Use of 212pb-dotatate in preparation of drug for treatment of gastroenteropancreatic neuroendocrine tumor with positive somatostatin receptor

Abstract

A use of a derivative of 212Pb of a somatostatin analogue in treatment of a gastroenteropancreatic neuroendocrine tumor with a positive somatostatin receptor. The derivative of 212Pb of the somatostatin analogue is 212Pb-DOTATATE. Also provided is a use of the derivative of 212Pb of the somatostatin analogue in preparation of a drug for treatment of the gastroenteropancreatic neuroendocrine tumor with the positive somatostatin receptor. Further provided is a composition for treatment of the gastroenteropancreatic neuroendocrine tumor with the positive somatostatin receptor. According to the use, 212Pb-DOTATATE is intravenously injected into AR42J tumor-bearing mice, and it is found that it has a better anti-tumor effect than 177Lu.

Description

212 Use of Pb-DOTATATE in the preparation of a medicament for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors Technical Field

[0001] This application relates to the field of medicine, in particular to a 212 Use of Pb-DOTATATE in preparing a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Background Art

[0002] Neuroendocrine tumors originate from the neuroendocrine system and primarily occur in the stomach, intestines, and pancreas. Although a rare disease with an incidence of approximately 5.25 cases per 100,000 people, it is the second most common gastrointestinal malignancy, and its incidence continues to rise. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) present with subtle signs and symptoms, and a wide variety of clinical manifestations, making them prone to misdiagnosis and missed diagnosis. As a result, most patients are diagnosed late, often having already spread locally and / or metastasized to distant sites, thus missing the opportunity for radical surgery. Subsequent treatment options are extremely limited, and the five-year survival rate for patients is only 35%. Therefore, innovative therapies have become a lifesaver for these patients.

[0003] Peptide receptor radionuclide therapy (PRRT) has been used to treat somatostatin receptor (SSTR)-positive NETs for more than 30 years. 111 In-DTPA-octreotide, a cell-internalized SSTR receptor agonist, can effectively relieve symptoms. 111 In has a low energy content and cannot meet the treatment needs. In addition, patients receiving treatment also experience complications such as leukemia and myelodysplastic syndrome. In order to overcome these problems, in the late 1990s, 90 Y-DOTATOC and 90 Y-DOTATATE was proposed one after another. 111 In, 90 Y emits pure beta rays with a range of 1.2 cm in tissue and a maximum energy of 2284 KeV, but it is not recommended for continued use due to its nephrotoxicity and hematotoxicity. 177 Lu is more suitable for smaller lesions and is used in the treatment of GEP-NETs. As a relatively safe radioactive metal, 177 Lu-related research has become the mainstream of PRRT. Therapeutic products for GEP-NETs 177Lu-DOTATATE was launched in the United States in 2018 under the trade name Lutathera. This was the first time a radiotherapy drug was approved for this indication, a landmark approval. This approval was based on two pivotal Phase III clinical trials, which demonstrated that some patients treated with Lutathera experienced tumor shrinkage or complete disappearance, prolonged progression-free survival by 19.9 months compared to the control group, and reduced the risk of disease progression or death by 79%. The study demonstrated a favorable safety profile and significantly improved health-related quality of life for these patients. While Lutathera treatment has achieved unprecedented success, it still falls short of meeting patient expectations regarding survival and mortality.

[0004] Summary of the Invention

[0005] The purpose of this application is to provide a 212 The application of Pb-DOTATATE in gastroenteropancreatic neuroendocrine tumors (NETs) expressing somatostatin receptor (SSTR). 212 After Pb-DOTATATE, it was found that it has 177 Lu has better anti-tumor efficacy.

[0006] The specific technical solutions of this application are as follows:

[0007] 1. A somatostatin analogue 212 Use of a Pb derivative in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the somatostatin analogue 212 The derivatives of Pb are 212 Pb-DOTATATE.

[0008] 2. A derivative of a somatostatin analogue 212 Use of a derivative of Pb in the preparation of a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the somatostatin analogue 212 The derivatives of Pb are 212 Pb-DOTATATE.

[0009] 3. The use according to item 1 or 2, wherein the 212 The single dose of Pb-DOTATATE is 1μCi to 100mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 100 mCi per kg of subject body weight per time.

[0010] 4. The use according to item 1 or 2, wherein the212 A single dose of Pb-DOTATATE is 1μCi-10mCi / kg body weight of the subject; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 10 mCi per kg of subject's body weight per time.

[0011] 5. The use according to item 1 or 2, wherein the 212 The single dose of Pb-DOTATATE is 250μCi-500mCi / subject; or 212 A single dose of Pb-DOTATATE can be 250 μCi-500 mCi / subject / time.

[0012] 6. The use according to item 1 or 2, wherein the 212 The single administration volume of Pb-DOTATATE is 1mL-30mL; or 212 A single dose of the drug of Pb-DOTATATE can be provided to the subject at 1 mL to 30 mL per subject per time, or

[0013] described 212 Pb-DOTATATE was administered at a concentration of 1-30 mCi / mL.

[0014] 7. The use according to item 1 or 2, wherein the 212 Pb-DOTATATE is administered every 3 to 16 weeks.

[0015] 8. The use according to item 1 or 2, wherein the 212 The total dose of Pb-DOTATATE administered was 0.1 mCi-2 Ci.

[0016] 9. The use according to item 1 or 2, wherein the 212 The total volume of Pb-DOTATATE administered is 1 mL to 300 mL.

[0017] 10. The use according to item 1 or 2, wherein the 212 Pb-DOTATATE is administered by intravenous injection.

[0018] 11. A composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the composition comprises a somatostatin analogue 212 Pb derivatives, somatostatin analogs 212 The derivatives of Pb are 212 Pb-DOTATATE.

[0019] In this application, DOTATATE can achieve 212 Pb labeling, after labeling, the radiochemical purity (hereinafter referred to as RCP) can reach 98.68% after quality control by Radio-iTLC; 212 After being placed at 2-8℃ for 2 hours, the RCP of Pb-DOTATATE can reach 98.05%, and its in vitro stability meets the test requirements. 212 Pb-DOTATATE and the same dose 177 Compared with Lu-DOTATATE, it has better anti-tumor efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG1 is a curve showing changes in body weight over time in experimental animals of the present application;

[0021] FIG2 is a curve showing changes in tumor volume over time in the experimental animals of the present application. DETAILED DESCRIPTION

[0022] The present application is described in detail below. Although specific embodiments of the present application are shown, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0023] It should be noted that certain words are used in the specification and claims to refer to specific components. Those skilled in the art should understand that technicians may use different nouns to refer to the same component. This specification and claims do not use the difference in nouns as a way to distinguish components, but use the difference in the functions of the components as the criterion for distinction. As mentioned throughout the specification and claims, "including" or "comprising" are open-ended terms and should be interpreted as "including but not limited to". The subsequent description of the specification is a preferred embodiment of the present application, but the description is based on the general principles of the specification and is not intended to limit the scope of the present application. The scope of protection of this application shall be as defined by the attached claims.

[0024] The present application provides a somatostatin analogue 212 Use of Pb derivatives in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, the somatostatin analogs 212 The derivatives of Pb are 212 Pb-DOTATATE.

[0025] The present application provides a derivative of somatostatin analogues. 212Use of a Pb derivative in preparing a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors.

[0026] 212 Pb and 212 Bi is a pair of mother and daughter radionuclides, the mother 212 Pb can obtain daughters through β decay 212 Bi, the latter can undergo two-way decay, emitting alpha and beta particles in the process. 212 Bi has a short half-life of only 1.0h, while 212 Pb has a half-life of 10.6 hours, so its application to the parent can compensate for the shorter lifespan of the daughter. Currently, there are no reports of 212Pb-DOTATATE being used to treat SSTR-positive GEP-NETs.

[0027] DOTATATE is a DOTA-conjugated peptide that can be radiolabeled for use in SPECT imaging and PRRT. The peptide sequence of DOTATATE is:

[0028] DOTA-D-Phe-Cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr-OH.

[0029] DOTATATE can be prepared from any preparation method in the prior art, as long as its function is achieved. Preferably, the preparation of DOTATATE refers to CN111944015A.

[0030] DOTATATE is 212 Precursor of Pb-DOTATATE, chelates DOTATATE 212 Pb can be obtained 212 Pb-DOTATATE.

[0031] 212 Pb-DOTATATE is a somatostatin-2 receptor analog that has a high affinity for the somatostatin-2 receptor. It works by binding to cells with somatostatin receptors, which may be present on certain tumors. After binding to the receptor, the drug enters the cell and damages the tumor cell through radiation.

[0032] Specifically, the 212 The molecular formula of Pb-DOTATATE is 212 Pb-C 65 H 90 N 14 O 19 S2, whose structural formula is shown in the following formula I:

[0033] In this application, neuroendocrine tumors are tumors that originate from neuroendocrine cells. Neuroendocrine cells are a large class of cells in the body that have a neuroendocrine phenotype and can produce a variety of hormones. According to the latest naming regulations for neuroendocrine tumors by WHO in 2010, "Neuroendocrine neoplasm (NEN)" refers to all tumors originating from neuroendocrine cells, among which well-differentiated neuroendocrine tumors are named Neuroendocrine tumor (NET, neuroendocrine tumor), and poorly differentiated neuroendocrine tumors are named Neuroendocrine carcinoma (NEC, neuroendocrine cancer). Neuroendocrine cells are distributed throughout the body, so neuroendocrine tumors can occur anywhere in the body, but the most common are neuroendocrine tumors of the digestive system such as the stomach, intestines, and pancreas, accounting for about 2 / 3 of all neuroendocrine tumors. Neuroendocrine tumors that occur in the digestive system of the stomach, intestines, and pancreas are gastroenteropancreatic neuroendocrine tumors (GEP-NENs).

[0034] In the present application, the term medicine generally refers to and is suitable for being applied to a patient, for example, can be a medicine applied to a human patient. In addition, the medicine can also include one or more (pharmaceutically effective) carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers and / or preservatives. In the application, the acceptable components of the medicine can be nontoxic to the recipient at the dosage and concentration used. The form of the medicine of the present application can be not limited to liquid, freezing and lyophilized compositions.

[0035] In this application, treatment refers to therapeutic treatment and preventive or prophylactic measures, the purpose of which is to prevent, slow down, improve and stop adverse physiological changes or disorders, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, alleviation or disappearance (whether partial or complete), extension of life expectancy compared to not receiving treatment, etc. Patients in need of treatment include patients who already have a disease or disorder, patients who are susceptible to a disease or disorder, or patients in need of prevention of the disease or disorder, who can or are expected to benefit from the administration of the disclosed herein. 212 Pb-DOTATATE is intended for use in the detection, diagnostic procedures, and / or treatment of patients who may benefit from it.

[0036] In this application, an agent refers to a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological material.

[0037] As used herein, a pharmaceutical agent or drug refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

[0038] In the present application, subjects or patients or treatment objects include but are not limited to humans and animals that can suffer from cancer, or any disease that can be directly or indirectly related to cancer. Research subjects include mammals. Such as humans, dogs, cows, horses, pigs, sheep, goats, cats, rats, rabbits, mice and transgenic non-human animals. Specifically, subjects or patients or treatment objects include companion animals, such as dogs, cats, rabbits and rats. Specifically, subjects or patients or treatment objects include livestock, such as cows, pigs, sheep, goats and rabbits. Specifically, subjects or patients or treatment objects include purebred or show animals, such as horses, pigs, cows and rabbits. Specifically, subjects or patients or treatment objects are humans, for example, humans who have or may have a risk of cancer.

[0039] In this application, the 212 The single dose of Pb-DOTATATE is 1μCi to 100mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 100 mCi per kg of subject body weight per time.

[0040] In some embodiments, the 212 The single dose of Pb-DOTATATE is 0.05 to 100 mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 0.05 to 100 mCi / kg of subject body weight / time.

[0041] In some embodiments, the 212 The single dose of Pb-DOTATATE is 0.1 to 100 mCi / kg body weight of the subject; or 212 A single dose of Pb-DOTATATE can be 0.1 to 100 mCi / kg of subject body weight / time.

[0042] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1μCi to 80mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 80 mCi per kg of subject body weight per time.

[0043] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1μCi to 60mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 60 mCi per kg of subject body weight per time.

[0044] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1 μCi-40 mCi / kg body weight of the subject; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 40 mCi per kg of subject body weight per time.

[0045] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1μCi-20mCi / kg body weight of the subject; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 20 mCi per kg of subject body weight per time.

[0046] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1μCi-10mCi / kg body weight of the subject; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 10 mCi per kg of subject's body weight per time.

[0047] In some embodiments, the 212 A single dose of Pb-DOTATATE is 1 to 10 mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 to 10 mCi / kg of subject body weight / time.

[0048] In some embodiments, the 212 A single dose of Pb-DOTATATE is 5 to 10 mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 5 to 10 mCi / kg of subject body weight / time.

[0049] In some embodiments, the 212 A single dose of Pb-DOTATATE is 0.01 to 0.15 mCi per kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 0.01 to 0.15 mCi / kg of subject body weight / time.

[0050] Specifically, the 212The single dose of Pb-DOTATATE can be 1 μCi / kg of subject weight, 0.01 mCi / kg of subject weight, 0.05 mCi / kg of subject weight, 0.1 mCi / kg of subject weight, 0.15 mCi / kg of subject weight, 0.2 mCi / kg of subject weight, 0.3 mCi / kg of subject weight, 0.4 mCi / kg of subject weight, 0.5 mCi / kg of subject weight, 0.6 mCi / kg of subject weight, 0.7 mCi / kg of subject weight, 0.8 mCi / kg of subject weight, 0.9 mCi / kg of subject weight, 1 mCi / kg of subject weight, 1.5 mCi / kg of subject weight, 2 mCi / kg of subject weight, 3 mCi / kg of subject weight, 4 mCi / kg of subject weight , 5mCi / kg subject weight, 6mCi / kg subject weight, 7mCi / kg subject weight, 8mCi / kg subject weight, 9mCi / kg subject weight, 10mCi / kg subject weight, 15mCi / kg subject weight, 20mCi / kg subject weight, 25mCi / kg subject weight, 30mCi / kg subject weight, 35mCi / kg subject weight, 40mCi / kg subject weight, 45mCi / kg subject weight, 50mCi / kg subject weight, 55mCi / kg subject weight, 60mCi / kg subject weight, 65mCi / kg subject weight, 70mCi / kg subject weight, 75mCi / kg subject weight, 80mCi / kg subject weight, 85mCi / kg subject body weight, 90mCi / kg subject body weight, 95mCi / kg subject body weight, 100mCi / kg subject body weight.

[0051] In this application, the 212 The single dose of Pb-DOTATATE is 50μCi-500mCi / subject; or 212 The single dose of Pb-DOTATATE can be 50μCi-500mCi / subject / time. (Subject weight is 50kg)

[0052] In some embodiments, the 212 The single dose of Pb-DOTATATE is 250μCi-500mCi / subject; or 212 The single dose of Pb-DOTATATE can be 250μCi-500mCi / subject / time. (Subject weight is 50kg)

[0053] In some embodiments, the 212 The single dose of Pb-DOTATATE is 50μCi-100mCi / subject; or 212 The single dose of Pb-DOTATATE can be 50μCi-100mCi / subject / time. (Subject weight is 50kg)

[0054] In some embodiments, the 212 The single dose of Pb-DOTATATE is 50μCi-200mCi / subject; or 212 The single dose of Pb-DOTATATE can be 50μCi-200mCi / subject / time. (Subject weight is 50kg)

[0055] In some embodiments, the 212 The single dose of Pb-DOTATATE is 50μCi-300mCi / subject; or 212 The single dose of Pb-DOTATATE can be 50μCi-300mCi / subject / time. (Subject weight is 50kg)

[0056] In some embodiments, the 212 The single dose of Pb-DOTATATE is 50μCi-400mCi / subject; or 212 The single dose of Pb-DOTATATE can be 50μCi-400mCi / subject / time. (Subject weight is 50kg)

[0057] Specifically, the subject is 50 kg, 212The single-dose administration of Pb-DOTATATE was 50 μCi / subject, 100 μCi / subject, 150 μCi / subject, 200 μCi / subject, 250 μCi / subject, 300 μCi / subject, 350 μCi / subject, 400 μCi / subject, 450 μCi / subject, 500 μCi / subject, 600 μCi / subject, 70 0 μCi / per subject, 800 μCi / per subject, 900 μCi / per subject, 1 mCi / per subject, 10 mCi / per subject, 50 mCi / per subject, 100 mCi / per subject, 150 mCi / per subject, 200 mCi / per subject, 250 mCi / per subject, 300 mCi / per subject, 350 mCi / per subject, or 400 mCi / per subject.

[0058] In this application, the 212 The single administration volume of Pb-DOTATATE is 1mL-30mL; or 212 A single dose of Pb-DOTATATE can be provided to a subject at 1 mL to 30 mL per subject per time.

[0059] Specifically, the 12 The single administration volume of Pb-DOTATATE can be 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, 24 ml, 25 ml, 26 ml, 27 ml, 28 ml, 29 ml or 30 ml.

[0060] In this application, the 212 Pb-DOTATATE was administered at a concentration of 1-30 mCi / mL.

[0061] Specifically, the 212The dosage concentration of Pb-DOTATATE can be 1mCi / mL, 2mCi / mL, 3mCi / mL, 4mCi / mL, 5mCi / mL, 6mCi / mL, 7mC i / mL, 8mCi / mL, 9mCi / mL, 10mCi / mL, 11mCi / mL, 12mCi / mL, 13mCi / mL, 14mCi / mL, 15mC i / mL, 16mCi / mL, 17mCi / mL, 18mCi / mL, 19mCi / mL, 20mCi / mL, 21mCi / mL, 22mCi / mL, 23 mCi / mL, 24mCi / mL, 25mCi / mL, 26mCi / mL, 27mCi / mL, 28mCi / mL, 29mCi / mL or 30mCi / mL.

[0062] In this application, the 212 Pb-DOTATATE is administered every 3 to 16 weeks.

[0063] Specifically, the 212 The administration frequency of Pb-DOTATATE can be once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, or once every 16 weeks.

[0064] In this application, the 212 The total dose of Pb-DOTATATE administered is 0.1 mCi-2 Ci (total human dose), or 212 The total dose of Pb-DOTATATE administered was 1 μCi-1 mCi (total dose administered to animals).

[0065] Specifically, the 212 The total dose of Pb-DOTATATE can be 1 μCi, 5 μCi, 10 μCi, 100 μCi, 1 mCi, 10 mCi, 50 mCi, 100 mCi, 200 mCi, 300 mCi, 400 mCi, 500 mCi, 600 mCi, 700 mCi, 800 mCi, 900 mCi, 1000 mCi, 1100 mCi, 1200 mCi, 1300 mCi, 1400 mCi, 1500 mCi, 1600 mCi, 1700 mCi, 1800 mCi, 1900 mCi, or 2000 mCi. (The total dose here refers to the total dose after multiple administrations, for example, the total dose after four administrations.)

[0066] described 212The dosage of Pb-DOTATATE should be based on the actual situation of the subject, combined with the dosage, dosage volume, dosage concentration and total dosage, to implement a dosage regimen suitable for the subject.

[0067] In this application, the 212 The total volume of Pb-DOTATATE administered is 1 ml to 300 ml.

[0068] Specifically, the 212 The total volume of Pb-DOTATATE administered can be 1 ml, 5 ml, 10 ml, 15 ml, 20 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, 55 ml, 60 ml, 65 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 200 ml, 210 ml, 220 ml, 230 ml, 240 ml, 250 ml, 260 ml, 270 ml, 280 ml, 290 ml or 300 ml.

[0069] described 212 The administration volume of Pb-DOTATATE can be determined based on the actual condition of the subject and the dosage.

[0070] In some embodiments, the dosage for neuroendocrine tumor patients is 200 mCi every 8 weeks, the volume of each administration is 20 mL, the concentration is 10 mCi / mL, the total number of administrations is 4 times, and the total dosage is 800 mCi.

[0071] In the present application, the composition, drug or agent may be administered by intraperitoneal injection, intravenous injection, oral administration or skin application. Specifically, the dosage administered to the subject varies depending on the route of administration, symptoms, age of the patient, etc., and can be determined by the clinician.

[0072] In some embodiments, the 212 Pb-DOTATATE is administered by intravenous injection.

[0073] In this application, 212 Pharmaceutically acceptable carriers or excipients may also be added to the Pb-DOTATATE drug or reagent.

[0074] Specifically, the drug or agent can be prepared in the following form: the protein synthesis inhibitor or a composition comprising the same is mixed with a pharmaceutically acceptable carrier to obtain, for example, oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions, films (e.g., orally disintegrating films), parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, instillations), external preparations (e.g., skin preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pills, nasal drops, respiratory preparations (inhalers), eye drops, etc. In addition, these preparations can be used as controlled-release preparations (e.g., sustained-release microcapsules), such as immediate-release preparations, sustained-release preparations, etc. Such preparations can be obtained by conventional preparation methods in the art.

[0075] Specifically, examples of the above-mentioned pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyrrolidone, etc.), lubricants (e.g., magnesium stearate, calcium stearate, talc, etc.), disintegrants (e.g., carboxymethyl cellulose calcium, talc, etc.), diluents (e.g., water for injection, saline, etc.), additives (e.g., stabilizers, preservatives, colorants, flavorings, dissolution aids, emulsifiers, buffers, isotonic agents, etc.), and the like.

[0076] The present application provides a composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein the composition comprises a somatostatin analogue 212 Pb derivatives, somatostatin analogs 212 The derivatives of Pb are 212 Pb-DOTATATE.

[0077] In this application, AR42J tumor-bearing mice were given a single intravenous injection of different doses of 212 Pb-DOTATATE, DOTATATE or 177 Lu-DOTATATE, 131 I-DOTATATE, 90 After Y-DOTATATE, the weight of the seven groups of animals showed a trend of first increasing, then decreasing, and then increasing. At the end of the experiment, the weight of the seven groups of animals increased by about 6.9-12.5%. During the experiment, the low-dose group (G1), the blank control group (G4) and 177 Lu control group (G5), 131 I comparison group (G6) and 90The tumor volume of animals in the control group (G7) showed a continuous increase from D0 to D35. The tumor volume of animals in the medium-dose group (G2) showed a gradual increase from D0 to D6, a continuous decrease from D7 to D14, and a gradual increase from D15 to D35. The tumor volume of animals in the high-dose group (G3) showed a gradual increase from D0 to D3, a continuous decrease from D4 to D27, and a slight increase from D28 to D35. At the end of the study, the T / C ratio of the low-dose group (G1) was 81.7% (>40%), which was statistically different from the control group (G4) (P < 0.05), indicating that the low-dose group had poor antitumor efficacy. The relative tumor growth rate (T / C ratio) of the medium-dose group (G2) was 48.9% (>40%), which was statistically different from the control group (G4) (P < 0.05), indicating that the medium-dose group had a certain antitumor effect. The relative tumor proliferation rate T / C of the high-dose group (G3) was 6.4% (<40%), and was statistically different from that of the control group (G4) (P<0.05), indicating that the high-dose group had effective antitumor efficacy. 177 Lu control group (G5), 131 I comparison group (G6) and 90 The relative tumor growth rates T / C of the control group (G7) were 99.2%, 100%, and 83.4% (all > 40%), respectively. There was no statistical difference (P > 0.05) compared with the blank control group (G4), indicating that the control group was ineffective in anti-tumor treatment. At the end of the experiment, the tumor volume and weight of G3 animals were significantly lower than those of the other groups; the TGI of G1, G2, G3, G5, G6, and G7 were significantly lower than those of G1, G2, G3, G5, G6, and G7. TV The tumor growth inhibition rates of G3 were significantly higher than those of G1, G2, G5, G6, and G7, which were 17.6%, 50.5%, 93.0%, 3.3%, 0.7%, and 0.0%, respectively. The human dose was estimated based on the surface area of ​​animals and humans and the experience of nuclear medicine use.

[0078] Example

[0079] This application provides general and / or specific descriptions of the materials and experimental methods used in the experiments. In the following examples, unless otherwise specified, % represents wt%, i.e., percentage by weight. All reagents or instruments used without manufacturer indication are commercially available conventional reagents.

[0080] All experimental operations in this application strictly complied with the "Technical Guidelines for Non-clinical Studies of Cytotoxic Anti-tumor Drugs" issued by the China Food and Drug Administration and the standard experimental operating procedures (SOPs) of Midu (Nanjing) Biotechnology Co., Ltd.

[0081] Example 1

[0082] 212 Preparation method of Pb-DOTATATE:

[0083] 18-70 nanomolar amounts of DOTATATE aqueous solution (1 mg / ml) were added to 212 Pb (1 MBq, 1 ml) was added to the pre-treated solution. Afterwards, 2 M Na2CO3 was added to the mixture to increase the pH value to 4.5-6.5.

[0084] mark 212 The final volume of Pb was 1 ml. The vessel containing the reaction mixture was placed in a thermostat at a temperature of (90±2)° C. The synthesis reaction was interrupted by cooling the mixture of the vessel and water at a temperature of 15° C.

[0085] The preparation of DOTATATE refers to CN111944015A.

[0086] 177 The labeling of Lu-DOTATATE refers to CN112584875A.

[0087] 131 The labeling of I-DOTATATE refers to Lungu, et.al, Chapter 14: Labeling of DOTA-TATE with 177Lu and 131I for diagnosis and targeted therapy: in vitro and in vivo comparative evaluation, Comparative evaluation of therapeutic radiopharmaceuticals, Pages 223-256

[0088] 90 The labeling of Y-DOTATATE refers to JBCwikla, et.al., Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): aphase II study, Annals of Oncology, Volume 21, Issue 4, 2010, Pages 787-794, ISSN 0923-7534.

[0089] Example 2

[0090] 2.1 Animal selection

[0091] In accordance with the "Technical Guidelines for Nonclinical Studies of Cytotoxic Anti-tumor Drugs," AR42J ectopic tumor-bearing BALB / c-nude mice were used as the experimental animal model for tissue distribution studies. The number of animals used was the minimum required to ensure scientific validity and statistical significance of the data; currently, no effective in vivo studies can replace this. The results of this application will provide important information for nonclinical and clinical studies.

[0092] 2.2 Basic information of animals

[0093] A total of 56 AR42J tumor-bearing mice (8 spare animals from the same batch were prepared) were used in this experiment. All of them were male and were modeled by Yikang (Beijing) Pharmaceutical Technology Co., Ltd. The tumor-bearing mice suffered from small cell lung cancer. BALB / c-nude mice were purchased from Spafor (Beijing) Biotechnology Co., Ltd. The experimental animal production license number is SCXK (Beijing) 2019-0010, and the experimental animal quality certificate number is 110324211106533021. Each animal has a unique ear tag identification number. The body weight of the enrolled animals at the time of administration was 19.9-24.5 g, and the tumor volume was 88.4-301.1 mm 3 .

[0094] 2.3 Animal Management

[0095] After the AR42J tumor-bearing mice arrived at the SPF-level barrier animal room of Midu (Nanjing) Biotechnology Co., Ltd., they were transferred to polycarbonate / polysulfone breeding boxes. 1 to 5 animals of the same sex were kept in each cage and quarantined according to Midu's relevant SOP. Healthy animals that passed the quarantine were selected before the experiment to enter the experiment. The animals were free to eat and drink water during the breeding period. The measured temperature and humidity of the environmental conditions met the set requirements throughout the experiment (room temperature 20℃~26℃, relative humidity 40%~70%). The temperature and humidity monitoring records are kept in the Midu archives. The lighting is set to alternate between light and dark for 12 hours. Due to the needs of the experimental operation, there is sometimes a short lighting period at night. Experimental Animal Use License: SYXK (Beijing) 2019-0028 (Yikang), SYXK (Su) 2020-0016.

[0096] 2.4 Dosage regimen trial design

[0097] In combination with the requirements of radiation safety and instrument detection, this test 212 Pb-DOTATATE, compounds (DOTATATE) and 177 Lu-DOTATATE, 131 I-DOTATATE and 90The dosage of Y-DOTATATE is set as shown in the table below. This study used a single intravenous injection. The specific animal grouping and dosing schedule are detailed in Table 1 below.

[0098] Table 1

[0099] Note a: The control group was given the same amount of DOTATATE as the high-dose group.

[0100] iv refers to administration by intravenous injection.

[0101] Storage method of test substances: Except during administration and analysis, the labeled test substances should be stored at 2-8°C.

[0102] Preparation method of test substance: 212 Pb-DOTATATE was administered in normal saline.

[0103] The information of the test substances is shown in Table 2.

[0104] Table 2

[0105] 2.5 Instruments and Reagents

[0106] Table 3 Test instruments

[0107] Table 4 Test reagents

[0108] Example 3 212 Quality Control of Pb-DOTATATE

[0109] In this study, Radio-iTLC was used to 212 Pb labeled product for quality control. Take a certain amount 212 The Pb-labeled compound was spotted onto a glass fiber plate and placed in a 0.05 M citric acid / sodium citrate (pH = 4.0) developing agent for chromatography. The radiochemical purity (RCP) was calculated by thin layer scanning. The RCP should be ≥ 95%.

[0110] A total of 1 batch was produced in this experiment 212 Pb-DOTATATE, batch number L21122401. Radio-iTLC analysis showed an RCP of 98.68%, meeting the test requirements. See Table 5 for specific results.

[0111] Table 5 212 Quality control results of Pb-DOTATATE

[0112] Example 4 212In vitro stability of Pb-DOTATATE

[0113] Will 212 Pb-DOTATATE was used as a test sample and stored in a labeled solution system at 2-8°C. The results were detected by Radio-iTLC. 212 The RCP of Pb-DOTATATE, as its in vitro stability data, is set with at least two detection time points. The first detection time point is 0 h, which is the purity test in quality control, and the last detection time point is later than the end of drug administration, specifically 2 h after drug discharge.

[0114] The results of Radio-iTLC testing showed: 212 The RCP of Pb-DOTATATE 2 hours after dispensing (later than the end of drug administration) was 98.05%, meeting the test requirements. Specific in vitro stability results are shown in Table 6.

[0115] Table 6 Different time points 212 In vitro stability data of Pb-DOTATATE

[0116] Example 5 Animal Dosing, Body Weight, Tumor Volume and Weight

[0117] Before dosing, the body weight and tumor volume of all participating animals were weighed and recorded. Tumor-bearing mice within the appropriate tumor volume range and in good tumor condition were selected and randomly divided into groups according to tumor volume (8 animals per group). During dosing, the initial radioactive dose, initial dose determination time, injection time, residual radioactive dose, residual dose determination time (G1-G3, G5-G7), and the injection time of DOTATATE in G4 were recorded.

[0118] 5.1 Actual dosage of animals

[0119] The actual dosages of animals are as follows: The planned dosages of G1, G2 and G3 animals were 1μCi / animal, 5μCi / animal and 10μCi / animal, respectively. After testing and calculation, the actual average dosages were 1.2μCi / animal (G1), 5.2μCi / animal (G2) and 10.5μCi / animal (G3), and the average dosage volumes were 5.6mL / kg (G1), 5.5mL / kg (G2) and 5.4mL / kg (G3). G4 was the blank control group, and was planned to be given the same dose of DOTATATE as G3. The actual dosage was approximately 0.93μg / animal, and the dosage volume was approximately 5.5mL / kg. G5 was the comparison group, and was planned to be given the same dose of 177 The actual dose of Lu-DOTATATE was about 11.6μCi / mouse, and the administration volume was about 4.9mL / kg. G6 was the control group, and the dose was the same as that of G3.131 I-DOTATATE, the actual dosage was about 11.3 μCi / animal, the dosage volume was about 5.0 mL / kg, G7 was the control group, and the dose was the same as that of G3. 90 For Y-DOTATATE, the actual dosage was approximately 9.9 μCi / animal, and the dosage volume was approximately 5.1 mL / kg. The body weight and actual dosage of each animal are detailed in Tables 7 and 8.

[0120] Table 7 G1 (low dose), G2 (medium dose), G3 (high dose) and G5 ( 177 Lu control group), G6( 131 I control group), G7 ( 90 Y control group) experimental animals grouping and drug administration information

[0121] Table 8G4 (blank control group) experimental animal grouping and medication information

[0122] 5.2 Animal Weight and Tumor Size Monitoring

[0123] After the animals were administered the test substance / normal saline, the tumor diameter and body weight were measured twice a week, with at least 2 days between each measurement.

[0124] 5.3. Treatment of experimental animals

[0125] In experimental animals given 212 Pb-DOTATATE, DOTATATE or 177 Lu-DOTATATE, 131 I-DOTATATE and 90 35 days after Y-DOTATATE (D35, the day of administration is D0, the first day of administration is D1, the second day of administration is D2, and so on), all experimental animals were euthanized after measuring the tumor diameter and weighing, and the tumors were removed, photographed, and weighed.

[0126] 5.4. Data collection and result calculation

[0127] The relative tumor volume (RTV) and relative tumor proliferation rate (T / C) were calculated based on the tumor diameter measurement data. The tumor mass inhibition rate (TG TW ), tumor volume inhibition rate (TG TV ), and draw a tumor growth curve based on the tumor volume. The calculation formula is as follows:

[0128] RTV=V t / V0(V tis the tumor volume at each measurement, V0 is the tumor volume measured at D0)

[0129] T / C=T RTV / C RTV *100%(T RTV : Test group RTV; C RTV : Blank control group RTV)

[0130] TGI TW =(1-average tumor weight of the test group / average tumor weight of the blank control group)×100%

[0131] TGI TV =(1-average tumor volume of the test substance group / average tumor volume of the blank control group)×100%.

[0132] During the experiment, the weight of the seven groups of animals showed an overall trend of first increasing, then decreasing, and then increasing again. At the end of the experiment, the weight of the five groups of animals increased by about 6.9-12.5%. Specific weight data are shown in Tables 9-15, and the specific weight average value change curve over time is shown in Figure 1.

[0133] Table 9 Body weight of G1 (low dose) experimental animals

[0134] Table 10 Body weight of G2 (medium dose) experimental animals

[0135] Table 11 Body weight of G3 (high dose) experimental animals

[0136] Table 12 Body weight of G4 (control group) experimental animals

[0137] Table 13G5( 177 The body weight of the experimental animals (Lu control group)

[0138] Table 14G6( 131 (1) Weight of experimental animals in the control group

[0139] Table 15G7( 90 Y control group) body weight of experimental animals

[0140] During the experiment, the low-dose group (G1), blank control group (G4) and 177 Lu control group (G5), 131 I comparison group (G6) and 90 The tumor volume of animals in the control group (G7) was 35Overall, it showed a continuous increasing trend; the tumor volume of animals in the medium-dose group (G2) showed a gradually increasing trend from D0 to D6, and from D7 to D 14 The tumor volume showed a continuous decreasing trend, D 15 ~D 35 The tumor volume increased slightly; the tumor volume of animals in the high-dose group (G3) showed a gradually increasing trend from D0 to D3, and from D4 to D 27 The tumor volume showed a continuous decreasing trend, D 28 ~D 35 The tumor volume increased slightly. During the experiment, the tumor volumes of animals in each group were basically equivalent from D0 to D3, and from D6 to D 35 The tumor volume rankings of each group were G3 < G2 < G1 < G5 < G6 < G7 < G4. At the end of the experiment, the average tumor volumes of animals in G1, G2, G3, G4, G5, G6, and G7 were 1245.1 mm 3 、747.7 mm 3 、105.4 mm 3 、1511.6 mm 3 、1461.2 mm 3 [[ID=2h]]、1501.3 mm 3 and 1511.0 mm 3 , and the tumor volume of G3 animals was significantly smaller than that of G4.

[0141] During the experiment, the relative tumor proliferation rates T / C of animals in G1, G2, G3, G5, G6, and G7 all showed a trend of first decreasing and then increasing. G1, G2, G3, G5, G6, and G7 reached the minimum values on D 14 、D 17 、D 31 、D 11 、D 11 and D3 respectively, specifically 64.3%, 23.7%, 3.3%, 81.5%, 89.7%, and 69.8%. During the experiment, the T / C of G1 animals did not reach the level of ≤40% (the overall T / C was between 64.3% (D 14 ) and 81.7% (D 35 )), and there was a statistically significant difference in the analysis of variance of the tumor volumes of G1 and G4 animals at D 35 (P = 0.05), indicating that the anti-tumor efficacy of the low-dose group was poor. The T / C of G2 animals was close to the level of 40% from D 11 ~D 31 , and the T / C at D 35 was 48.9% (>40%), indicating that the medium-dose group had a certain anti-tumor drug effect. The T / C of G3 animals dropped to 21.0% at D 11 , and from D 11 ~D 31The T / C continued to decrease to 3.3% (D 31 ), in D 32 ~D 35 Slightly increased to 6.4% (D 35 );D 11 ~D 35 The T / C of G3 and G4 animals were all lower than 40%, and the tumor volume of G3 and G4 animals was 11 ~D 35 There was a statistically significant difference between the time periods (P<0.05), indicating that the high-dose group had effective anti-tumor drug efficacy. The T / C ratios of animals in groups G5, G6, and G7 did not reach a level of ≤40% (the overall T / C ratio ranged from 69.8% to 100%). Furthermore, the tumor volumes of animals in groups G5, G6, and G7 showed no statistically significant difference from those in G4 (P>0.05), indicating that the anti-tumor drug in the three control groups was ineffective.

[0142] During the experiment, the tumor volume inhibition rates of G1, G2, G3, G5, G6 and G7 showed a trend of increasing first and then decreasing, respectively. 14 、D 17 、D 31 、D 11 、D 11 and D3 reached peak values ​​of 35.2%, 76.0%, 96.5%, 20.5%, 11.3% and 16.4%; at the end of the experiment, the average tumor weights of G1, G2, G3, G4, G5, G6 and G7 were 2.1913g, 1.5205g, 0.1389g, 2.7726g, 2.6381g, 2.6748g and 2.7582g, respectively. The tumor weight of G3 animals was significantly lower than that of G4, and there was a statistical difference with the tumor weight of G4 (P < 0.05). The average tumor weights of G1 and G5, G6 and G7 groups were similar and had no statistical difference with G4 group. The tumor weight inhibition rate (TGI) of G1, G2, G3, G5, G6 and G7 TW ) were 21.0%, 45.2%, 95.0%, 4.9%, 3.5% and 0.5% respectively, indicating that the tumor growth inhibition rate of G3 was significantly higher than that of G1, G2, G5, G6 and G7.

[0143] Specific tumor volumes are shown in Tables 16 to 22, RTV data are shown in Tables 23 to 29, T / C and TGI TV The data are shown in Table 30, tumor weight and TGI TW The data are shown in Table 31, the results of variance analysis of tumor volume and tumor weight of each group are shown in Table 32, and the curve of the change of the average tumor volume over time is shown in Figure 2.

[0144] Table 16 Tumor volume of G1 (low dose group) experimental animals

[0145] Table 17 Tumor volume of G2 (medium dose group) experimental animals

[0146] Table 18 Tumor volume of G3 (high dose group) experimental animals

[0147] Table 19 Tumor volume of G4 (control group) experimental animals

[0148] Table 20G5( 177 Tumor volume of experimental animals (Lu control group)

[0149] Table 21G6( 131 (1) Tumor volume of experimental animals in the control group

[0150] Table 22G5( 90 Y control group) tumor volume of experimental animals

[0151] Table 23 Relative tumor volume of G1 (low dose group) experimental animals

[0152] Table 24 Relative tumor volume of G2 (medium dose) experimental animals

[0153] Table 25 Relative tumor volume of G3 (high dose) experimental animals

[0154] Table 26 Relative tumor volume of G4 (control group) experimental animals

[0155] Table 27G5( 177 Relative tumor volume of experimental animals (Lu control group)

[0156] Table 28G6( 131 Relative tumor volume of experimental animals (control group)

[0157] Table 29G7( 90 Relative tumor volume of experimental animals (Y control group)

[0158] Table 30 G1 (low dose), G2 (medium dose), G3 (high dose) and G5 ( 177 The relative tumor proliferation rate T / C and tumor volume inhibition rate (TGI) of the experimental animals in the Lu control groupTV )

[0159] Table 31 Tumor mass and tumor mass inhibition rate (TGI) of experimental animals TW )

[0160] Table 32 Statistical results of variance analysis of tumor volume and tumor mass of animals in different groups

[0161] Example 6 Observation of Animal Conditions

[0162] Immediately after administration, observe the animals for any abnormal reactions. All animals should be observed daily during the experiment. Observations should include, but are not limited to, the animal's mental state, behavioral activity, respiratory status, secretions, feces, and diet. If an animal dies during the experiment, notify the project leader immediately, perform an autopsy, and photograph the animal. The photographs should be retained as original data.

[0163] During the whole experiment, the animals were observed once a day. On D3, a wound was found on the left foot of G1-M-03 animal, which had scab on D5. 12 The scabs fell off and the patient returned to normal. On D4, G3-M-05 and G3-M-07 were observed to have injuries on their feet. The next day, the wounds had scabs formed. 11 Observe that the scabs fall off. 12 It was found that G6-M-04 and G6-M-05 animals had back injuries. 13 ~D 14 The wound on the back was observed to have scabbed over. 20 Back to normal. 23 It was found that the G5-M-02 animal had a wound on its back. 25 Scabbed, D 31 The scab fell off. G4-M-06 animal in D 30 Blackening of the tumor was observed and continued until the end of the experiment (D 35 No obvious abnormal symptoms were observed in the other animals.

[0164] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application in any other manner. Any person skilled in the art may utilize the above disclosed technical content to modify or modify the present application into equivalent embodiments with equivalent variations. However, any simple modifications, equivalent variations, and modifications to the above embodiments that do not depart from the technical content of the present application and are based on the technical essence of the present application shall still fall within the scope of protection of the present application.

Claims

1. A somatostatin analog 212 Use of a derivative of Pb in treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein: The somatostatin analog 212 The derivatives of Pb are 212 Pb-DOTATATE.

2. A derivative of a somatostatin analogue 212 Use of a derivative of Pb in the preparation of a drug for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein: The somatostatin analog 212 The derivatives of Pb are 212 Pb-DOTATATE.

3. The use according to claim 1 or 2, wherein Said 212 The single dose of Pb-DOTATATE is 1μCi to 100mCi / kg of subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 100 mCi / kg of subject body weight / time.

4. The use according to claim 1 or 2, wherein Said 212 A single dose of Pb-DOTATATE is 1μCi-10mCi / kg subject body weight; or 212 A single dose of Pb-DOTATATE can be 1 μCi to 10 mCi / kg of subject body weight / time.

5. The use according to claim 1 or 2, wherein Said 212 The single dose of Pb-DOTATATE is 250μCi-500mCi / each subject; or 212 A single dose of Pb-DOTATATE can be 250 μCi-500 mCi / subject / time.

6. The use according to claim 1 or 2, wherein Said 212 The single administration volume of Pb-DOTATATE is 1mL-30mL; or contains 212 A single dose of the drug of Pb-DOTATATE can be provided to the subject at 1 mL to 30 mL per subject per time, or Said 212 Pb-DOTATATE was administered at a concentration of 1-30 mCi / mL.

7. The use according to claim 1 or 2, wherein Said 212 Pb-DOTATATE is administered every 3-16 weeks.

8. The use according to claim 1 or 2, wherein Said 212 The total dose of Pb-DOTATATE administered was 0.1 mCi-2Ci.

9. The use according to claim 1 or 2, wherein Said 212 The total volume of Pb-DOTATATE administered is 1 mL-300 mL.

10. The use according to claim 1 or 2, wherein Said 212 Pb-DOTATATE is administered by intravenous injection.

11. A composition for treating somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, wherein: The composition includes a somatostatin analog 212 Pb derivatives, somatostatin analogs 212 The derivatives of Pb are 212 Pb-DOTATATE.

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