the treating physician. The dosage and administration schedule can be determined and adjusted based on the severity of the patient's illness or condition, which can be monitored throughout the treatment period according to common practices of clinicians or those described here. In some incarnations, the radioactive conjugate is given 225 Ac in a single dose. In some formulations, the radioactive conjugate is administered. 225 Ac more than once, i.e., multiple doses. When administering the radioactive conjugate 225 AC more than once, the dose for each administration may be the same or different.Pharmaceutical formulations containing a radioactive conjugate can be formulated 225 AC is for use according to the methods and systems identified in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers may also be included in the formulation to achieve the appropriate formulation. Examples of appropriate formulations are found in Remington's Pharmaceutical Sciences Mack Publishing Company, Philadelphia, PA, 17th ed., 1985. For a brief review of drug delivery methods, see, for example, Langer Science 249:1527-1533, 1990)). giving The accompanying radioactive 225 Ac The current discovery provides avenues for treating patients with PSMA-expressing cancer. One approach involves administering a therapeutically effective dose of the radioconjugate to the patient. 225 Ac , Where the radioactive conjugate is included 225 Ac on 225 Ac Chelated to a compound of formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof: (I)، Where the radioactive conjugate is given 225 AC at a dose of approximately 50 kBc / kg to approximately 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 4-6 weeks. As explained above, a dose of approximately 75 kBc / kg indicates a dose range of 75 ± 10% kBc / kg, i.e., from 67.5 kBc / kg to 82.5 kBc / kg, including the two limiting values. Similarly, a dose of approximately 50 kBc / kg indicates a dose range of 50 ± 10% kBc / kg, i.e., from 45 kBc / kg to 55 kBc / kg, including the two limiting values. Therefore, the radioactive conjugate can be administered 225 AC at a dose of 45 kBc / kg, 46 kBc / kg, 47 kBc / kg, 48 kBc / kg, 49 kBc / kg, 50 kBc / kg, 51 kBc / kg, 52 kBc / kg, 53 kBc / kg, 54 kBc / kg, 55 kBc / kg, 56 kBc / kg, 57 kBc / kg, 58 kBc / kg, 59 kBc / kg, 60 kBc / kg, 61 kBc / kg, 62 kBc / kg, 63 kBc / kg, 64 kBc / kg, 65 kBc / kg, 66 kBc / kg, 67 kBc / kg, 68 kBc / kg, 69 kJ / kg, 70 kJ / kg, 71 kJ / kg, 72 kJ / kg, 73 kJ / kg, 74 kJ / kg, 75 kJ / kg, 76 kJ / kg, 77 kJ / kg, 78 kJ / kg, 79 kJ / kg, 80 kJ / kg, 81 kJ / kg, or 82 kJ / kg, or any dose in between. In some incarnations, the dose of the radioactive conjugate 225 The Ac dose is 74 to 76 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 72 to 77 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 70 to 80 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 68 to 82 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is 65 to 85 kBc / kg of the patient's body weight. In some incarnations, the dose of the radioactive conjugate 225 Ac is approximately 65 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 67 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 69 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 71 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 73 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 75 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 77 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 79 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 81 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 83 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 85 kBc / kg of the patient's body weight. In some incarnations, the dose of the radioactive conjugate 225 Ac is approximately 50 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 45-55 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is 40-60 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 50 kBc / kg of the patient's body weight every 4 weeks. In some formulations, the radioactive conjugate dose is 225 The Ac dose is 45-55 kBc / kg of the patient's body weight every 4 weeks. In some formulations, the radioactive conjugate dose is 225 Ac is 40-60 kBc / kg of the patient's body weight every 4 weeks. In some incarnations, the dose of the radioactive conjugate 225 Ac is approximately 75 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 70-80 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 65-85 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 75 kBc / kg of the patient's body weight every 6 weeks. In some formulations, the radioactive conjugate dose is 225 The Ac dose is 70-80 kBc / kg of the patient's body weight every 6 weeks. In some formulations, the radioactive conjugate dose is 225 Ac is 65-85 kBc / kg of the patient's body weight every 6 weeks. In some incarnations, the dose of the radioactive conjugate 225 Ac is approximately 100 kBc / kg of the patient's body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is 95-105 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 The Ac dose is 90-110 kBc / kg of patient body weight. In some embodiments, the radioactive conjugate dose is 225 Ac is approximately 100 kBc / kg of the patient's body weight every 8 weeks. In some formulations, the radioactive conjugate dose is 225 The Ac dose is 95-105 kBc / kg of patient body weight every 8 weeks. In some formulations, the radioactive conjugate dose is 225 Ac is 90-110 kBc / kg of the patient's body weight every 8 weeks. As used here, the term "cycle" refers to a period of treatment followed by a period of optional rest. Cycles can be repeated on a regular schedule. In some incarnations, a cycle is 4 to 8 weeks. In some incarnations, a cycle is 4 to 6 weeks. In some incarnations, a cycle is approximately 4 weeks. In some incarnations, a cycle is approximately 5 weeks. In some incarnations, a cycle is approximately 6 weeks. In some incarnations, a cycle is approximately 7 weeks. In some incarnations, a cycle is approximately 8 weeks. The radioactive conjugate can be given 225 AC according to a dosing schedule every 4-6 weeks, e.g., every 4 weeks, or every 5 weeks, or every 6 weeks. Formula I compounds include all their stereoisomers (e.g., diisomers or isomers) and prototypical drugs (e.g., oleaster, oleamide, or olephosphate). In some incarnations, the radioactive conjugate includes 225 Ac on 225 Ac chelated with the following structure, i.e. 225 Ac-PSMA-I&T: In certain incarnations, the radioactive conjugate includes 225 Ac on 225 Ac chelated to the following structure, i.e., PSMA-I&T in the (R) isoform with respect to the steric center on the carbon adjacent to DOTA: In certain incarnations, the radioactive conjugate includes 225 Ac on 225 Ac chelated with the following structure, i.e., PSMA-I&T in the (S) isomer with respect to the spherical center on the carbon adjacent to DOTA: In some incarnations, the radioactive conjugate is given 225 AC at a dose of 50-75 kBc / kg of the patient’s body weight (including the two limiting values) according to a dosing schedule every 4 or 6 weeks. In some incarnations, the radioactive conjugate is given 225 AC at a dose of 50 kBc / kg of the patient’s body weight according to a dosing schedule every 4 weeks, or a dose of 75 kBc / kg of the patient’s body weight according to a dosing schedule every 6 weeks. The radioactive conjugate can be given 225 AC for multiple cycles (e.g., 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, or more) with each cycle being 4-6 weeks. In some incarnations, the radioactive conjugate is given 225 Ac is given to the patient for at least 4 cycles. For example, the radioconjugate is given 225 AC is administered at a dose of 50 kBc / kg of the patient's body weight according to a dosing schedule every 4 weeks for a minimum of 4 cycles (e.g., 4 cycles, 5 cycles, or 6 cycles). For example, the radioactive conjugate is given 225 AC at a dose of 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 6 weeks for a minimum of 4 cycles (e.g., 4 cycles, 5 cycles, or 6 cycles). In some incarnations, the radioactive conjugate is given 225 Ac at a dose of 7-9 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 7-9 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 7-9 megabecquerels every 6 weeks. In some incarnations, a radioactive conjugate is given. 225 Ac at a dose of approximately 8 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac is administered at a dose of approximately 8 megabecquerels every 6 weeks. In some incarnations, a radioactive conjugate is given. 225 Ac at a dose of 7–9 megabecquerels per cycle. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of approximately 8 megabecquerels per cycle. In some incarnations, the radioactive conjugate is administered. 225 Ac is administered at a dose of 7-9 megabecquerels per cycle, with each cycle lasting 6 weeks. In some formulations, a radioactive conjugate is given. 225 AC at a dose of approximately 8 megabecquerels per cycle, where the cycle is 6 weeks. In some incarnations, the radioactive conjugate is given 225 Ac at a dose of 9-11 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 9-11 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 9-11 megabecquerels every 6 weeks. In some incarnations, a radioactive conjugate is given. 225 Ac at a dose of approximately 10 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of approximately 10 megabecquerels every 6 weeks. In some incarnations, the radioconjugate is given. 225 Ac at a dose of 9–11 Mbcg per cycle. In some formulations, the radioactive conjugate is administered. 225 Ac is administered at a dose of approximately 10 megabecquerels per cycle. In some formulations, the radioactive conjugate is given. 225 Ac is administered at a dose of 9-11 megabecquerels per cycle, with each cycle lasting approximately 6 weeks. In some formulations, a radioactive conjugate is given. 225 AC at a dose of approximately 10 megabecquerels per cycle, with the cycle being approximately 6 weeks. In some incarnations, the radioactive conjugate is given 225 Ac at a dose of 11-13 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 11-13 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of 11-13 megabecquerels every 6 weeks. In some incarnations, a radioactive conjugate is given. 225 Ac at a dose of approximately 12 megabecquerels. In some formulations, the radioactive conjugate is administered. 225 Ac is administered at a dose of approximately 12 megabecquerels every 6 weeks. In some incarnations, a radioactive conjugate is given. 225 Ac at a dose of 11-13 Mbcg per cycle. In some formulations, the radioactive conjugate is administered. 225 Ac at a dose of approximately 12 megabecquerels per cycle. In some formulations, the radioactive conjugate is administered. 225 Ac is administered at a dose of 11-13 megabecquerels per cycle, with each cycle lasting approximately 6 weeks. In some formulations, a radioactive conjugate is given. 225 AC at a dose of approximately 12 megabecquerels per cycle, with the cycle being approximately 6 weeks. In some incarnations, the radioactive conjugate is given 225 Ac is administered for at least 4 treatment cycles, at a dose of approximately 12 MBc per cycle for cycles 1 and 2, and at a dose of approximately 8 MBc per cycle for cycles 3 and 4. In some embodiments, the radioconjugate is given 225 Ac is administered for at least 4 treatment cycles, at a dose of approximately 12 MBc every 6 weeks for cycles 1 and 2, and at a dose of approximately 8 MBc every 6 weeks for cycles 3 and 4. In some embodiments, the radioconjugate is given 225 Ac is administered for at least four treatment cycles, at a dose of approximately 12 MBc per cycle for cycles 1 and 2, and at a dose of approximately 8 MBc per cycle for cycles 3 and 4, with each cycle lasting approximately six weeks. In some formulations, the radioconjugate is given. 225 AC was administered for at least four treatment cycles, at a dose of approximately 12 MBcg every six weeks for cycles 1 and 2, and at a dose of approximately 8 MBcg every six weeks for cycles 3 and 4, with each cycle lasting approximately six weeks. In some formulations, administration resulted in an absorbed dose of at least 10 Gy per cycle (e.g., at least 12 Gy per cycle, at least 14 Gy per cycle, at least 16 Gy per cycle, at least 18 Gy per cycle, or at least 20 Gy per cycle) in the tumor of the aforementioned patient. In some embodiments, administration results in a cumulative absorbed dose of not less than 30 Gy (e.g., not less than 35 Gy, not less than 40 Gy, not less than 45 Gy, not less than 50 Gy, not less than 55 Gy, not less than 60 Gy, not less than 65 Gy, not less than 70 Gy, not less than 75 Gy, or not less than 80 Gy) in a tumor in the aforementioned patient. In some embodiments, administration results in an absorbed dose of no more than 25 Gy per cycle (e.g., no more than 20 Gy per cycle, no more than 15 Gy per cycle, or no more than 10 Gy per cycle) in the salivary gland of the aforementioned patient. In some embodiments, administration results in a cumulative absorbed dose of no more than 100 Gy (e.g., no more than 95 Gy, no more than 90 Gy, no more than 85 Gy, no more than 80 Gy, no more than 75 Gy, no more than 70 Gy, no more than 65 Gy, no more than 60 Gy, no more than 55 Gy, or no more than 50 Gy) in the salivary gland of the aforementioned patient. the Formulas Pharmaceutical formulations can be formulated for injection, intranasal, surface, oral, or topical administration, such as transdermal methods, for prevention and / or treatment. They can be administered by injection (e.g., intravenously, intramuscularly, or subcutaneously), by oral ingestion, surface application, or intra-articular injection into areas affected by vascular or cancerous conditions. Additional routes of administration include intravascular, intra-arterial, intratumoral, intraperitoneal, intradural, intranasal, intraocular, intrasclera, intraorbital, rectal, surface, or aerosol inhalation. Sustained administration, by means such as injectable reservoirs, implants, or corrosive components, is also a specific consideration. Suitable formulations include formulations containing active ingredients (e.g., the compounds disclosed here) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, such as water, buffered water, saline solution, or PBS, among others, for injection.Formulations may contain pharmaceutically acceptable excipients to mimic physiological conditions, such as pH-regulating agents, buffer solutions, tonics, wetting agents, or detergents, among others. In some formulations, formulations are designed for oral administration; for example, they may contain inert ingredients such as binders or fillers to form a unit-dose form, such as a tablet or capsule. In some formulations, formulations are designed for topical administration; for example, they may contain inert ingredients such as solvents or emulsifiers to form a cream, ointment, gel, paste, or eye drop. Preparations can be sterilized, for example, by conventional sterilization techniques or sterile filtration. Aqueous solutions can be filled for use as is or freeze-dried, in which case the freeze-dried preparation is combined with a sterile aqueous carrier before administration. The pH of preparations is usually between 3 and 11, preferably between 5 and 9 or between 6 and 8, and ideally between 6 and 7, such as 6 to 6.5. Effects Therapeutic effect refers to the desired or beneficial effect of a drug or medical treatment in treating a disease, condition, or symptom. It is the intended effect that the drug or treatment is designed to achieve in order to improve the patient's health or well-being. The therapeutic effect of the drug, or pharmaceutical formulation as described here, may include symptom relief, treatment or cure of disease, prevention of the condition from worsening, or improvement of general health and quality of life. The therapeutic effect for cancer patients depends on the type of cancer and the stage of the disease. The goal of cancer treatment is to eliminate or control cancer cells while minimizing damage to healthy cells in the body. In some cases, the therapeutic effect includes a reduction in tumor size, a stable tumor size, or a reduced rate of tumor growth. In other cases, the therapeutic effect includes a reduction in the rate of recurrence or metastasis. In some incarnations, the therapeutic effect of the method described here is a reduction in tumor size. In some incarnations, the tumor size decreases by approximately 5% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 10% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 20% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 30% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 40% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 50% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 60% compared to the size before treatment with the method described here. In some incarnations, the tumor size decreases by approximately 70% compared to the size before treatment with the method described here.In some cases, the tumor size decreases by approximately 80% compared to its size before treatment with the method described here. In other cases, the tumor size decreases by approximately 90% compared to its size before treatment with the method described here. In some incarnations, the tumor volume decreases by approximately 5-10% compared to the size before treatment using the method described here. In some incarnations, the tumor volume decreases by approximately 10-30% compared to the size before treatment using the method described here. In some incarnations, the tumor volume decreases by approximately 30-50% compared to the size before treatment using the method described here. In some incarnations, the tumor volume decreases by approximately 50-70% compared to the size before treatment using the method described here. In some incarnations, the tumor volume decreases by approximately 70-90% compared to the size before treatment using the method described here. In some incarnations, the tumor volume decreases by approximately 90-100% compared to the size before treatment using the method described here. In some incarnations, tumor size is measured approximately one week after treatment using the method described here. In some incarnations, tumor size is measured approximately four weeks after treatment using the method described here. In some incarnations, tumor size is measured approximately three months after treatment using the method described here. In some incarnations, tumor size is measured approximately six months after treatment using the method described here. In some incarnations, tumor size is measured approximately one year after treatment using the method described here. In some incarnations, tumor size is measured approximately two years after treatment using the method described here. In some incarnations, tumor size is measured approximately three years after treatment using the method described here. In some incarnations, a patient treated as described here does not develop one or more metastases approximately one week after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately four weeks after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately three months after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately six months after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately one year after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately two years after treatment. In some incarnations, a patient treated as described here does not develop one or more metastases approximately three years after treatment. In some embodiments, xerostomia can be measured using a clinically graduated scale. For example, radiation-induced xerostomia can be graded into 3 levels using the revised CTCAE version 3.0 criteria: Degree Properties 1. Light Symptoms (dry or sticky saliva) without significant dietary changes 2, average Symptoms or a significant change in oral intake (e.g., large amounts of water, other lubricants, or a diet restricted to purees and / or soft, moist foods) 3, very Symptoms that lead to an inability to adequately feed orally; intravenous fluids, tube feeding, or parenteral feeding are required. In some simulations, the patient treated with the method described here, which involves administering a radiopharmaceutical, experiences less severe radiation-induced xerostomia than the patient treated with a higher dose of radiopharmaceutical. In some simulations, the patient treated with the method described here, which involves administering a radiopharmaceutical, does not experience radiation-induced xerostomia. In some simulations, the patient treated with the method described here, which involves administering a grade 1 radiopharmaceutical, experiences radiation-induced xerostomia. In some simulations, the patient treated with the method described here, which involves administering a grade 2 radiopharmaceutical, experiences radiation-induced xerostomia. Factors Other In some incarnations, the methods revealed here also include the administration of an antiproliferative agent, a radiosensitizing agent, an immunoregulatory agent, or an immunomodulator. The terms "antiproliferative agent" or "anti-proliferative agent," as they are used interchangeably here, refer to any anticancer substance, including the antiproliferative agents listed in Schedule 1, any of which may be used in combination with a radiopharmaceutical (e.g., a radioconjugate). 225 Ac) which is disclosed here for the treatment of a condition or disorder. Antiproliferative agents also include organoplatinum derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and its anthraquinone derivatives. By “immunomodulatory agent” or “immunomodulator,” as used interchangeably here, means any immunomodulator, including those listed in Table 1, any of which may be used in combination with a radiopharmaceutical described here. As used here, a "radiosensitizer" includes any substance that increases the sensitivity of cancer cells to radiation therapy. Radiosensitizers may include, but are not limited to, 5-fluorouracil, platinum isotopes (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesil transferase inhibitors, COX-2 inhibitors, bFGF antagonists, and VEGF antagonists. Table 1 alkylating agents Boslovan Dakarbzin ephosphamide Hexamethyl melamine Theotepa Dakarbzin Lomustine Cyclophosphamide Chlorambucil Procarbazine Altriamine Estramustine phosphate Mechlorethamine Streptozoxin Temozolomide Simosteen Platinum factors Spiroplatin Tetraplatin Ormaplatin Iproplatin Picplatin Oxaliplatin Carboplatin Lobaplatin (Aeterna) Satterplatin (Johnson Matthey) BBR-3464 (Hoffmann-La Roche) Myriplatin AP-5280 (Access) Cisplatin Antimetabolic agents Azacetidine Fluorouridine 2-Chlorodeoxyadenosine 6-Mercaptopurine 6-Thioguanine cytarabine 2-Fluorodeoxycytidine Methotrexate Tomodex Fludarabine Raltrexd Trimetrites Deoxycoformycin Pentostatin hydroxyurea Decitabine (SuperGen) Clofarabine (Bioenvision) Aerofulvin (MGI Pharma) DMDC (Hoffmann-La Roche) Ethinylcytidine (Taiho) Jamesptabine Capicetabine Topoisomerase inhibitors amsacrine Epirubicin etoposide Teniposide or Metoxantrone 7-Ethyl-10-hydroxy-camptothecin Dexrazoxanite (TopoTarget) Bexantron (Novuspharma) Ribecamycin analogue (Exelixis) BBR-3576 (Novuspharma) Rubitikan (SuperGen) Irinotecan (CPT-11) Topotekan Exatican Messylates (Daiichi) Quinamide (ChemGenex) Gemaetikan (Sigma-Tau) Diflumotekan (Beaufour-Ipsen) TAS-103 (Taiho) Ilsamitrosin (Spectrum) edotekarin Kositikan Pelotican Hydroxycamptothecin (SN-38) Anti-tumor antibiotics Valropicin Therabucin idarubicin Rubidazon Plexamicin Porphyomycin Mitoxantron (Novantron) Amonavid Azunavid Anthrapiazole xantrazol Losoxantrone Saparubicin Epirubicin mitoxantrone Doxorubicin Anti-cell division Colchicine vinblastine Faindecin Dolastatin 10 (NCI) Rhizoxin (Fujisawa) Mefobolin (Warner-Lambert) C Madutin (BASF) RPR 109881A (Aventis) TXD 258 (Aventis) Epothylone B (Novartis) T 900607 (Tularik) T 138067 (Tularik) Cryptophosin 52 (Eli Lilly) Phenflurin (Fabre) Oristatin PE (Teikoku Hormone) BMS 247550 (BMS) BMS 184476 (BMS) BMS 188797 (BMS) Taxofrexine (Protarga) SB 408075 (GlaxoSmithKline) Venorilpine Trichostatin A E7010 (Abbott) PG-TXL (Cell Therapeutics) IDN 5109 (Bayer) A 105972 (Abbott) A 204197 (Abbott) LU 223651 (BASF) D 24851 (ASTAMedica) ER-86526 (Eisai) Combretastatin A4 (BMS) Isohomohalicondine-B (PharmaMar) ZD 6126 (AstraZeneca) AZ10992 (Asahi) IDN-5109 (Indena) AVLB (Prescient NeuroPharma) Azaibutylone B (BMS) BNP-7787 (BioNumerik) CA-4 is a prodrug (OXiGENE). Dolastatin-10 (NIH) CA-4 (OXiGENE) Doxtaxel Vinchristine paclitaxel Aromatase inhibitors Aminoglutethimide Atamistine (BioMedicines) Letrozole Anastrozole YM-511 (Yamanouchi) Formistin Exemestane thymidylate synthase inhibitors Pemetrexed (Eli Lilly) ZD-9331 (BTG) Nolatrexide (Eximias) CoFactorTM (BioKeys) DNA anti-DNA Trabictidine (PharmaMar) Glufosphamide (Baxter International) Two albums + 32P (Isotope Solutions) Thymectasin (NewBiotics) Idotrotide (Novartis) Mafosfamide (Baxter International) Abazikuan (Spectrum Pharmaceuticals) O6 Benzylguanine (Paligent) Farnesil transferase inhibitors Argilabine (NuOncology Labs) Lunafarnib (Schering-Plough) BAY-43-9006 (Bayer) Tipiparnib (Johnson & Johnson) Peryl alcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Tarikidar (Xenova) MS-209 (Schering AG) Zosukedar trihydrochloride (Eli Lilly) Berikodar Disitat (Vertex) Histone acetyltransferase inhibitors Tasidenaline (Pfizer) SAHA (Aton Pharma) MS-275 (Schering AG) Bivalyloxymethylbutyrate (Titan) Dipsipeptide (Fujisawa) metalloproteinase inhibitors Nevostat (Aeterna Laboratories) Marimastate (British Biotech) CMT-3 (CollaGenex) BMS-275291 (Celltech) ribonucleoside reductase inhibitors Galeo Multilate (Titan) Triabine (Vion) Tizacitabine (Aventis) Didox (Molecules for Health) TNF-α agonists / inhibitors Ferrolizine (Lorus Therapeutics) CDC-394 (Celgene) Riffimed (Celgene) endothelin receptor antagonist A Atrasentan (Abbott) ZD-4054 ​​(AstraZeneca) YM-598 (Yamanouchi) Retinoic acid receptor agonists Phenyretinoinide (Johnson & Johnson) LGD-1550 (Ligand) Alitretinoin (Ligand) immune regulators Interferon Oncophage (Antigenics) GMK (Progenics) Adenocarcinoma vaccine (Biomira) CTP-37 (AVI BioPharma) IRX-2 (Immuno-Rx) PEP-005 (Peplin Biotech) Syncrovax vaccines (CTL Immuno) Melanoma vaccine (CTL Immuno) p21 RAS vaccine (GemVax) MAGE-A3 (GSK) Nivolumab (BMS) Apatasept (BMS) Pembrolizumab (Merck) Dextromethorphan treatment (Anosys) Penterix (Australian Cancer Technology) ISF-154 (Tragen) Cancer vaccine (Intercell) Norelin (Biostar) BLP-25 (Biomira) MGV (Progenics) β-Allethyn (Dovetail) CLL treatment (Vasogen) Ipilimumab (BMS) CM-10 (cCam Biotherapeutics) Atezolizumab (Genentech) Hormones and antihormonal agents estrogen conjugated estrogen Ethinylestradiol Chloriteriacine Edenstrol Hydroxyprogesterone caproate Medroxyprogesterone Testosterone Testosterone propionate; Fluoxymsterone Methyltestosterone Diethylstilbestrol Megestrol Bicalutamide Flutamide Nilutamide Dexamethasone Prednisone Methylprednisolone prednisolone Aminoglutethimide Librolide Octreutide Mitotan P-04 (Novogen) 2-Methoxyestradiol (EntreMed) Arzoxifen (Eli Lilly) Tamoxifen Toremifene Jocerin leuporylene Bicalutamide Dynamic optical factors Talaporphine (Light Sciences) Theralux (Theratechnologies) Motifexin gadolinium (Pharmacyclics) Pd-Bacterio phytoporphyrid (Yeda) Motifexin Lutetium Hypericin Kinase inhibitors Imatinib (Novartis) leflunomide (Sugen / Pharmacia) ZD1839 (AstraZeneca) Erlotinib (Oncogene Science) Canertinib (Pfizer) Squalamine (Genaera) SU5416 (Pharmacia) SU6668 (Pharmacia) ZD4190 (AstraZeneca) ZD6474 (AstraZeneca) Phatalanib (Novartis) PKI166 (Novartis) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) Trastuzumab (Genentech) OSI-774 (TarcevaTM) CI-1033 (Pfizer) SU11248 (Pharmacia) RH3 (York Medical) Genistine Radicinol Met-MAb (Roche) EKB-569 (Wyeth) Kahalid F (PharmaMar) CEP-701 (Cephalon) CEP-751 (Cephalon) MLN518 (Millenium) PKC412 (Novartis) Phenoxodiol (Novogen) C225 (ImClone) rhu-Mab (Genentech) MDX-H210 (Medarex) 2C4 (Genentech) MDX-447 (Medarex) ABX-EGF (Abgenix) IMC-1C11 (ImClone) Terfostin Gefitinib (Iressa) PTK787 (Novartis) EMD 72000 (Merck) Emodin Radicinol Femurafenib (B-Raf enzyme inhibitor, Daiichi Sankyo) SR-27897 (CCK A inhibitor, Sanofi-Synthelabo) Tocladecin (cyclic AMP activator, Ribapharm) Alfusidep (CDK inhibitor, Aventis) CV-247 (COX-2 Inhibitor, Ivy Medical) P54 (COX-2 inhibitor, Phytopharm) CapCell TM (منشط CYP450، Bavarian Nordic) GCS-100 (anticoagulant gal3, GlycoGenesys) G17DT immunogen (gastrin inhibitor, Aphton) Ivaprexeral (Oxygenating Agent, Allos Therapeutics) PI-88 (Heparanase Inhibitor, Progen) Tesmilifine (an antihistamine, YM BioSciences) Histamine (H2 receptor activator, Maxim) Thiazophrenia (IMPDH inhibitor, Ribapharm) Silengetide (an anti-integrin, Merck KGaA) SR-31747 (IL-1 Inhibitor, Sanofi-Synthelabo) CCI-779 (mTOR kinase inhibitor, Wyeth) Exisolend (PDE V inhibitor, Cell Pathways) CP-461 (PDE V inhibitor, Cell Pathways) AG-2037 (GARFT Inhibitor, Pfizer) WX-UK1 (Plasminogen activator inhibitor, Wilex) PBI-1402 (PMN activator, ProMetic LifeSciences) Bortezomib (proteasome inhibitor, Millennium) SRL-172 (T-cell activator, SR Pharma) TLK-286 (Glutathione S Transferase Inhibitor, Telik) PT-100 (Growth Factor Activator, Point Therapeutics) Midosturen (PKC inhibitor, Novartis) Priostatin-1 (PKC activator, GPC Biotech) CDA-II (Programmed Cell Death Inducer, Everlife) SDX-101 (programmed cell death inducer, Salmedix) Rituximab (anti-CD20, Genentech) Carmusteen mitoxantrone Blemmycin Absinthe Chrysophanic acid Cesium oxides BRAF inhibitors PD-L1 inhibitors MEK inhibitors bevacizumab angiogenesis inhibitors dabrafenib Cyflaton (programmed cell death inducer, ChemGenex) BCX-1777 (PNP inhibitor, BioCryst) Ranperinase (Ribonuclease activator, Alfacell) Galarubicin (RNA synthesis inhibitor, Dong-A) Terabazamine (reducing agent, SRI International) N-Acetylcysteine ​​(reducing agent, Zambon) R-Fluorbiprofen (NF-kappaB inhibitor, Encore) 3CPA (NF-kappaB inhibitor, Active Biotech) Ceoxalcitol (Vitamin D receptor activator, Leo) 131-I-TM-601 (Anti-DNA, TransMolecular) Eflornithine (ODC inhibitor, ILEX Oncology) Menodronic acid (osteoblast inhibitor, Yamanouchi) Indesolam (p53 activator, Eisai) Aplidine (PPT inhibitor, PharmaMar) Gemtuzumab (anti-CD33, Wyeth Ayerst) PG2 (Hematopoietic Enhancer, Pharmagenesis) ImmunolTM (Triclosan Oral Wash, Endo) Triacetyluridine (Uliuridine drug, Wellstat) SN-4071 (Stromal Tumor Factor, Signature BioScience) TransMID-107TM (Immunotoxin, KS Biomedix) PCK-3145 (Procyon, apoptosis inducer) Durani-Dazole (programmed cell death inducer, Pola) CHS-828 (Cytotoxic Agent, Leo) Retinoic acid (Cellular Differentiation Factor, NIH) MX6 (programmed cell death inducer, MAXIA) Apomene (programmed cell death inducer, ILEX Oncology) Urocidin (programmed cell death inducer, Bioniche) Ro-31-7453 (Apoptosis inducer, La Roche) Prostalcin (programmed cell death inducer, Pharmacia) β-Lapachon Gelonin Cafestol Kahwell Caffeic acid Terfostin AG PD-1 inhibitors CTLA-4 inhibitors Sorafenib Incarnations Numbered 1. A method for treating a patient with prostate-specific antigen (PSMA) cancer, where the method involves administering a therapeutically effective amount of radioconjugate to the patient. 225 Ac, Where the radioactive conjugate is included 225 Ac on 225 Ac chelated with a compound of formula I, or a prodrug thereof: (I)، Where the radioactive conjugate is given 225 AC at a dose of approximately 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 4-6 weeks. 2. The method according to embodiment 1, where the radioactive conjugate is included 225 Ac on 225 Ac is chelated to the following structure: . 3. The method according to embodiment 1 or 2, where the radioactive conjugate is given 225 AC at a dose of 75 kBc / kg of the aforementioned patient's body weight. 4. The method according to any of the previous incarnations, where the radioactive conjugate is given 225 AC according to a dosing schedule every 4 or 6 weeks. 5. The method according to any of the previous incarnations, where the radioactive conjugate is given 225 AC at a dose of 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 6 weeks. 6. The method according to any of the previous incarnations, where the radioactive conjugate is given 225 Ac for the patient for a minimum of 4 cycles. 7. The method according to any of the previous incarnations, where the radioactive conjugate is included 225 Ac on 225 Ac is chelated to the following structure: Where the radioactive conjugate is given 225 AC at a dose of 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 6 weeks. 8. The method according to any of the previous incarnations, where administration results in an absorbed dose of not less than 10 Gy per cycle in a tumor in the aforementioned patient. 9. The method according to any of the previous embodiments, where the administration results in a cumulative absorbed dose of no less than 30 Gy in a tumor in the aforementioned patient. 10. The method according to any of the previous incarnations, where the administration results in an absorbed dose of no more than 25 Gy per cycle in the salivary gland of the aforementioned patient. 11. The method according to any of the previous incarnations, where the administration results in a cumulative absorbed dose not exceeding 100 Gy in the salivary gland of the aforementioned patient. 12. The method according to any of the previous incarnations, where the cancer expressing PSMA is prostate cancer. 13. The method according to any of the previous incarnations, which also includes giving an anti-proliferative agent, a radiosensitizing agent, or an immunomodulatory agent.14. The method according to any of the previous incarnations, where the radioactive conjugate is included 225 Ac on 225 Ac is chelated to the following structure: 15. The method according to any of the previous incarnations, where the radioactive conjugate is included 225 Ac on 225 Ac is chelated to the following structure: Where the radioactive conjugate is given 225 AC at a dose of 75 kBc / kg of the patient’s body weight, according to a dosing schedule every 6 weeks. Examples Materials: The compounds used in the methods described here were synthesized from commercially available chemicals and / or from compounds described in chemical references, following standard organic synthesis techniques familiar to those experienced in the field. Commercially available chemicals can be obtained from standard commercial sources including, but not limited to, ABX Advanced Biochemical Compounds GmbH (Radeberg, Germany), Acros Organics (Pittsburgh, PA), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science (USA), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Haupauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Frontier Scientific (Logan, UT), and ICN Biomedicals, Inc.(Costa Mesa, California), ITM (Munich, Germany), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, New Hampshire), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Sigma-Aldrich (USA), Spectrum Quality Product, Inc. (New Brunswick, New Jersey), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), VWR (Radnor, Pennsylvania, USA), Wako Chemicals USA, Inc. (Richmond, Virginia), and Wuxi-Apptech Inc. (Shanghai, China). Example 1. Synthesis of radiopharmaceuticals containing the compound formula I Formula I compounds are small molecules that are anti-PSMA, and can be radiolabeled with a radioactive nuclide such as actinium-225 ( 225 Ac) to form radiopharmaceuticals bound to the radionuclide. The following documents can be consulted for the synthesis of the formula I compound, or the radiopharmaceuticals bound to the corresponding radionuclide: Weineisen M, et al. EJNMMI Research, 2014, 4:63; Weineisen M, et al. J Nucl Med 2015, 56:1169–1176; US 11,129,912 B1; and WO 2018 / 108287 Al. Example 2. Preparation of pharmaceutical formulations containing the radioactive conjugate 225 Ac Pharmaceutical formulations containing the radioactive conjugate can be prepared 225 Ac from formula I by following or referring to the protocols specified below. 1. To prepare a 0.001 M HCl solution: Add 4.4 microliters of concentrated hydrochloric acid (TraceSelect or equivalent) to 40 milliliters of water (TraceSelect), then mix the solution until it is completely homogeneous. 2. Preparation of a 0.05 M HCl solution: 220 microliters of concentrated hydrochloric acid (TraceSelect or equivalent) are added to 40 milliliters of water (TraceSelect), and the solution is then mixed until it is completely homogeneous. 3. Preparation of Sodium Acetate-Gentisic Acid Buffer Solution: Add 0.09–0.11 g of 2,5-dihydroxybenzoic acid (gentisic acid) to a weighing tank using a plastic spoon. Transfer the gentisic acid quantitatively to a 150 mL Biotainer. Transfer 3.9–4.3 g of sodium acetate to a 150 mL Biotainer. Add 50 mL of water (TraceSelect) to the Biotainer using a properly sized plastic serological syringe. Close the Biotainer and mix the resulting solution until it is completely homogeneous. 4. Preparation of the Ascorbate-DTPA Buffer Solution: Transfer 0.0055–0.0065 g of DTPA to a 150 mL Biotainer. Transfer 5.94–6.06 g of sodium ascorbate to a 150 mL Biotainer. Add 100 mL of water (TraceSelect) to the Biotainer using a properly sized plastic serological syringe. Add 2.5 mL of 0.05 M hydrochloric acid to the Biotainer using a properly sized plastic serological syringe. Close the Biotainer and mix the resulting solution until it is completely homogeneous. Use pH paper to verify that the pH of the buffer solution is between 6.0 and 7.0. 5. Preparation of a 0.045 M NaOH solution: Add 0.06–0.08 g (M1) of sodium hydroxide granules to a 50 mL conical tube. Calculate the required volume of water (TraceSelect) (M2 mL) using the following equation: (M2 = 1000 × (M1 / 1.8)). Add M2 mL of water (TraceSelect) to the conical tube using a properly sized serological syringe. Mix the solution until it is completely homogeneous. 6. Reconstitution of Ac-225 / Ac-227 Accelerator and Ac-225 Generator Vials: A 1 mL syringe with a 21G 2” needle is used to transfer 0.5 mL of 0.001 M HCl solution into vial V containing [Ac-225]. Another 1 mL syringe with a 21G 2” needle is used to transfer 0.5 mL of 0.001 M HCl solution into vial V containing [Ac-227]. At least 14 hours are allowed before proceeding to the next step. The [Ac-225] vial is measured, and the radioactivity value is recorded in microcuries (µC). The radioactivity of [Ac-227] from the appropriate certificate of analysis is also recorded in µC. Ac-225 and Ac-227 are reconstituted using 0.001 M HCl (total volume 1 mL) so that it contains 0.43 mCi of Ac-225 and 0.035 mCi of Ac-227. 7. Preparation of PSMA I&T Buffer Solution: 1.0 mL of sodium acetate-gentisic acid buffer solution is transferred to a starting material vial containing 0.5 mg of PSMA I&T. The concentration of the resulting solution in the starting material vial is determined in micrograms / mL. The vial is shaken for thirty seconds, stirring several times, until the contents are completely dissolved and a homogeneous solution is obtained. 8. Radiolabeling: The PSMA I&T buffer solution described above is transferred to a 15 mL "reaction" tube containing Ac-225. The contents of the "reaction" tube are gently shaken for 30 seconds to ensure adequate mixing. The "reaction" tube is then heated on a Thermomixer at 90°C for 25 minutes. Afterward, the "reaction" tube is transferred to a lead container and allowed to cool to room temperature for 5–10 minutes. 9. Preparation of the Final Product: The entire contents of the "Reaction" tube are transferred using a 5 mL syringe into the final product vial labeled "Ac-225-PSMA-I&T Bulk Product." The solution is shaken slowly and carefully for 30 seconds to ensure complete mixing in the "Ac-225-PSMA-I&T Bulk Product" vial. The "Ac-225-PSMA-I&T Bulk Product" vial is stored in a lead container labeled "Ac-225-PSMA-I&T Bulk Product Vial" at room temperature for at least 14 hours before use. The "Ac-225-PSMA-I&T Bulk Product" vial is measured in a dose-calibrating device. The radioactivity value of the final product is recorded in microcuries (µC). Example 3. Evaluating the stability of the formulations The stability of the pharmaceutical formulation is assessed according to the protocol specified below. The final bulk product containing 225 Ac-PSMA-I&T described above in the stability test, in a glass or plastic container. The test sample is assessed for stability by turning it over in a protected container at the appropriate storage temperature. The storage location, date, and time corresponding to the batch number are recorded. At least six hours before the expiry date and time (no less than 72 hours), the test sample is removed from storage for testing and allowed to reach room temperature for at least 30 minutes. The date and time of sample removal are recorded, corresponding to the batch number. Temperature monitoring data for the relevant time period of the test sample storage location is attached to this protocol; the absence of temperature deviations is also verified. The reliability of the test sample is assessed based on the quality characteristics shown in Table 2 below. Table 2. Stability and Quality Characteristics of Pharmaceutical Formulations Quality characteristics The method Appearance visual examination pH pH indicator strip Radioactive purity by TLC TLC radioactive detector Sterilization Direct insemination chemical content HPLC-UV chemical impurities HPLC-UV Example 4. Administering formulations in cancer treatment The pharmaceutical formulation containing the radioactive conjugate is given 225 Ac for a patient with cancer expressing PSMA according to the protocols defined below. to prepare Dose Each dose is prepared individually before administration. The dose calibrator used to measure the dose given to the participant must be the same device used during the calibration process at the start of the study. The dose is prepared sterilely for administration under standard site environmental conditions and standard operating procedures (SOPS). The following procedure is followed for administration preparation: A vial containing the investigational drug product (IMP) is allowed to thaw in the lead container on the table at room temperature. The thawing time is estimated at one hour, but sites may use their own judgment when thawing to ensure the IMP reaches room temperature before administration. The preparation area must be checked for cleanliness before dispensing. Before putting on gloves, the operator's hands should be washed or sanitized with an alcohol-based hand sanitizer. Once the gloves are on, it is advisable to spray them with 70% isopropyl alcohol (IPA). The vial membrane is wiped with a sterile IPA cloth. The wiped membrane is allowed to dry before piercing it. A sterile, disposable syringe and needle are used to prepare injections and are assembled immediately before preparation. The syringes and needles are assembled in a clean (or sterile, if possible) environment. Sterile contacts are not handled directly. The concentration of radioactivity of the product at the time of calibration (TOC). TOC is the date and time at which the supplied radionuclide matches the stated radioactivity of the radionuclide. After TOC, the radioactivity decreases. The concentration of radioactivity, and the date and time of calibration, are stated in the Certificate of Analysis (CoA). A decay correction factor is used. 225 AC to correct physical decomposition to the nearest hour. to give 225 Ac-PSMA-I&T, the participant's actual body weight from the general check-up visit is used to calculate the dose 225 Ac-PSMA-I&T. The estimated size of is calculated 225 The Ac-PSMA-I&T will be given to the participant in need as follows: Size ( milliliters ) = [level Dose ( kilo Becquerel / kg ) × weight body per kilogram C Ram] / [ factor revision decomposition Ac-225 × concentration Activity when TOC ( kilo Becquerel / milliliters ) ] giving Dose The pharmaceutical formulation is administered following these procedures for administration 225 Ac-PSMA-I&T for the participant. IMP should not be diluted or given with any other intravenous fluids, combined with other drugs, or given through an infusion set used at the same time for any purpose other than administering the current IMP. IMP is administered by slow intravenous infusion (IV, 2-5 minutes). 225 Ac-PSMA-I&T, the dose given depends on the participant's weight and the assigned study group. The injection can be administered via a peripheral (preferred) or central vein. A three-way valve is recommended during injection to ensure proper intravenous delivery of the product and to guarantee proper priming and flushing. After administration, the line should be thoroughly flushed with normal saline to ensure delivery of the full dose. After administration, the injection line must be removed from the participant and not used for any other procedures. The syringe and all contaminated tubing must be measured in the same dose-measuring device to determine the net dose administered. The volume injected, time of administration, and the participant's net dose must be recorded. Example 5. Doses 225 Ac-PSMA-I&T Based on the acceptable safety characteristics associated with 177 Lu-PSMA RLT, which is administered every 8 weeks, has also had shorter treatment periods explored. Tolerability and efficacy have also been established. 177 Lu-PSMA-617 was administered with a 6-week dosing schedule. Hoffman and Emmett reported the results of two phase 2 studies in 30 and 14 patients with mCRPC treated with Lu-PSMA, respectively. In both studies, patients had previously been treated with second-generation antiandrogens (abiraterone and / or enzalutamide) and taxane-based chemotherapy. Hoffman reported a PSA50 response in 17 (57%) patients. Results included high response rates, low toxicity, and pain reduction. Overall, the treatment was well tolerated. 177 Lu-PSMA-617 performed well, with mainly grade 1 treatment-related toxicity that was self-limiting and easily managed. The most common treatment-related toxic effect was dry mouth, which was reported exclusively as grade 1. The incidence of grade 3–4 treatment-related hematological toxicity was low (Hofman et al., 2018; Emmett et al., 2019). In a study involving 54 patients, the following was given 177 Lu-PSMA-617 (7400 MBcg) was administered every 4 weeks. This dosing schedule was safe with two cases of grade 3 leukopenia, one case of grade 3 anemia, and no grade 3 thrombocytopenia. PSA reductions of ≥50% and ≥80% were observed in 58% and 35% of patients, respectively. Median overall survival (OS) was 119 weeks; median progression-free survival (PFS) was 25 weeks. Patients with any PSA reduction had significantly longer PFS (27 vs. 15 weeks, p<0.0001) and OS (median PFS not reached vs. 52 weeks, p<0.001) values ​​compared to patients with no PSA reduction. It was concluded that this regimen 177 Intensive Lu-PSMA RLT with cycles given every 4 weeks was well tolerated and provided a preferred response rate, PFS, and overall survival (Rasul et al, 2020). In another small retrospective study, it was given 177 Lu-PSMA RLT was administered every 4 weeks at a fixed dose (approximately 7400 MBcg). The results showed that the regimen was safe and effective, producing a significant reduction in PSA. A large proportion of patients [approximately 60% (N=10)] experienced a significant reduction in PSA of more than 50%, which was associated with improved overall survival (OS) and PFS. The median OS was 1.6 years. It was concluded that a shorter treatment duration may extend the therapeutic window for mCRPC patients with large disease volume and rapidly rising PSA levels (Kemppainen et al., 2022). justification system Doses 225 Ac -PSMA-I&T Acute toxicity associated with radiopharmaceuticals can be 225 Ac is predominantly hematologic, with thrombocytopenia and dose-dependent leukopenia, requiring time to recover between treatment cycles with certain agents (Kratochwil 2020). The hematologic characteristics of 225 Ac-PSMA-I&T and 225 Ac-PSMA-617 was investigated in various retrospective studies where patients were treated with any of the radiopharmaceuticals. In a cohort patient trial across these studies, over 150 patients with mCRPC were treated with a dose of 100 kBc / kg every 8 weeks. No clinically significant bone marrow suppression associated with this treatment was observed. 225 Ac-PSMA-I&T and 225 Ac-PSMA-617, which is given every 8 weeks, was very low and not life-threatening, indicating that it can be given 225 Ac-PSMA-I&T is safely administered with a shorter dosing frequency of less than every 8 weeks (Ling 2022). Safety, bioavailability, and volumetric measurements were compared for 177 Lu-PSMA-I&T and 177 Lu-PSMA-617 in patients with mCRPC (Schuchardt et al., 2022). The effective half-life of Lu-PSMA-617 was determined. 177 Lu-PSMA-I&T is found in the whole body (35 hours), kidneys (33 hours), lacrimal glands (25 hours), and parotid glands (23 hours). The effective half-life of Lu-PSMA-I&T is estimated to be... 225 Ac-PSMA-I&T takes approximately 24 to 38 hours in these organs, taking into account the longer half-life of physical degradation of 225 Ac (9.92 days) compared to Lu-177 (6.7 days). Based on this estimated effective half-life, elimination is expected. 225 Ac-PSMA-I&T is completely eliminated from the body within four weeks of administration. Therefore, no accumulation of absorbed radiation dose in these organs is expected when multiple cycles are administered at 4-week or 6-week dose frequencies. In this study, safety, bioavailability, and volumetric measurements were found to be similar between 177 Lu-PSMA-I&T and 177 Lu-PSMA-617. A kinetic volumetric model of the group was published using imaging data for 177 Lu-PSMA-617 in prostate cancer patients by Siebinga et al. (Siebinga 2023). Based on similar biodistribution between 177 Lu-PSMA-I&T and 177 In Lu-PSMA-617 patients with mCRPC, whole-body radioactivity was simulated. 225 Ac-PSMA-I&T with model parameters 177 LuPSMA617. The results of this simulation also support the absence of a clear accumulation of absorbed radiation doses when multiple courses are given at a dose frequency of either every 4 weeks or every 6 weeks. justification Doses Approved on the weight for 225 Ac -PSMA-I&T A lower dose per cycle may reduce 225 Ac-PSMA-I&T 225 AcPSMAI&T) is toxic without affecting efficacy when given at a similar dose intensity (e.g., 50 kBc / kg every 4 weeks or 75 kBc / kg every 6 weeks). Estimates of volumetric measurements were extrapolated for 225 Ac-PSMA-I&T accounts 225 Ac-PSMA-617, performed by Kratochwil (Kratochwil et al, 2017), is based on time-activity curves derived from a survey. 177 Lu-PSMA-617 sequence extrapolated to the physical half-life of 225 Assuming a relative biological activity of 5, volumetric measurement estimates of 225 Ac-PSMA-617 was administered at an average dose of 0.74 Sv / megabecquerel to the kidneys. (In the study) 225 Ac-PSMA-I&T-202, will be given 225 Ac-PSMA-I&T is administered at a dose of 100 kBc / kg once every eight weeks for up to four cycles, or 75 kBc / kg once every six weeks for up to six cycles, or 50 kBc / kg once every four weeks for up to nine cycles. Assuming a participant's body weight of 70 kg, the expected cumulative renal dose is approximately 23 Gy. 225 Ac-PSMA-I&T. In this study, patients with grade 2 or higher renal impairment (creatinine clearance <60 mL / min) are excluded. Additionally, renal function will be monitored throughout the study, and management of potential toxicity will be provided during treatment with Ac-PSMA-I&T. 225 Ac-PSMA-I&T to ensure participant safety. The proposed systems will deliver a similar cumulative dose of 225 Ac-PSMA-I&T at a similar dosage intensity and the limit of 450 kBc / kg will not be exceeded in any treatment regimen. Shorter treatment periods may extend the therapeutic window and improve RLT outcomes, particularly among mCRPC patients with large-volume disease and a rapid rise in PSA. It is worth noting that another alpha-emitting radiotherapy drug, radium chloride-223 (Xofigo), is FDA-approved at a dose of 55 kBc / kg given every 4 weeks for up to six cycles in men with prostate cancer with bone metastases. justification Doses Fixed for 225 Ac -PSMA-I&T To ensure more consistent drug exposure and minimize variability due to weight differences, fixed-dose regimens in the 5–12 MBcg range, administered every 4 or 6 weeks, will be evaluated in Part B of the study. This approach aims to enhance the reliability of the results by reducing the impact of body weight variation, while maintaining exposure levels consistent with those achieved through weight-based dosing. Both Lutathera (luteatate Lu 177) and Pluvicto (febvotide luteatate Lu 177) have been approved by the FDA as fixed-dose, not weight-adjusted, therapies, according to the following dosing schedule: Lutathera is administered at a fixed dose of 7.4 Gbcq (200 mCi) per dose, given every eight weeks for a total of four cycles. This fixed-dose approach simplifies administration and has proven effective across a range of patients (Lutathera FDA Multi-Discipline Review and Evaluation 2018). Pluvicto is also given at a fixed dose, usually 7.4 Gbcq (200 mCi) per cycle, every six weeks until disease progression or unacceptable toxicity (Pluvicto FDA Multi-Discipline Review and Evaluation 2018). To determine the appropriate fixed dose for 225 In the Ac-PSMA-I&T study, body weight (BW) distribution was assessed based on baseline BW data from 16 participants. Both non-group analysis (NCA) and group pharmacokinetic analysis (popPK) showed that 225 Ac-PSMA-I&T exhibits radiolabeled linear plasma pharmacokinetics, with dose-proportional exposures across the tested dose ranges (50 kBc / kg - 100 kBc / kg). Furthermore, using the popPK model, a simulation was performed on 500 patients per dose group (body weight range 50-120 kg with a mean body weight of 91 kg) to compare fixed doses of 225 Ac-PSMA-I&T with equivalent doses based on body weight, to ensure similar exposure levels. A comparison of exposures showed 225 Ac-PSMA-I&T (AUC 0-72 and C max Across different dosing approaches, there was overlap in simulated exposure at any dose level, confirming the suitability of fixed doses. Table 1 summarizes the exposure (AUC). 0-72 ) for 225 Ac-PSMA-I&T in the simulated group after fixed doses confirmed near-perfect overlap with that achieved by body weight-based doses. While fixed doses may result in higher exposures in lighter patients and lower exposures in heavier patients compared to body weight-based doses, overall exposure across the body weight range remained similar to the safe and tolerable dose observed with the highest tested body weight-based dose of 100 kBc / kg in the clinical trial of [the study / initiative]. 225 Ac-PSMA-I&T. A high dose of 12 megabecquerels will be administered during the first two cycles, followed by a dose reduction to 8 megabecquerels for the final two cycles. This strategy supports literature findings showing a decrease in tumor uptake across cycles. Specifically, when patients were treated with 177 In Lu--PSMA-I&T, a significant decrease in tumor uptake rates was identified during subsequent cycles (compared to cycle 1, uptake decreased to 73%, 50%, and 44% in cycles 2, 3, and 4–7, respectively) (Siebinga et al. 2024). This approach allows for more precise targeting, where the highest dose is administered only when it is most likely to be effective, thus enhancing therapeutic efficacy while simultaneously managing and minimizing the likelihood of adverse side effects. Table 1: Exposure 225 Ac-PSMA-I&T in a simulated group pharmacokinetic model AUC 0-72 (hour·kilobecquerel / milliliter) Dosage range Doses BW Group* average minimum maximum Standard Deviation (SD) Proposed fixed dosage groups 8 Megabecquerels BW<91 3.077 1.558 5.709 0.766 BW>=91 2.641 1.408 5.329 0.663 10 Megabecquerels BW<91 3.94 2.1 7.182 0.987 BW>=91 3.236 1.675 5.818 0.784 12 Megabecquerels BW<91 4.603 2.357 8.482 1.076 BW>=91 3.959 1.984 7.065 0.937 Doses based on equivalent BW* 88 kBc / kg BW<91 2.834 1.342 4.821 0.625 BW>=91 2.922 1.59 5.082 0.672 110 kBc / kg BW<91 3.37 1.73 6.674 0.837 BW>=91 3.601 1.819 6.506 0.881 132 kBc / kg BW<91 4.205 2.415 7.383 0.989 BW>=91 4.316 1.846 7.469 0.965 * Equivalent doses were calculated based on the average body weight of 91 kg of the study group. AUC exposure 0-72h (hr·kBc / mL) predicted from the pharmacokinetic model of the group after the first dose of 225 Ac-PSMA-I&T in cycle 1 in patients who received 88 kBc / kg equivalent to 8 MBc, 110 kBc / kg equivalent to 10 MBc, and 132 kBc / kg equivalent to 12 MBc. In Part 3 of the study, the dosing regimen chosen from Part 2 of the study to continue the study will be determined based on recommendations from the Data and Safety Monitoring Committee (DSMB), which will review the safety, efficacy, and drug exposure results from Part 2 of the study.Example 6. Safety and effectiveness 225 Ac-PSMA-I&T Tested 225 Ac-PSMA-I&T is an open-label, randomized, multicenter, part 2 study investigating the safety, tolerability, and antitumor activity of three dosing regimens of 225 Ac-PSMA-I&T, followed by Part 3 for effectiveness assessment 225 Ac-PSMA-I&T versus standard care in patients with PSMA-positive, castration-resistant metastatic prostate cancer (mCRPC) who have previously been treated with [177Lu]-PSMA-617 or other [177Lu]-PSMA radiotherapy. In Part 2, approximately 60 patients will be randomly assigned (20 per dosing regimen) (1:1:1) to receive 225 Ac-PSMA-I&T with one of three different dosing regimens: • Group 1: 50 kBc / kg of 225 Ac-PSMA-I&T intravenously every 4 weeks (± three days); • Group 2: 75 kBc / kg of 225 Ac-PSMA-I&T intravenously every 6 weeks (± five days); • Group 3: 100 kBc / kg of 225 Ac-PSMA-I&T intravenously every eight weeks (± seven days). Patient distribution and prior treatment Group 1: 50 kBc / kg n (٪) N = 3 Group 2: 75 kBc / kg n (٪) N = 2 Group 3: 100 kBc / kg n (٪) N = 2 Total: n (٪) N = 7 Random distribution 5 5 5 15 Treatment / Safety Group 3 (100.0) 2 (100.0) 2 (100.0) 7 (100.0) The group that can be evaluated for effectiveness in Part Two 2 (66.7) 0 2 (100.0) 4 (57.1) Currently under treatment 3 (100.0) 2 (100.0) 2 (100.0) 7 (100.0) Stop treatment 0 0 0 0 The safety analysis group includes all patients receiving at least one dose of the study treatment. Patients will be grouped according to the treatment and dosing regimen they received. The efficacy-evaluation Part 2 cohort includes all patients who were randomly assigned, received at least one dose of the study therapy, had a baseline PSA measurement, had at least one post-baseline PSA measurement, or discontinued early due to disease progression, unacceptable toxicity, or treatment- or disease-related death. A treatment-associated adverse event (TEAE) is defined as any adverse event (AE) that occurs or worsens during the treatment period (after the first dose of 225 Ac-PSMA-I&T and ≤1 month after the last dose of 225 Ac-PSMA-I&T) or adverse events that can be attributed to 225 Ac-PSMA-I&T occurs within 24 months of the last treatment with 225 Ac-PSMA-I&T. Four patients (57.1%) reported at least one TEAE, one at each of the 50 kBc / kg and 75 kBc / kg dose levels, and two at the 100 kBc / kg dose level. Hematological and non-hematological adverse events are recorded according to the NCI CTCAE. The severe TEAEs and TEAEs reported by the seven patients are shown by organ organ class, preferred pathway, and severity in Table 2. With the exception of one patient with grade 3 pelvic pain, grade 3 or higher TEAEs were not reported. category MedDRA For a member The device path MedDRA the favorite worst intensity the group 1: 50 kilobecquerels / kg ( N = 3) n ( ٪ ) Y the group 2: 75 kilobecquerels / kg ( N = 2) n ( ٪ ) Y the group 3: 100 kilobecquerels / kg ( N = 2) n ( ٪ ) Y Total: ( N = 7) n ( ٪ ) Y number patients ( ٪ from patients number Events The number of patients who suffered from at least one TEAE 1 (33.3) 3 1 (50.0) 2 2 (100.0) 5 4 (57.1) 10 Disorders The device digestive 0 1 (50.0) 1 2 (100.0) 4 3 (42.9) 5 nausea 0 0 2 (100.0) 2 2 (28.6) 2 Grade 1 0 0 1 (50.0) 1 1 (14.3) 1 Grade 2 0 0 1 (50.0) 1 1 (14.3) 1 diarrhea 0 0 1 (50.0) 1 1 (14.3) 1 Grade 1 0 0 1 (50.0) 1 1 (14.3) 1 dry mouth 0 1 (50.0) 1 0 1 (14.3) 1 Grade 1 0 0 0 0 Grade 2 0 1 (50.0) 1 0 1 (14.3) 1 vomiting 0 0 1 (50.0) 1 1 (14.3) 1 Grade 1 0 0 1 (50.0) 1 1 (14.3) 1 Disturbances public and cases location Giving 1 (33.3) 1 1 (50.0) 1 0 2 (28.6) 2 fatigue 1 (33.3) 1 1 (50.0) 1 0 2 (28.6) 2 Grade 1 1 (33.3) 1 0 0 1 (14.3) 1 Grade 2 0 1 (50.0) 1 0 1 (14.3) 1 Injury poisoning and complications procedures 0 0 1 (50.0) 1 1( 14.3) 1 Fall 0 0 1 (50.0) 1 1( 14.3) 1 Grade 1 0 0 1 (50.0) 1 1( 14.3) 1 Disorders The device reproductive and the breast 1 (33.3) 2 0 0 1 (14.3) 2 Pelvic pain 1 (33.3) 2 0 0 1 (14.3) 2 Grade 1 0 (0.0) 1 0 0 0 (0.0) 1 Grade 2 0 0 0 0 Grade 3 1 (33.3) 1 0 0 1 (14.3) 1 As shown in Figure 1, Group 1 received a 50 kBc / kg body weight dose every 4 weeks (Q4W). Each line represents the percentage change in individual patient serum prostate-specific antigen (PSA) levels, measured sequentially at four-week intervals. The dashed line represents the 50% reduction threshold (PSA50). This threshold must be exceeded to indicate a biochemical response. Of the 9 patients represented by the 9 different lines, only one patient exceeded the PSA50 threshold. This indicates a primary biochemical response at this dose and schedule. 225 Ac-PSMA-I&T. As shown in Figure 2, Group 2 received a dose of 75 kBc / kg of body weight every 6 weeks (Q6W). Each line represents the percentage change in individual patient serum prostate-specific antigen (PSA) levels, measured sequentially at four-week intervals. The dashed line represents the 50% reduction threshold (PSA50). This threshold must be exceeded to indicate a biochemical response. Of the 9 patients represented by the 9 different lines, none exceeded the PSA50 threshold. This indicates the absence of primary biochemical response activity at this dose and schedule. 225 Ac-PSMA-I&T. As shown in Figure 3, Group 3 received a dose of 100 kBc / kg of body weight every 8 weeks. Each line represents the percentage change in individual patient serum prostate-specific antigen (PSA) levels, measured sequentially at four-week intervals. The dashed line represents the 50% reduction threshold (PSA50). This threshold must be exceeded to indicate a biochemical response. Of the 9 patients represented by the 9 different lines, 2 patients exceeded the PSA50 threshold. This indicates a primary biochemical response at this dose and schedule. 225 Ac-PSMA-I&T. the reviewer Emmett L, et al. Results of a Prospective Phase 2 Pilot Trial of (177)Lu-PSMA-617 Therapy for metastatic castration-resistant prostate cancer including imaging predictors of treatment response and patterns of progression. Clin Genitourin Cancer. 2019;17:15-22. Hofman MS, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825-33. Kemppainen J, et al. Single Center Experience with a 4-Week 177Lu-PSMA-617 Treatment Interval in Patients with Metastatic Castration-Resistant Prostate Cancer. Cancers (Basel). 2022;14(24):6155. Kratochwil C, et al. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225 Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding. J Nucl Med. 2017;58(10):1624-1631. Kratochwil C, Haberkorn U, Giesel FL. 225 Ac-PSMA-617 for Therapy of Prostate Cancer. Semin Nucl Med . 2020;50(2):133-140. doi:10.1053 / j.semnuclmed.2020.02.004. Ling SW, et al. Advances in 177Lu-PSMA and 225 Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer. Pharmaceutics. 2022;14(10):2166. Lutathera FDA Multi-Discipline Review and Evaluation, 2018. https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2018 / 208700orig1s000multidiscipliner.pdf Pluvicto FDA Multi-Discipline Review and Evaluation, 2020. https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2022 / 215833Orig1s000MultidisciplineR.pdf Rasul S, et al. Clinical outcome of standardized 177Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks. Eur J Nucl Med Mol Imaging. 2020;47(3):713-720. Schuchardt C, et al. Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry. J Nucl Med. 2022;63(8):1199-1207. Siebinga H, et al. CPT Pharmacometrics Syst Pharmacol. Population pharmacokinetic dosimetry model using imaging data to assess variability in pharmacokinetics of 177 Lu-PSMA-617 in prostate cancer patients. 2023;12(8):1060-1071. Other incarnations An expert in the field will recognize, or be able to deduce, numerous equivalents for the specific incarnations described here using only routine experimentation. The following safeguards are intended to include such equivalents.

Claims

1. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered at a dosage of about 50 kBq / kg to about 75 kBq / kg of body weight of said patient on a dosing schedule of every 4-6 weeks.

2. The method of claim 1, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:. 3. The method of claim 1 or 2, wherein said 225Ac-radioconjugate is administered at a dosage of 50-75 kBq / kg (inclusive) of body weight of said patient.

4. The method of any one of the preceding claims, wherein said 225Ac-radioconjugate is administered on a dosing schedule of every 4 or 6 weeks.

5. The method of any one of the preceding claims, wherein said 225Ac-radioconjugate is administered at a dosage of 50 kBq / kg of body weight of said patient on a dosing schedule of every 4 weeks, or a dosage of 75 kBq / kg of body weight of said patient on a dosing schedule of every 6 weeks.

6. The method of any one of the preceding claims, wherein said 225Ac-radioconjugate is administered at least 4 cycles to said patient.

7. The method of any one of the preceding claims, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:,wherein said 225Ac-radioconjugate is administered at a dosage of 50 kBq / kg of body weight of said patient on a dosing schedule of every 4 weeks, or a dosage of 75 kBq / kg of body weight of said patient on a dosing schedule of every 6 weeks.

8. The method of any one of the preceding claims, wherein said administering results in an absorbed dose of at least 10 Gy per cycle in a tumor of said patient.

9. The method of any one of the preceding claims, wherein said administering results in a cumulative absorbed dose of at least 30 Gy in a tumor of said patient.

10. The method of any one of the preceding claims, wherein said administering results in an absorbed dose of at most 25 Gy per cycle in the salivary gland of said patient.

11. The method of any one of the preceding claims, wherein said administering results in a cumulative absorbed dose of at most 100 Gy in the salivary gland of said patient.

12. The method of any one of the preceding claims, wherein the PSMA expressing cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, renal cell cancer, bladder cancer, testicular cancer, neuroendocrine cancer, and brain tumor.

13. The method of any one of the preceding claims, wherein the PSMA expressing cancer is prostate cancer.

14. The method of any one of the preceding claims, further comprising administering an antiproliferative agent, a radiation sensitizer, or an immunomodulatory agent.

15. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered at a dosage of about 8 MBq at Q6W.

16. The method of claim 15, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:. 17. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered at a dosage of about 10 MBq at Q6W.

18. The method of claim 17, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:.  19. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered for at least 4 cycles of treatment, at a dosage of about 12 MBq at Q6W for cycles 1 and 2, andat a dosage of about 8 MBq at Q6W for cycles 3 and 4,wherein a cycle is about 6 weeks.

20. The method of claim 19, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:.

21. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered at a dosage of about 8 MBq per cycle.

22. The method of claim 21, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:. 23. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered at a dosage of about 10 MBq per cycle.

24. The method of claim 23, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:.

25. A method for treating a patient having cancer expressing Prostate Specific Membrane Antigen (PSMA), wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of an 225Ac-radioconjugate, wherein said 225Ac-radioconjugate comprises 225Ac chelated with a compound of Formula I, a pharmaceutically acceptable salt thereof, or a prodrug thereof:(I), wherein the 225Ac-radioconjugate is administered for at least 4 cycles of treatment, at a dosage of about 12 MBq per cycle for cycles 1 and 2, andat a dosage of about 8 MBq per cycle for cycles 3 and 4.

26. The method of claim 25, wherein said 225Ac-radioconjugate comprises 225Ac chelated with the following structure:.

27. The method of any of claim 21-26, wherein a cycle is about 6 weeks.   

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