Ph-responsive liposome pharmaceutical composition loaded with radiopharmaceutical

Abstract

The present invention relates to a pH-responsive liposome pharmaceutical composition loaded with a radiopharmaceutical, and a preparation method therefor.

Description

pH-responsive liposomal pharmaceutical composition loaded with a radiopharmaceutical

[0001] The present invention relates to a pH-responsive liposomal pharmaceutical composition loaded with a radiopharmaceutical and a method for manufacturing the same.

[0002] Meanwhile, this application was supported by the following national research and development project.

[0003] [National R&D projects that supported this invention]

[0004] [Project ID] 2710009979

[0005] [Assignment No.] 2021R1A2C2003301

[0006] [Ministry Name] Ministry of Science and ICT

[0007] [Name of Project Management (Specialized) Agency] National Research Foundation of Korea

[0008] [Research Project Name] Mid-career Research

[0009] [Project Title] Development of pH- and Temperature-Sensitive Nanocomposite-Based Nanocarriers to Enhance Loading, Tumor Selectivity, and Retention of Mitochondrial-Targeted Tumor Therapeutic Drugs

[0010] [Name of Project Performing Organization] Bundang Seoul National University Hospital

[0011] [Research Period] 2021.03.01 ~ 2026.02.28

[0012]

[0013] [National R&D projects that supported this invention]

[0014] [Project ID] 2460002725

[0015] [Project No.] RS-2024-00512498

[0016] [Ministry Name] Ministry of Health and Welfare

[0017] [Name of Project Management (Specialized) Agency] Korea Health Industry Development Institute

[0018] [Research Project Name] Korean ARPA-H Project

[0019] [Project Title] Development of Radioligand Therapeutics for Refractory Triple-Negative Breast Cancer and Pancreatic Cancer through Generative AI-based Ultra-Fast Drug Discovery and Rapid Validation

[0020] [Name of Project Performing Organization] Seoul National University Hospital

[0021] [Research Period] 2024.11.01 ~ 2029.04.30

[0022] Radiopharmaceuticals are medicines containing radionuclides used for diagnostic or therapeutic purposes. These radiopharmaceuticals may be radioligands, in which a radionuclide is bound to a ligand that selectively binds to specific biological targets; they may also be non-ligand radiopharmaceuticals that reflect physiological or metabolic pathways without target ligands; or, if necessary, the radionuclide itself may be in a form exhibiting appropriate biological properties. Such radiopharmaceuticals can be utilized not only for molecular imaging diagnostics, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), but also for therapeutic purposes by delivering radiation emitted from radionuclides to tumor cells to induce apoptosis. Currently approved radiopharmaceuticals are utilized in various disease diagnostic fields, including tumor imaging, central nervous system imaging, cardiovascular imaging, renal imaging, lung imaging, liver imaging, and bone imaging; in particular, the most active research and development is being conducted in the fields of tumor imaging and therapy.

[0023] Recently, radiopharmaceuticals utilizing ligands designed based on binding affinity to specific molecular targets are being actively developed. For example, radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) include [ 18 F]PSMA-1007, [ 68 Ga]Ga-PSMA-11 and [ 99mTc]Tc-MIP-1404, etc. are being utilized for tumor imaging, and for therapeutic purposes [ 177 Lu]Lu-PSMA-617 and [ 225 Radiopharmaceuticals such as [Ac]Ac-PSMA have been developed and are being used clinically. In addition, radiopharmaceuticals targeting fibroblast activation protein (FAP) expressed in the tumor microenvironment include [ 68 Ga]Ga-FAPI-04, [ 68 Ga]Ga-FAPI-46 and [ 18 F]FAPI-74 and others are being utilized for tumor imaging, and for therapeutic purposes [ 177 Lu]Lu-FAPI or [ 177 Radiopharmaceuticals such as [Lu]Lu-FAP-2286 are being studied. Along with this, radiopharmaceuticals targeting the translocator protein (TSPO), a mitochondrial outer membrane protein, include [ 11 C]PK11195, [ 18 F]DPA-714, [ 18 F]GE180 and others have been developed, and their potential for use in imaging diagnosis of neuroinflammation and tumors is being reported.

[0024] However, problems still persist regarding these radiopharmaceuticals; after administration, they may not accumulate sufficiently in tumor tissues or accumulate at relatively high levels in normal organs such as the liver, kidneys, and bone marrow. In particular, radioligands tend to preferentially distribute to the liver or kidneys during circulation, and this accumulation in non-target organs not only reduces therapeutic efficiency but can also induce dose-limiting toxicities, such as nephrotoxicity and myelotoxicity. Therefore, there is a continuously being raised need for new drug delivery systems that can enable radiopharmaceuticals to act more selectively within tumor tissues or the tumor microenvironment and reduce non-specific accumulation in normal tissues.

[0025] One objective of the present invention is to provide a pharmaceutical composition in the form of a pH-responsive liposome that improves the selective targeting ability of a radiopharmaceutical in tumor lesions.

[0026] Another objective of the present invention is to provide a liposome-based delivery system in which the composition and structure of the liposome are optimized to be suitable for the delivery of radiopharmaceuticals.

[0027] Another objective of the present invention is to provide a method for preparing the above-described liposome-type pharmaceutical composition.

[0028] Another objective of the present invention is to provide a use for imaging or the diagnosis and treatment of tumors comprising the above-described pharmaceutical composition.

[0029] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0030] Various embodiments described herein are described with reference to the drawings. In the following description, for a complete understanding of the invention, various specific details, such as specific forms, compositions, and processes, are described. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to unnecessarily obscure the invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that the particular features, forms, compositions, or characteristics described in association with the embodiment are included in one or more embodiments of the invention. Accordingly, the context of "in one embodiment" or "an embodiment" expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. Additionally, particular features, forms, compositions, or characteristics may be combined in any suitable way in one or more embodiments.

[0031]

[0032] Conventional radiopharmaceuticals have a problem in that, when injected into the body, they are preferentially absorbed in normal organs such as the liver and kidneys rather than target sites such as tumor lesions. To solve this problem, the inventors have developed a pharmaceutical composition provided in the form of a liposome in which the radiopharmaceutical is encapsulated within a specific pH-responsive liposome so that the radiopharmaceutical can selectively act in the tumor microenvironment, which has a relatively acidic environment compared to normal organs, and exhibit a high absorption rate.

[0033] Meanwhile, unlike conventional drugs, radiopharmaceuticals are characterized by being used in minute quantities at the nanomolar to picomolar level. However, since liposome delivery systems were originally developed to carry relatively large amounts of drugs, the size or dosage of the liposomes may become relatively excessive when radiopharmaceuticals are applied. This can lead to increased non-specific accumulation in organs of the reticuloendothelial system, such as the liver and spleen, or distorted distribution characteristics within the body. Accordingly, the present invention not only provides a simple liposome formulation of a specific radiopharmaceutical but also achieves enhanced tumor selectivity by optimizing the liposome structure itself to be suitable for the delivery of low-concentration radiopharmaceuticals.

[0034]

[0035] According to one embodiment of the present invention, the invention relates to a composition for delivering a radioactive drug comprising: a radioactive drug to be delivered to a target; and a pH-responsive liposome.

[0036] In this specification, "pH-responsive liposome" refers to a liposome designed to change its structure or release a drug in response to changes in the pH of the surrounding environment. In the present invention, the pH-responsive liposome refers to a liposome designed to disintegrate in the acidic microenvironment of a tumor, thereby releasing the substance inside the liposome. For example, the pH-responsive liposome may disintegrate in an environment where the pH is 6.8 or lower, such as under weakly acidic conditions of pH 6.0 to 6.8, allowing the substance inside the liposome, i.e., a radiopharmaceutical, to be released outside the liposome.

[0037] The above pH-responsive functional group can be immobilized on the phospholipid bilayer of the liposome.

[0038] The above pH-responsive liposome may include pegylated phospholipids containing pH-responsive functional groups.

[0039] The pegylated phospholipid containing the above pH-reactive functional group may be a phospholipid represented by the following chemical formula 1:

[0040] [Chemical Formula 1]

[0041]

[0042] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0043] m is an integer from 1 to 3, and

[0044] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other.

[0045] [Chemical Formula 2]

[0046]

[0047] In the above chemical formula 2, * indicates the part where the bond is formed, and R2 is a phospholipid residue.

[0048] The above R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It may be a residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, R2 may be a residue derived from 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), but is not limited thereto.

[0049] The pegylated phospholipid containing the above pH-reactive functional group may be represented by the following chemical formula 3 or 4:

[0050] [Chemical Formula 3]

[0051]

[0052] [Chemical Formula 4]

[0053]

[0054] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

[0055] The above-described pH-responsive functional group according to the present invention can be decomposed in an acidic tumor microenvironment (TME) as shown in Reaction Scheme 1 below:

[0056] [Reaction Equation 1]

[0057]

[0058] In the above chemical formulas 1, 3 and 4, n may be an integer of 350 to 2,000, 350 to 1,000, 350 to 500, 500 to 700, or 700 to 1,000.

[0059] Considering that the radiopharmaceutical encapsulated inside the liposome in the present invention is generally used in minute quantities at the level of several nanomolar to several picomolar, if the length of the PEG chain is excessively long, the size of the liposome may increase and non-specific uptake in normal organs such as the liver may increase. In addition, if the length of the PEG chain is excessively long, the drug loading efficiency may decrease due to a reduction in the ratio of drug to lipid. Therefore, the pegylated phospholipid may have a shorter PEG chain length compared to PEG2000, and n, which represents the length of the PEG chain, may be 350 to 1,000, or 350 to 500, or 500 to 700, or n may be 700 to 1,000. Having a PEG length within this range can increase the uptake rate in tumor tissue while reducing non-specific uptake in normal organs such as the liver, and simultaneously increase the loading rate of the radiopharmaceutical while reducing the size of the liposome.

[0060] For example, the above n may be 2,000, but is not limited thereto.

[0061] As another example, the above n may be 1,000, but is not limited thereto.

[0062] As another example, the above n may be 550, but is not limited thereto.

[0063] As another example, the above n may be 350, but is not limited thereto.

[0064] In addition, in the present invention, when using a phospholipid with a PEG length n of 350 to 1,000, to compensate for changes in the liposome structure caused by the reduction in PEG length, the pegylated phospholipid containing the pH-responsive functional group may be a phospholipid in which two or more pH-responsive lipids are combined, as represented by Chemical Formula 4. Accordingly, the liposome of the present invention can optimize its liposome structure to maintain selective drug release characteristics in the tumor microenvironment while reducing the liposome size and lipid usage by reducing the PEG chain length.

[0065] The above pH-responsive liposome may further include a second phospholipid. Here, the second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;It may be one or more selected from the group consisting of POPG, phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, the phospholipid additionally included in the liposome may include distearoyl phosphatidylcholine (DSPC), but is not limited thereto.

[0066] The above pH-responsive liposomes may additionally include cholesterol or cholesterol analogs.

[0067] The above pH-responsive liposome may comprise a pegylated phospholipid containing a pH-responsive functional group; a second phospholipid; and a lipid bilayer containing cholesterol or a cholesterol analog.

[0068] The above pH-responsive liposome may comprise a pegylated phospholipid containing the above pH-responsive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, the above pH-responsive liposome may comprise a pegylated phospholipid containing the above pH-responsive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1, but is not limited thereto.

[0069] The above pH-responsive liposomes may further include pegylated phospholipids bound to mannose. The introduction of such mannose-bound phospholipids can regulate the distribution characteristics of the liposomes within the body, and preferably, the radiopharmaceutical delivered through the liposomes can reduce non-specific uptake in normal organs such as the liver and improve accumulation characteristics in tumor tissues.

[0070] The pegylated phospholipid with the mannose group attached above may be represented by the following chemical formula 5:

[0071] [Chemical Formula 5]

[0072]

[0073] In the above chemical formula 5, p may be an integer from 1,000 to 5,000. As an example, p may be from 1,000 to 3,000, but is not limited thereto. As another example, p may be 2,000, but is not limited thereto.

[0074] The above pH-responsive liposome may comprise a lipid bilayer comprising a pegylated phospholipid containing the above pH-responsive functional group; a second phospholipid; cholesterol or a cholesterol analog; and a pegylated phospholipid to which a mannose is bound.

[0075] The above pH-responsive liposome may comprise a pegylated phospholipid containing the above pH-responsive functional group; a second phospholipid; cholesterol or a cholesterol analog; and a pegylated phospholipid bound to mannose in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, the above pH-responsive liposome may comprise a pegylated phospholipid containing the above pH-responsive functional group; a second phospholipid; cholesterol or a cholesterol analog; and a pegylated phospholipid bound to mannose in a molar ratio of 0.2 to 1 : 1.5 to 3 : 0.2 to 1 : 0.2 to 1, but is not limited thereto.

[0076] The average diameter of the liposome may be in the range of about 1 nm to about 500 nm, about 10 nm to about 300 nm, or about 10 nm to about 200 nm, about 10 nm to about 150 nm, about 10 nm to about 100 nm, about 20 nm to about 80 nm, or about 30 nm to about 70 nm. The diameter of the liposome may be measured using a dynamic light scattering (DLS) method, but is not limited thereto.

[0077] The above liposomes may have a polydispersity index (PDI) of 0.5 or less, 0.4 or less, or 0.3 or less, and preferably 0.3 or less. The polydispersity index (PDI) of the liposomes may be measured using dynamic light scattering (DLS) methods, but is not limited thereto.

[0078] In the present invention, the liposome may be optimized to be suitable for selectively delivering a radiopharmaceutical to a target site, such as a tumor tissue. Specifically, in the liposome according to the present invention, the pH-responsive functional group described above decomposes in an acidic tumor microenvironment (TME) as shown in Reaction Scheme 1, and the radiopharmaceutical encapsulated inside the liposome can be released into the tumor microenvironment.

[0079] In this specification, "radiopharmaceutical" refers to a pharmaceutical product containing a radioisotope used for medical purposes (e.g., diagnosis, imaging, treatment, prognosis assessment, evaluation of treatment response, or alleviation of tumor-related symptoms). The radiopharmaceutical is administered into the body, binds to specific tissues or tumors, and then performs a therapeutic role by diagnosing diseases through imaging (PET, SPECT) or destroying cancer cells by emitting radiation. The radiopharmaceutical refers to a drug, kit, precursor, or composition containing one or more radionuclides (radioisotope / radionuclide) (typically including preparations where the amount of substance administered is extremely small, so the effect of radiation is central rather than pharmacological effect). The radionuclides may include radiometals, radiohalogens, and other light element nuclides, but for example, 18 F, 11 C, 13 N, 44 Sc, 47 Sc, 51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 62 Zn, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga,68 Ga, 82 Rb, 89 Zr, 86 Y, 90 Y, 99m Tc, 111 In, 117m Sn, 123 I, 125 I, 131 I, 134 La, 152 Eu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 175 Lu, 177 Lu, 153 Sm, 186 Re, 188 Re, 203 Pb, 211 Pb, 　212 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac or 227 It may include Th, etc., but may also include any radionuclide capable of emitting alpha particles, beta particles, or gamma rays upon decay without limitation.

[0080] In the above radiopharmaceutical, the radionuclide can be conjugated to a ligand or pharmaceutical substance through direct or indirect labeling methods such as direct labeling, chelator-mediated labeling, prosthetic group labeling, isotope exchange labeling, click chemistry-mediated conjugation, or bioconjugation.

[0081] The above prostatic group is, for example, N-succinimidyl-4-[ 18F]fluorobenzoate([ 18 F]SFB), 4-[ 18 F]fluorobenzaldehyde([ 18 F]FBA), 4-[ 18 F]fluorobenzylamine([ 18 F]FBAm), 4-[ 18 F]fluorobenzyl bromide([ 18 F]FBB), 4-[ 18 F]fluorobenzyl azide([ 18 F]FBAz), [ 18 F]fluoropropionic acid([ 18 F]FPA), [ 18 F]fluoropropionate, [ 18 F]fluoroacetate, [ 18 F]fluorobenzoyl chloride, [ 18 F]fluorobenzyl alcohol, N-succinimidyl-4-[ 18 F]fluorobenzoate ester, N-succinimidyl-3-[ 18 F]fluoropropionate([ 18 F]NFP), [ 18 F]fluoroalkyl azide, [ 18 It may include [F]fluoroalkyne, or derivatives thereof, but is not limited thereto.

[0082] The chelator is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTA-NCS, DOTA-NHS ester, DOTA-Bz-NCS, tris(t-bu)DOTA, HBED-CC-TFP ester, DTPA (Diethylene triamine penta aeetic acid), DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NODAGA (1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid), It may be TE3A (1,4,8,11-tetraazabicyclotetradecane-1,4,8-triacetic acid), TE2A (1,4,8,11-tetraazabicyclohexadecane-4,11-diacetic acid), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1,11,13-triene-3,6,9-triacetic acid), Cyclen, Cyclam, or DFO (Deferrioxamine), but is not limited thereto. If the above radionuclide is a technetium or rhenium-based radiometal, the radionuclide may be provided in the form of a metal tricarbonyl core, for example, [ 99m Tc(CO)3(H2O)3] + , [ 99m Tc(CO)3] + , [Re(CO)3(H2O)3] + , or [Re(CO)3] +It may be in the form of the above. The metal tricarbonyl core may be bound to a ligand or a pharmaceutical substance by forming a metal complex through coordinate bonding to a donor atom containing nitrogen, oxygen, or sulfur within the ligand.

[0083] Furthermore, the above radiopharmaceutical may be a radioligand that binds to a specific biological target depending on the type (target binding moiety includes, but is not limited to, examples such as PSMA, TSPO, SSTR, FAP, GRPR, integrin, HER2, PD-L1, etc.), a non-ligand type small molecule / metabolite that reflects physiological or metabolic pathways without a target ligand, or a radiolabeled peptide, protein / antibody, or fragment thereof (including nanobodies). In addition, the specific form of the above radiopharmaceutical is not limited by the examples above and may include all various radiopharmaceuticals known to those skilled in the art or that may be developed in the future within the scope of the technical spirit and purpose of the present invention.

[0084] In the present invention, the type of radiopharmaceutical delivered by the composition is not particularly limited and may be a radiopharmaceutical for various medical purposes, and may include, for example, a radiopharmaceutical for positron emission tomography (PET), a radiopharmaceutical for single photon emission computed tomography (SPECT), or a radionuclide therapy drug.

[0085] As an example, the above radiopharmaceutical is fluorodeoxyglucose ([ 18 F]FDG), [ 18 F]NaF, [ 18 F]FLT, [ 18 F]FMISO, [ 18 F]FET, [ 18F]FACBC(fluciclovine), [ 18 F]PSMA-1007, [ 18 F]DCFPyL(piflufolastat), [ 18 F]flotufolastat, [ 11 C]choline, [ 11 C]acetate, [ 11 C]methionine, [ 68 Ga]Ga-PSMA-11, [ 68 Ga]Ga-PSMA-617, [ 68 Ga]Ga-PSMA-I&T, [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-DOTATOC, [ 68 Ga]Ga-DOTANOC, [ 68 Ga]Ga-FAPI-02, [ 68 Ga]Ga-FAPI-04, [ 68 Ga]Ga-FAPI-46, [ 68 Ga]Ga-FAP-2286, [ 64 Cu]Cu-DOTATATE, [ 64 Cu]Cu-PSMA, [ 64 Cu]Cu-SarPSMA, [ 89 Zr]Zr-trastuzumab, [ 89 Zr]Zr-cetuximab, [ 124 I]I-girentuximab, [ 99m Tc]Tc-sestamibi, [ 99m Tc]Tc-tetrophosmin, [ 99m Tc]Tc-MIP-1404, [ 99m Tc]Tc-MDP, [ 99m Tc]Tc-HDP, [ 99m Tc]Tc-MAG3, [ 99m Tc]Tc-DTPA, [ 99m Tc]Tc-ECD, [ 99m Tc]Tc-HMPAO, [ 111 In]In-pentetreotide, [ 111 In]In-DTPA-octreotide, [123 I]MIBG, [ 131 I]MIBG, [ 131 I]sodium iodide, [ 177 In]In-DOTATATE, [ 177 Lu]Lu-PSMA-617, [ 177 Lu]Lu-PSMA-I&T, [ 177 Lu]Lu-FAPI, [ 177 Lu]Lu-FAP-2286, [ 177 Lu]Lu-EB-FAPI, [ 177 Lu]Lu-rhPSMA, [ 90 Y]Y-ibritumumab tiuxetan, [ 153 Sm]Sm-EDTMP, [ 186 Re]Re-HEDP, [ 188 Re]Re-lipiodol, [ 223 Ra]Ra-dichloride, [ 225 Ac]Ac-PSMA-617, [ 225 Ac]Ac-PSMA-I&T, [ 225 Ac]Ac-FAPI, [ 212 Pb]Pb-DOTAMTATE, [ 67 Cu]Cu-PSMA, [ 67 Cu]Cu-ServicePSMA, 또는 [ 99m Tc]Tc-CB259 Add a page to your page, a page on your page.

[0086] As another example, the radiopharmaceutical may be a radioligand that binds to a specific biological target, and said targets may include, but are not limited to, examples such as prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR), fibroblast activating protein (FAP), gastrin-releasing peptide receptor (GRPR), integrin, human epidermal growth factor receptor 2 (HER2), programmed apoptosis ligand-1 (PD-L1), CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), etc. Additionally, the radiopharmaceutical may be a radiopharmaceutical that targets the translocator protein (TSPO), which is a mitochondrial outer membrane protein (e.g., [ 11 C]PK11195, [ 11 C]PBR28, [ 11 C]DPA-713, [ 18 F]DPA-714, [ 18 F]FEPPA, [ 18 F]PBR111, [ 18 F]GE180, [ 11 C]ER176, [ 99m [Tc]Tc-CB259, etc.), FAP targeted radiopharmaceuticals (e.g., [ 68 Ga]Ga-FAPI-04, [ 177 Lu]Lu-FAPI-04, [ 68 Ga]Ga-FAPI-46, [ 68 Ga]Ga-FAP-2286, [ 177 Lu]Lu-FAP-2286, etc.), or PSMA-targeted radiopharmaceuticals (e.g., [ 68 Ga]Ga-PSMA-11, [ 177 Lu]Lu-PSMA-617, [ 68 Ga]Ga-PSMA-I&T, [ 177 It may include, but is not limited to, [Lu]Lu-PSMA-I&T, etc.

[0087] As another example, the radiopharmaceutical may be a radioligand that specifically binds to the translocator protein 18kDa (TSPO), but is not limited thereto.

[0088] As another example, the radiopharmaceutical may be a TSPO-specific ligand labeled with a radionuclide, but is not limited thereto.

[0089] As another example, the radiopharmaceutical may be a CB259 compound labeled with a radionuclide. The CB259 compound may be represented by the following chemical formula 6.

[0090] [Chemical Formula 6]

[0091]

[0092] As another example, the above radiopharmaceutical may be a radiocomplex represented by the following chemical formula 7.

[0093] [Chemical Formula 7]

[0094]

[0095] In the above chemical formula 7, M is 188 Re or 99m It could be Tc.

[0096] As another example, the above radiopharmaceutical may be a radiocomplex represented by the following chemical formula 8.

[0097] [Chemical Formula 8]

[0098]

[0099] In the above chemical formula 8, M 1 silver 18 F, 125 I or 131 It could be I.

[0100] The above radiopharmaceutical may be included at a concentration of about 1 pmol to about 100 nmol. Given the characteristics of radiopharmaceuticals, which are generally used at very low concentrations at the picomolar or nanomolar level, the pH-responsive liposome of the present invention may have a structure optimized to effectively load and deliver such low-concentration radiopharmaceuticals.

[0101] The radioactivity / lipid weight ratio of the above composition may be about 1 MBq / mg to about 7,400 MBq / mg, but is not limited thereto. Alternatively, the radioactivity / lipid weight ratio of the above composition may be about 50 μCi / mg to 200 mCi / mg, but is not limited thereto.

[0102] The encapsulation rate of the radiopharmaceutical in the liposome may be 50% or more, 55% or more, or 60% or more. The encapsulation rate may be measured using ultrafiltration, but is not limited thereto.

[0103]

[0104] According to another embodiment of the present invention, the invention relates to a method for manufacturing a composition for delivering radioactive pharmaceuticals as described above.

[0105] The above manufacturing method may include the step of dissolving a radiopharmaceutical and a lipid component comprising a pegylated phospholipid containing a pH-reactive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a solvent.

[0106] In the dissolving step, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; and cholesterol or cholesterol analog may be mixed in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, in the dissolving step, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; and cholesterol or cholesterol analog may be mixed in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1, but are not limited thereto.

[0107] The solvent used for dissolving the above lipid components and radiopharmaceuticals may be methanol, ethanol, chloroform, dichloromethane, or a mixture of two or more of these, but is not limited thereto.

[0108] In the above dissolving step, a pegylated phospholipid with mannose bonded to the lipid component may be further dissolved. In this case, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; cholesterol or cholesterol analog; and the pegylated phospholipid with mannose bonded may be mixed in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, in the above dissolving step, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; cholesterol or cholesterol analog; and the pegylated phospholipid with mannose bonded may be mixed in a molar ratio of 0.2 to 1 : 1.5 to 3 : 0.2 to 1 : 0.2 to 1, but are not limited thereto.

[0109] Regarding the pegylated phospholipids containing the above-mentioned pH-reactive functional groups, second phospholipids, cholesterol or cholesterol analogs, pegylated phospholipids bound to mannose, and types of radiopharmaceuticals, their description below is omitted to avoid excessive complexity in the specification, as they overlap with what was previously described in the composition.

[0110] The above manufacturing method may include the step of manufacturing liposomes from the above solution.

[0111] The step of preparing the above liposome can be performed by drying the solution under vacuum to form a lipid film and sonicating it.

[0112] In terms of the stability of the phospholipid and / or radiopharmaceutical, it is preferable to perform the above drying while removing the solvent under an inert gas atmosphere such as nitrogen (N) or argon (Ar).

[0113] The above ultrasonic treatment can be performed after adding distilled water, deionized water, or water to the dried lipid film.

[0114] The above ultrasonic treatment can be performed at an amplitude of about 10 to 40%. Additionally, the above ultrasonic treatment can be performed in pulse mode, for example, by repeating a cycle of irradiating for about 5 to 10 seconds followed by resting for about 3 to 10 seconds. This ultrasonic treatment can be performed for a total of about 5 to 20 minutes.

[0115] The step of manufacturing the above liposomes can be performed by injecting the above solution into a microfluidic device. In the microfluidic device, an organic phase containing lipid components and a radiopharmaceutical and an aqueous phase are mixed within a channel, and liposomes can be formed by the self-assembly of lipids. Here, the organic phase can be prepared by dissolving the lipid components and the radiopharmaceutical in methanol, ethanol, chloroform, or a mixture thereof. Additionally, water can be used as the aqueous phase. By using a microfluidic device for the manufacture of the above liposomes, liposomes of a uniform size can be manufactured within a very short time of tens of seconds, and there is an advantage of excellent process reproducibility.

[0116] The above manufacturing method may further include the step of separating and purifying liposomes encapsulated with a radiopharmaceutical using size-exclusion chromatography.

[0117] The average diameter of the pH-responsive liposomes encapsulated with the radiopharmaceutical prepared by the above method may be in the range of about 1 nm to about 500 nm, about 10 nm to about 300 nm, or about 10 nm to about 200 nm, about 10 nm to about 150 nm, about 10 nm to about 100 nm, about 20 nm to about 80 nm, or about 30 nm to about 70 nm. The diameter of the liposomes may be measured using dynamic light scattering (DLS) methods, but is not limited thereto.

[0118] In addition, the polydispersity index (PDI) of the liposome may be 0.5 or less, 0.4 or less, or 0.3 or less, and preferably 0.3 or less. The polydispersity index (PDI) of the liposome may be measured using a dynamic light scattering (DLS) method, but is not limited thereto.

[0119] In addition, the encapsulation rate of the radiopharmaceutical within the liposome may be 50% or more, 55% or more, or 60% or more. The encapsulation rate may be measured using ultrafiltration, but is not limited thereto.

[0120]

[0121] According to another embodiment of the present invention, the invention relates to an imaging composition comprising, as an active ingredient, a pH-responsive liposome encapsulated with a radiopharmaceutical.

[0122] A radiopharmaceutical suitable for use as the above imaging composition may be labeled with a radionuclide that emits positrons (β+) or gamma rays (γ). For example, 18 F, 68 Ga, 64 Cu, 11 C, 13 N, 89 Zr, 124 I, 99m Tc, 111 In, 123 I, 201 Tl and 67 It may be a radiopharmaceutical labeled with one or more radionuclides selected from the group consisting of Ga, and more specifically, [ 18 F]FDG, [ 18 F]FLT, [ 18 F]FET, [ 18 F]PSMA-1007, [ 18 F]DCFPyL, [ 68 Ga]Ga-PSMA-11, [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-FAPI-04, [ 64 Cu]Cu-DOTATATE, [ 89 Zr]Zr-trastuzumab, 99m Tc-sestamibi, 99m Tc-tetrofosmin, 99m Tc-MDP, 111 In-pentetreotide, 123 I-MIBG or99m It may be Tc-CB259, etc., but is not limited thereto, and any radiopharmaceutical that can be used for imaging may be included without special restrictions.

[0123] As another example, the radiopharmaceutical may be a radioligand that specifically binds to the translocator protein 18kDa (TSPO), but is not limited thereto.

[0124] As another example, the above radiopharmaceutical is 18 F, 68 Ga, 64 Cu, 11 C, 13 N, 89 Zr, 124 I, 99m Tc, 111 In, 123 I, 201 Tl and 67 It may be a TSPO-specific ligand labeled with one or more radionuclides selected from the group consisting of Ga, but is not limited thereto.

[0125] As another example, the above radiopharmaceutical is 18 F, 68 Ga, 64 Cu, 11 C, 13 N, 89 Zr, 124 I, 99m Tc, 111 In, 123 I, 201 Tl and 67 It may be a CB259 compound labeled with one or more radionuclides selected from the group consisting of Ga, but is not limited thereto. The CB259 compound may be represented by the following chemical formula 6.

[0126] [Chemical Formula 6]

[0127]

[0128] As another example, the above radiopharmaceutical may be a radioactive complex represented by the following chemical formula 7, but is not limited thereto.

[0129] [Chemical Formula 7]

[0130]

[0131] In the above chemical formula 7, M is 99m It could be Tc.

[0132] As another example, the above radiopharmaceutical may be a radiocomplex represented by the following chemical formula 8.

[0133] [Chemical Formula 8]

[0134]

[0135] In the above chemical formula 8, M 1 silver 18 It could be F.

[0136] The above liposome includes an internal space surrounded by a lipid bilayer, and the radiopharmaceutical can be enclosed in the internal space.

[0137] The above lipid bilayer may include pegylated phospholipids containing pH-responsive functional groups.

[0138] The pegylated phospholipid containing the above pH-reactive functional group may be a phospholipid represented by the following chemical formula 1:

[0139] [Chemical Formula 1]

[0140]

[0141] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0142] m is an integer from 1 to 3, and

[0143] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other.

[0144] [Chemical Formula 2]

[0145]

[0146] In the above chemical formula 2, * indicates the part where the bond is formed, and R2 is a phospholipid-derived residue.

[0147] The above R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It may be a residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, R2 may be a residue derived from 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), but is not limited thereto.

[0148] The pegylated phospholipid containing the above pH-reactive functional group may be represented by the following chemical formula 3 or 4:

[0149] [Chemical Formula 3]

[0150]

[0151] [Chemical Formula 4]

[0152]

[0153] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

[0154] The above pH-responsive functional group can be immobilized on the phospholipid bilayer of the liposome.

[0155] In the above chemical formulas 1, 3 and 4, n may be an integer of 350 to 2,000, 350 to 1,000, 350 to 500, 500 to 700, or 700 to 1,000.

[0156] For example, the above n can be 2,000. For another example, the above n can be 1,000. For yet another example, the above n can be 550. For yet another example, the above n can be 350.

[0157] The above lipid bilayer may further include a second phospholipid. Here, the second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;It may be one or more selected from the group consisting of POPG, phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, the phospholipid additionally included in the liposome may include distearoyl phosphatidylcholine (DSPC), but is not limited thereto.

[0158] The above lipid bilayer may further include cholesterol or a cholesterol analog.

[0159] As an example, the lipid bilayer may comprise a pegylated phospholipid containing a pH-reactive functional group; a second phospholipid; and cholesterol or a cholesterol analog.

[0160] Pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; and cholesterol or a cholesterol analog may be included in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; and cholesterol or a cholesterol analog may be included in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1, but are not limited thereto.

[0161] The above lipid bilayer may further include pegylated phospholipids bound to mannose. The introduction of such mannose-bound phospholipids can regulate the distribution characteristics of liposomes within the body, and preferably, the radiopharmaceutical delivered through the liposomes can reduce non-specific uptake in normal organs such as the liver and improve accumulation characteristics in tumor tissues.

[0162] The pegylated phospholipid with the mannose group attached above may be represented by the following chemical formula 5.

[0163] [Chemical Formula 5]

[0164]

[0165] In the above chemical formula 5, p may be an integer from 1,000 to 5,000. As an example, p may be from 1,000 to 3,000, but is not limited thereto. As another example, p may be 2,000, but is not limited thereto.

[0166] The lipid bilayer may comprise a pegylated phospholipid containing the pH-reactive functional group; a second phospholipid; cholesterol or a cholesterol analog; and a pegylated phospholipid to which mannose is attached.

[0167] Pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; cholesterol; and pegylated phospholipid bound to mannose may be included in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; cholesterol; and pegylated phospholipid bound to mannose may be included in a molar ratio of 0.2 to 1 : 1.5 to 3 : 0.2 to 1 : 0.2 to 1, but is not limited thereto.

[0168] The radioactivity / lipid weight ratio of the above composition may be about 1 MBq / mg to about 7,400 MBq / mg, but is not limited thereto, and can be appropriately adjusted depending on the type of radiopharmaceutical and its application use.

[0169] The radioactivity / lipid weight ratio of the above composition may be about 50 μCi / mg to about 200 mCi / mg, but is not limited thereto, and can be appropriately adjusted depending on the type of radiopharmaceutical and its application use.

[0170] The average diameter of the liposomes may be in the range of about 1 nm to about 500 nm, about 10 nm to about 300 nm, or about 10 nm to about 200 nm, about 10 nm to about 100 nm, about 20 nm to about 80 nm, or about 30 nm to about 70 nm. The diameter of the liposomes may be measured using a dynamic light scattering (DLS) method, but is not limited thereto.

[0171] The above liposomes may have a polydispersity index (PDI) of 0.5 or less, 0.4 or less, or 0.3 or less, and preferably 0.3 or less. The polydispersity index (PDI) of the liposomes may be measured using dynamic light scattering (DLS) methods, but is not limited thereto.

[0172] The composition of the present invention can be used as a diagnostic imaging agent, preferably for positron emission tomography (PET), single photon emission computed tomography (SPECT), or PET-CT or SPECT-CT imaging combined with computed tomography (CT).

[0173] When the above liposomes reach the microenvironment of a target site to be imaged, for example, a tumor or inflammation, the pH-responsive functional groups contained in the lipid bilayer are decomposed by the acidic conditions of the tumor or inflammation microenvironment, thereby releasing the radiopharmaceutical encapsulated within the lipid bilayer. The released radiopharmaceutical can be selectively accumulated in tumor tissue, and accordingly, the composition of the present invention can be usefully utilized for imaging lesion sites such as tumors.

[0174] Herein, the tumor may be a solid tumor. The solid tumor may include, but is not limited to, thyroid cancer, pancreatic cancer, stomach cancer, prostate cancer, melanoma, fallopian tube cancer, brain cancer, small intestine cancer, esophageal cancer, lymphoma, gallbladder cancer, endocrine gland cancer, oral cancer, liver cancer, biliary tract cancer, colorectal cancer, rectal cancer, cervical cancer, ovarian cancer, kidney cancer, duodenal cancer, breast cancer, testicular cancer, brain tumor, lung cancer, uterine cancer, colon cancer, bladder cancer, ureteral cancer, bone / soft tissue sarcoma, or skin cancer.

[0175] Accordingly, the above composition can be used to predict whether the above-mentioned tumor develops, whether the tumor progresses, or the prognosis after treatment.

[0176] The radiopharmaceutical included in the above composition may be represented by Chemical Formula 7 or 8. In this case, the liposome may decompose under acidic conditions in the microenvironment surrounding neuroinflammation or the microenvironment surrounding a tumor, thereby releasing the radiopharmaceutical. The radiopharmaceutical having the above structure can specifically bind to TSPO and may selectively accumulate in neuroinflammation where TSPO is highly expressed, or in cancers where TSPO is overexpressed, such as, for example, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, gastric cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer. Accordingly, the imaging composition of the present invention comprising the radiopharmaceutical represented by Chemical Formula 7 or 8 may be used to image TSPO overexpression diseases.

[0177]

[0178] According to another embodiment of the present invention, the invention relates to an imaging method comprising the steps of: administering the imaging composition to a subject; and imaging the subject.

[0179] The above subject may preferably be a human individual, but may also include non-human animal individuals. Suitable animal individuals may be mammals, including but not limited to primates such as humans, monkeys, apes, etc.; bovines, such as cattle, oxen, etc.; ovines, such as sheep, etc.; caprines, such as goats, etc.; porcines, such as pigs, hogs, etc.; equines, such as horses, donkeys, zebras, etc.; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, etc.; or rodents, such as mice, rats, etc.

[0180] The dosage of the above composition may be administered in an amount such that the radionuclides contained in the radiopharmaceutical are detectable by imaging. For example, the dosage of the radiopharmaceutical may be administered at a radioactive dose in the range of about 0.1 mCi to about 100 mCi, preferably about 1 mCi to about 50 mCi. However, this dosage is determined by the attending physician or diagnostician and may be higher or lower than this range.

[0181] In addition, the above composition can be administered to a subject within about 10 hours after synthesis to prevent loss of effect due to radioactive decay.

[0182] Any ordinary carrier known to those skilled in the art, such as a sterile saline solution or plasma, may be administered together with the above composition.

[0183] In addition, the method of administering the above composition may be carried out by various conventional methods, such as intravenous injection, oral administration, inhalation administration, rectal administration, subcutaneous administration, sub-subcutaneous, intraperitoneal, or vaginal administration, and preferably by intravenous injection, but is not limited thereto.

[0184] The above composition can be imaged immediately after administration to the subject (0 hours) or within about 4 hours after administration, and preferably within about 2 hours after administration.

[0185] The above imaging may be positron emission tomography (PET), single-photon emission tomography (SPECT), PET-CT, or SPECT-CT.

[0186] The above imaging may be performed on the entire body of the subject, but may also be performed on a region of interest. Here, the region of interest may be organs such as the thyroid, stomach, pancreas, prostate, and brain, but is not limited thereto.

[0187] During the above imaging process, an image can be formed by placing an object in a PET scanner or SPECT scanner and detecting radiation emitted from radionuclides. In the case of PET, positrons (β-) emitted from radionuclides + An image can be formed by detecting two gamma photons generated as an electron annihilates, and in the case of SPECT, an image can be formed by directly detecting gamma rays emitted from a radioactive nuclide.

[0188] Accordingly, the presence or intensity of a signal emitted from the compound can be detected from the image obtained in the imaging step. From the presence or intensity of such a signal, the presence of solid cancer can be predicted or confirmed, or the progression of solid cancer can be monitored.

[0189]

[0190] According to another embodiment of the present invention, the invention relates to a pharmaceutical composition comprising a pH-responsive liposome containing a radiopharmaceutical as an active ingredient.

[0191] pH-responsive liposomes containing the aforementioned radiopharmaceutical are omitted below to avoid excessive complexity in the specification, as they overlap with those described in the preceding imaging composition.

[0192] The pharmaceutical composition provided in the present invention can be used for the prevention or treatment of diseases or for diagnosis, depending on the type of radioactive pharmaceutical or the type of isotope included in the radioactive pharmaceutical.

[0193] In this specification, the "medicinal composition" may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the medicinal composition may be characterized as being intended for animals, specifically humans.

[0194] The above pharmaceutical compositions are not limited to these, but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, as well as topical preparations, suppositories, and sterile injectable solutions, according to conventional methods. The pharmaceutical compositions of the present invention may include pharmaceutically acceptable carriers. For oral administration, pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. For injectable preparations, buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc., may be mixed and used; and for topical administration, bases, excipients, lubricants, preservatives, etc., may be used. The formulations of the pharmaceutical compositions of the present invention may be prepared in various ways by mixing with pharmaceutically acceptable carriers as described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injectables, it can be manufactured in the form of unit dosing ampoules or multiple dosing ampoules. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release formulation, etc.

[0195] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Additionally, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

[0196] In the present invention, the pharmaceutical composition may further comprise a radical scavenger in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof. The radical scavenger may be used to prevent radiolysis. Radiolysis is a process in which the ionization of oxygen or water molecules induced by a radionuclide forms other reactive chemical species such as superoxide, hydrogen peroxide, hydrogen radicals, ozone, and hydroxyl radicals. These reactive chemical species can also cause damage to DNA and other cellular structures. In some embodiments, the radical scavenger is an antioxidant selected from carnosic acid, green tea extract, apigenin, diosmin, rosmarinic acid, lipoic acid, beta-carotene, L-ascorbic acid (vitamin C), N-acetylcysteine ​​(NAC), δ-tocopherol, rutin, amifostin, resveratrol, gentisic acid, and gallic acid. In some embodiments, the radical scavenger may be an antioxidant selected from gallic acid, L-ascorbic acid, and N-acetylcysteine ​​(NAC), but is not limited thereto.

[0197] The routes of administration of the pharmaceutical composition according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, or rectal. Oral or parenteral administration is preferred, and the “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0198] In addition, the above-mentioned pharmaceutical composition may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, release rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the above-mentioned pharmaceutical composition may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and duration, and may be administered at a dose of 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, coated tablet, capsule, liquid, gel, syrup, slurry, or suspension.

[0199] The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

[0200]

[0201] According to another embodiment of the present invention, the invention relates to a pharmaceutical composition for the diagnosis or treatment of TSPO-related diseases, comprising as an active ingredient a pH-responsive liposome comprising a radiopharmaceutical represented by the following chemical formula 7 or 8.

[0202] [Chemical Formula 7]

[0203]

[0204] In the above chemical formula 7, M is 188 Re or 99m It could be Tc,

[0205] [Chemical Formula 8]

[0206]

[0207] In the above chemical formula 8, M 1 silver 18 F, 125I or 131 It could be I.

[0208] The radioactivity / lipid weight ratio of the above composition may be about 1 MBq / mg to about 7,400 MBq / mg, but is not limited thereto, and can be appropriately adjusted depending on the type of radiopharmaceutical and its application use.

[0209] The radioactivity / lipid weight ratio of the above composition may be about 50 μCi / mg to about 200 mCi / mg, but is not limited thereto, and can be appropriately adjusted depending on the type of radiopharmaceutical and its application use.

[0210] The above liposome includes an internal space surrounded by a lipid bilayer, and a radiopharmaceutical represented by the above chemical formula 7 or 8 can be enclosed in the internal space.

[0211] The above lipid bilayer may include pegylated phospholipids containing pH-responsive functional groups.

[0212] The pegylated phospholipid containing the above pH-reactive functional group may be a phospholipid represented by the following chemical formula 1:

[0213] [Chemical Formula 1]

[0214]

[0215] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0216] m is an integer from 1 to 3, and

[0217] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other.

[0218] [Chemical Formula 2]

[0219]

[0220] In the above chemical formula 2, * indicates the part where the bond is formed, and R2 is a phospholipid-derived residue.

[0221] The above R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It may be a residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, R2 may be a residue derived from 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), but is not limited thereto.

[0222] The pegylated phospholipid containing the above pH-reactive functional group may be represented by the following chemical formula 3 or 4:

[0223] [Chemical Formula 3]

[0224]

[0225] [Chemical Formula 4]

[0226]

[0227] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

[0228] The above pH-responsive functional group can be immobilized on the phospholipid bilayer of the liposome.

[0229] In the above chemical formulas 1, 3 and 4, n may be an integer of 350 to 2,000, 350 to 1,000, 350 to 500, 500 to 700, or 700 to 1,000.

[0230] For example, the above n can be 2,000. For another example, the above n can be 1,000. For yet another example, the above n can be 550. For yet another example, the above n can be 350.

[0231] The above lipid bilayer may further include a second phospholipid. Here, the second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;It may be one or more selected from the group consisting of POPG, phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). As an example, the phospholipid additionally included in the liposome may include distearoyl phosphatidylcholine (DSPC), but is not limited thereto.

[0232] The above lipid bilayer may further include cholesterol or a cholesterol analog.

[0233] As an example, the lipid bilayer may comprise a pegylated phospholipid containing a pH-reactive functional group; a second phospholipid; and cholesterol or a cholesterol analog.

[0234] Pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; and cholesterol or a cholesterol analog may be included in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; and cholesterol or a cholesterol analog may be included in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1, but are not limited thereto.

[0235] The above lipid bilayer may further include pegylated phospholipids bound to mannose. The introduction of such mannose-bound phospholipids can regulate the distribution characteristics of liposomes within the body, and preferably, the radiopharmaceutical delivered through the liposomes can reduce non-specific uptake in normal organs such as the liver and improve accumulation characteristics in tumor tissues.

[0236] The pegylated phospholipid with the mannose group attached above may be represented by the following chemical formula 5.

[0237] [Chemical Formula 5]

[0238]

[0239] In the above chemical formula 5, p may be an integer from 1,000 to 5,000. As an example, p may be from 1,000 to 3,000, but is not limited thereto. As another example, p may be 2,000, but is not limited thereto.

[0240] The lipid bilayer may comprise a pegylated phospholipid containing the pH-reactive functional group; a second phospholipid; cholesterol or a cholesterol analog; and a pegylated phospholipid to which mannose is attached.

[0241] Pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; cholesterol; and pegylated phospholipid bound to mannose may be included in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10 : 0.1 to 10. As an example, pegylated phospholipid containing the pH-reactive functional group within the lipid bilayer; a second phospholipid; cholesterol; and pegylated phospholipid bound to mannose may be included in a molar ratio of 0.2 to 1 : 1.5 to 3 : 0.2 to 1 : 0.2 to 1, but is not limited thereto.

[0242] The average diameter of the liposomes may be in the range of about 10 nm to about 100 nm, about 20 nm to about 80 nm, or about 30 nm to about 70 nm. The diameter of the liposomes may be measured using dynamic light scattering (DLS) methods, but is not limited thereto.

[0243] The above liposomes may have a polydispersity index (PDI) of 0.5 or less, 0.4 or less, or 0.3 or less, and preferably 0.3 or less. The polydispersity index (PDI) of the liposomes may be measured using dynamic light scattering (DLS) methods, but is not limited thereto.

[0244] The encapsulation rate of the radiopharmaceutical represented by Chemical Formula 7 or 8 within the liposome may be 50% or more, 55% or more, or 60% or more. The encapsulation rate may be measured using ultrafiltration, but is not limited thereto.

[0245] The above TSPO-related diseases are lesions associated with TSPO overexpression, such as neuroinflammatory lesions, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer areas, but are not limited thereto.

[0246]

[0247] According to another embodiment of the present invention, the invention relates to a method for diagnosing a TSPO-related disease, comprising the steps of: administering a pharmaceutical composition for diagnosing the TSPO-related disease to a subject; and imaging.

[0248] In the present invention, the imaging technology may be positron emission tomography (PET), single-photon emission tomography (SPECT), PET-CT, or SPECT-CT, but is not limited thereto.

[0249] The above imaging may be performed on the entire body of the subject, but may be performed on a region of interest. Here, the region of interest may be a lesion where TSPO is overexpressed, such as a neuroinflammatory lesion site, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer area, but is not limited thereto.

[0250] In the present invention, the degree of TSPO expression can be detected to diagnose whether a TSPO-related disease has developed, or to monitor the progression of the disease or the prognosis of the disease after treatment.

[0251] The diagnostic method of the present invention may further include the step of obtaining an anatomical image of a subject using magnetic resonance imaging or computed tomography; and the step of overlaying the images obtained as above to position an image related to the TSPO-expressing tissue of the subject within the anatomical image.

[0252] In the present invention, if it is predicted through the above imaging that a disease related to TSPO expression has developed or is highly likely to develop, the method may further include the step of surgically removing the TSPO overexpressing tissue from the subject.

[0253] In addition, if the present invention predicts through the above imaging that a disease related to TSPO expression has developed or is highly likely to develop, the method may further include the step of administering a preventive, corrective, or therapeutic agent for the TSPO overexpression disease to the subject. At this time, the preventive, corrective, or therapeutic agent for the TSPO overexpression disease may be an anti-inflammatory agent or a therapeutic agent with anticancer activity, and may include a therapeutic radioisotope, and may also be an anticancer agent, an immunotherapy agent, a gene therapy agent, etc., but is not limited thereto.

[0254]

[0255] According to another embodiment of the present invention, the invention relates to a method for treating a TSPO-related disease, comprising the step of administering the above-described pharmaceutical composition for treating a TSPO-related disease to a subject.

[0256] The subject may be an individual having a lesion in which TSPO is overexpressed, such as a neuroinflammatory lesion site, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer area, but is not limited thereto.

[0257]

[0258] The present invention includes the following items:

[0259] 1. A composition for delivering a radiopharmaceutical, comprising: a radiopharmaceutical to be delivered to a subject; and a pH-responsive liposome, wherein the pH-responsive liposome comprises a pegylated phospholipid comprising a pH-responsive group represented by the following chemical formula 1:

[0260] [Chemical Formula 1]

[0261]

[0262] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0263] m is an integer from 1 to 3, and

[0264] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and

[0265] [Chemical Formula 2]

[0266]

[0267] In the above chemical formula 2, * represents the part where the bond is formed, and

[0268] R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It is a residue derived from phospholipids selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0269] 2. In the first embodiment, the pegylated phospholipid containing the pH-reactive functional group may be represented by the following chemical formula 3 or 4.

[0270] [Chemical Formula 3]

[0271]

[0272] [Chemical Formula 4]

[0273]

[0274] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

[0275] 3. In the second embodiment, the pegylated phospholipid containing the pH-reactive functional group may be represented by Chemical Formula 3.

[0276] 4. In the second embodiment, the pegylated phospholipid containing the pH-reactive functional group may be represented by Chemical Formula 4.

[0277] 5. In at least one of the first to fourth embodiments, n may be an integer from 350 to 2,000.

[0278] 6. In at least one of the first to fourth embodiments, n may be an integer from 350 to 1,000.

[0279] 7. In at least one of the first to fourth embodiments, n may be an integer from 350 to 500.

[0280] 8. In at least one of the first to fourth embodiments, n may be an integer from 500 to 700.

[0281] 9. In at least one of the first to fourth embodiments, n may be an integer from 700 to 1,000.

[0282] 10. In at least one of the first to fourth embodiments, n may be 1,000.

[0283] 11. In at least one of the first to fourth embodiments, n may be 550.

[0284] 12. In at least one of the first to fourth embodiments, n may be 350.

[0285] 13. In at least one of the first to twelfth embodiments, the pH-responsive liposome may further include a second phospholipid.

[0286] 14. In the 13th embodiment, the second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;It may be one or more selected from the group consisting of POPG), phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0287] 15. In the 14th embodiment, the second phospholipid may include distearoyl phosphatidylcholine (DSPC).

[0288] 16. In at least one of the first to fifteen embodiments, the pH-responsive liposome may further include cholesterol or a cholesterol analog.

[0289] 17. In the 16th embodiment, the pH-responsive liposome may comprise a pegylated phospholipid containing the pH-responsive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10.

[0290] 18. In the 16th embodiment, the pH-responsive liposome may comprise a pegylated phospholipid containing the pH-responsive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1.

[0291] 19. In at least one of the first to eighteen embodiments, the pH-responsive liposome may further comprise a pegylated phospholipid to which mannose is bound.

[0292] 20. In the 19th embodiment, the pegylated phospholipid to which the mannose is bound may be represented by the following chemical formula 5:

[0293] [Chemical Formula 5]

[0294]

[0295] In the above chemical formula 5, p can be an integer from 1,000 to 5,000.

[0296] 21. In the 20th embodiment, p may be 1,000 to 3,000.

[0297] 22. In the 20th embodiment, p may be 2,000.

[0298] 23. In at least one of the 19th to 22nd embodiments, the pegylated phospholipid; the second phospholipid; cholesterol or cholesterol analog; and the pegylated phospholipid bound to mannose may be included in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10 : 0.1 to 10.

[0299] 24. In at least one of the 19th to 22nd embodiments, the pegylated phospholipid; the second phospholipid; cholesterol or cholesterol analog; and the pegylated phospholipid combined with mannose may be included in a molar ratio of 0.2 to 1 : 1.5 to 3 : 0.2 to 1 : 0.2 to 1.

[0300] 25. In at least one of the first to 24 embodiments, the average diameter of the liposome may be 1 nm to 500 nm.

[0301] 26. In at least one of the first to 24 embodiments, the average diameter of the liposome may be 10 nm to 300 nm.

[0302] 27. In at least one of the first to 24 embodiments, the average diameter of the liposome may be 10 nm to 150 nm.

[0303] 28. In at least one of the first to 24 embodiments, the average diameter of the liposome may be 10 nm to 100 nm.

[0304] 29. In at least one of the first to 28 embodiments, the liposome may have a polydispersity index (PDI) of 0.5 or less.

[0305] 30. In at least one of the first to 28 embodiments, the liposome may have a polydispersity index (PDI) of 0.4 or less.

[0306] 31. In at least one of the first to 28 embodiments, the liposome may have a polydispersity index (PDI) of 0.3 or less.

[0307] 32. In at least one of the first to third-first embodiments, the radiopharmaceutical may include one or more radioisotopes / radionuclides.

[0308] 33. In the 32nd embodiment, the radioactive nuclide may include radiometals, radiohalogens, and other light element nuclides.

[0309] 34. In the 33rd embodiment, the radioactive nuclide is 18 F, 11 C, 13 N, 44 Sc,47 Sc, 51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 62 Zn, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 82 Rb, 89 Zr, 86 Y, 90 Y, 99m Tc, 111 In, 117m Sn, 123 I, 125 I, 131 I, 134 La, 152 Eu, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 175 Lu, 177 Lu, 153 Sm, 186 Re, 188 Re, 203 Pb, 211 Pb, 　212 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac or 227 It may include Th.

[0310] 35. In at least one of the first to third-fourth embodiments, the radiopharmaceutical may include a radiopharmaceutical for positron emission tomography (PET), a radiopharmaceutical for single photon emission computed tomography (SPECT), or a radionuclide therapy drug.

[0311] 36. In at least one of the first to 35 embodiments, the radioactive pharmaceutical is fluorodeoxyglucose ([ 18 F]FDG), [ 18 F]NaF, [ 18 F]FLT, [ 18 F]FMISO, [ 18 F]FET, [ 18 F]FACBC(fluciclovine), [ 18 F]PSMA-1007, [ 18 F]DCFPyL(piflufolastat), [ 18 F]flotufolastat, [ 11 C]choline, [ 11 C]acetate, [ 11 C]methionine, [ 68 Ga]Ga-PSMA-11, [ 68 Ga]Ga-PSMA-617, [ 68 Ga]Ga-PSMA-I&T, [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-DOTATOC, [ 68 Ga]Ga-DOTANOC, [ 68 Ga]Ga-FAPI-02, [ 68 Ga]Ga-FAPI-04, [ 68 Ga]Ga-FAPI-46, [ 68 Ga]Ga-FAP-2286, [ 64 Cu]Cu-DOTATATE, [ 64 Cu]Cu-PSMA, [ 64Cu]Cu-SarPSMA, [ 89 Zr]Zr-trastuzumab, [ 89 Zr]Zr-cetuximab, [ 124 I]I-girentuximab, [ 99m Tc]Tc-sestamibi, [ 99m Tc]Tc-tetrophosmin, [ 99m Tc]Tc-MIP-1404, [ 99m Tc]Tc-MDP, [ 99m Tc]Tc-HDP, [ 99m Tc]Tc-MAG3, [ 99m Tc]Tc-DTPA, [ 99m Tc]Tc-ECD, [ 99m Tc]Tc-HMPAO, [ 111 In]In-pentetreotide, [ 111 In]In-DTPA-octreotide, [ 123 I]I-MIBG, [ 131 I]I-MIBG, [ 131 I]sodium iodide, [ 177 Lu]Lu-DOTATE, [ 177 Lu]Lu-PSMA-617, [ 177 Lu]Lu-PSMA-I&T, [ 177 Lu]Lu-FAPI, [ 177 Lu]Lu-FAP-2286, [ 177 Lu]Lu-EB-FAPI, [ 177 Lu]Lu-rhPSMA, [ 90 Y]Y-ibritumomab tiuxetan, [ 153 Sm]Sm-EDTMP, [ 186 Re]Re-HEDP, [ 188 Re]Re-lipiodol, [ 223 Ra]Ra-dichloride, [ 225 Ac]Ac-PSMA-617, [ 225 Ac]Ac-PSMA-I&T, [ 225 Ac]Ac-FAPI, [ 212 Pb]Pb-DOTAMTATE, [ 67Cu]Cu-PSMA, [ 67 Cu]Cu-SarbisPSMA, or [ 99m It may include Tc]Tc-CB259.

[0312] 37. In at least one of the first to 36 embodiments, the radioactive pharmaceutical may be a radioligand targeting prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR), fibroblast activating protein (FAP), gastrin-releasing peptide receptor (GRPR), integrin, human epidermal growth factor receptor 2 (HER2), programmed apoptosis ligand-1 (PD-L1), CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor (VEGF).

[0313] 38. In at least one of the first to 37 embodiments, the radiopharmaceutical may be a radiopharmaceutical targeting TSPO, FAP, or PSMA.

[0314] 39. In at least one of the first to third eighth embodiments, the radioactive pharmaceutical is [ 11 C]PK11195, [ 11 C]PBR28, [ 11 C]DPA-713, [ 18 F]DPA-714, [ 18 F]FEPPA, [ 18 F]PBR111, [ 18 F]GE180, [ 11 C]ER176, [ 99m Tc]Tc-CB259, [ 68 Ga]Ga-FAPI-04, [ 177 Lu]Lu-FAPI-04, [ 68 Ga]Ga-FAPI-46, [ 68 Ga]Ga-FAP-2286, [ 177 Lu]Lu-FAP-2286, [ 68 Ga]Ga-PSMA-11, [ 177Lu]Lu-PSMA-617, [ 68 Ga]Ga-PSMA-I&T, and [ 177 It may include one or more selected from the group consisting of Lu]Lu-PSMA-I&T.

[0315] 40. In the 38th embodiment, the radioactive pharmaceutical may be a radioactive ligand that specifically binds to the transgenic protein 18kDa (TSPO).

[0316] 41. In the 40th embodiment, the radiopharmaceutical may be a TSPO-specific ligand labeled with a radionuclide.

[0317] 42. In the 40th embodiment, the radioactive pharmaceutical may be a CB259 compound labeled with a radionuclide.

[0318] 43. In at least one of the first to 35 embodiments, the radioactive pharmaceutical may be a radioactive complex represented by the following chemical formula 7.

[0319] [Chemical Formula 7]

[0320]

[0321] In the above chemical formula 7, M is 188 Re or 99m It could be Tc.

[0322] 44. In at least one of the first to 35 embodiments, the radioactive pharmaceutical may be a radioactive complex represented by the following chemical formula 8.

[0323] [Chemical Formula 8]

[0324]

[0325] In the above chemical formula 8, M 1 silver 18 F, 125 I or 131 I could be.

[0326] 45. In at least one of the first to fourth embodiments, the radioactive pharmaceutical may be included at a concentration of 1 pmol to 100 nmol.

[0327] 46. ​​In at least one of the first to fourth-fifth embodiments, the radioactivity / lipid weight ratio of the composition may be about 1 MBq / mg to about 7,400 MBq / mg.

[0328] 47. In at least one of the first to fourth-fifth embodiments, the radioactivity / lipid weight ratio of the composition may be 50 μCi / mg to 200 mCi / mg.

[0329] 48. In at least one of the first to fourth seven embodiments, the encapsulation rate of the radioactive pharmaceutical in the liposome may be 50% or more.

[0330] 49. This invention relates to a method for preparing a composition for delivering a radioactive drug of at least one of the first to fourth eighth embodiments.

[0331] 50. In the 49th embodiment, the manufacturing method may include the step of dissolving a lipid component comprising a pegylated phospholipid containing a pH-reactive functional group; a second phospholipid; and cholesterol or a cholesterol analog in a solvent and a radiopharmaceutical.

[0332] 51. In the 50th embodiment, in the dissolving step, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; and cholesterol or cholesterol analog may be mixed in a molar ratio of 0.1 to 10 : 0.1 to 10 : 0.1 to 10.

[0333] 52. In the 50th embodiment, in the dissolving step, the pegylated phospholipid containing the pH-reactive functional group; the second phospholipid; and cholesterol or cholesterol analog may be mixed in a molar ratio of 0.5 to 1 : 1.5 to 3 : 0.5 to 1.

[0334] 53. In at least one of the 49th to 52nd embodiments, the manufacturing method may include the step of manufacturing liposomes from the solution.

[0335] 54. In the 53rd embodiment, the step of preparing the liposome may be performed by drying the solution under vacuum to form a lipid film and sonicating it.

[0336] 55. In the 54th embodiment, the solvent may be removed during drying under an inert gas atmosphere such as nitrogen (N) or argon (Ar).

[0337] 56. In the 54th or 55th embodiment, the ultrasonic treatment may be performed after adding distilled water, deionized water, or water to the lipid film dried during the ultrasonic treatment.

[0338] 57. In at least one of the 54th to 56th embodiments, the ultrasonic treatment may be performed at an amplitude of about 10 to 40%.

[0339] 58. In at least one of the 54th to 57th embodiments, the ultrasonic treatment may be performed at an amplitude of 10 to 40%.

[0340] 59. In the 58th embodiment, the ultrasonic treatment may be performed in pulse mode.

[0341] 60. In the 58th or 59th embodiment, the ultrasonic treatment may be performed by repeating a cycle of irradiating for 5 to 10 seconds followed by resting for 3 to 10 seconds for 5 to 20 minutes.

[0342] 61. In the 53rd embodiment, the step of preparing the liposome may be performed by injecting the solution into a microfluidic device.

[0343] 62. In the 61st embodiment, an organic phase containing lipid components and a radiopharmaceutical and an aqueous phase are mixed within a channel in the microfluidic device, and liposomes can be formed by the self-assembly of lipids.

[0344] 63. This invention relates to an imaging composition comprising a pH-responsive liposome containing a radiopharmaceutical as an active ingredient.

[0345] 64. In the 63rd embodiment, the imaging composition may include at least one radioactive drug delivery composition among the 1st to 48th embodiments.

[0346] 65. In the 63rd or 64th embodiment, the radioactive pharmaceutical is 18 F, 68 Ga, 64 Cu, 11 C, 13 N, 89 Zr, 124 I, 99m Tc, 111 In, 123 I, 201 Tl and 67 It may be a TSPO-specific ligand labeled with one or more radionuclides selected from the group consisting of Ga.

[0347] 66. In the 63rd or 64th embodiment, the radioactive pharmaceutical is 18 F, 68 Ga, 64 Cu, 11 C,13 N, 89 Zr, 124 I, 99m Tc, 111 In, 123 I, 201 Tl and 67 It may be a CB259 compound labeled with one or more radionuclides selected from the group consisting of Ga.

[0348] 67. In the 63rd or 64th embodiment, the radiopharmaceutical may be a radioactive complex represented by Formula 7. Here, M is 99m It could be Tc.

[0349] 68. In the 63rd or 64th embodiment, the radiopharmaceutical may be a radioactive complex represented by Formula 8. Here, M 1 silver 18 It could be F.

[0350] 69. In at least one of the 63rd to 68th embodiments, the imaging may be positron emission tomography (PET), single photon emission tomography (SPECT), PET-CT, or SPECT-CT.

[0351] 70. A method for imaging, comprising the steps of administering at least one imaging composition of the 63rd to 69th embodiments to a subject; and imaging the subject.

[0352] 71. In the 70th embodiment, the imaging may be positron emission tomography (PET), single photon emission tomography (SPECT), PET-CT, or SPECT-CT.

[0353] 72. In the 70th or 71st embodiment, the presence or intensity of a signal emitted from the compound can be detected from the image obtained in the imaging step.

[0354] 73. In the 71st or 72nd embodiment, the presence of solid cancer can be predicted or confirmed from the image obtained in the imaging step, or the progression of solid cancer can be monitored.

[0355] 74. This invention relates to a pharmaceutical composition comprising a pH-responsive liposome containing a radiopharmaceutical as an active ingredient.

[0356] 75. In the 74th embodiment, the pharmaceutical composition may include at least one radioactive pharmaceutical delivery composition among the 1st to 48th embodiments.

[0357] 76. In the 74th or 75th embodiment, the pharmaceutical composition may be used for the diagnosis or treatment of TSPO-related diseases.

[0358] 77. In at least one of the 74th to 76th embodiments, the radiopharmaceutical may be a radioactive complex represented by Formula 7. Here, M is 188 Re or 99m It could be Tc.

[0359] 78. In at least one of the 74th to 76th embodiments, the radiopharmaceutical may be a radioactive complex represented by Formula 8. Here, M 1 silver 18 F, 125 I or 131 It could be I.

[0360] 79. A method for diagnosing a TSPO-related disease, comprising the steps of administering at least one pharmaceutical composition of the 74th to 78th embodiments to a subject; and imaging.

[0361] 80. A method for treating a TSPO-related disease comprising the step of administering at least one pharmaceutical composition of Examples 74 to 78 to a subject.

[0362] 81. In the 79th or 80th embodiment, the TSPO-related disease may be a lesion in which TSPO is overexpressed.

[0363] 82. In the 81st embodiment, the TSPO-related disease may be a disease in which TSPO is overexpressed.

[0364] 83. In the 82nd embodiment, the TSPO overexpression disease may be neuroinflammation, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer.

[0365] The pH-responsive liposomes of the present invention can improve the uptake rate in tumor tissues by selectively releasing radiopharmaceuticals under acidic conditions in the tumor microenvironment. Furthermore, by controlling the structure and composition of the liposomes in consideration of the characteristic of radiopharmaceuticals being used at very low concentrations at the nanomolar to picomolar level, the encapsulation efficiency of the radiopharmaceutical can be maintained or improved while reducing the size of the liposomes. Therefore, the liposomes of the present invention can be usefully utilized for tumor imaging, diagnosis, and treatment as a delivery platform applicable to various radiopharmaceuticals.

[0366] FIG. 1 is according to the present invention in Experimental Example 1. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL) and the control group 99m Tc-CB259 encapsulated standard liposomes ( 99m This shows the results of analyzing the diameter and polydispersity index of Tc-CB259@NL using DLS.

[0367] FIG. 2 shows the method according to the present invention under pH 7.4, pH 6.4, and pH 5.4 conditions in Experimental Example 2. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m This shows a photograph of the shape change of Tc-CB259@pRL observed by TEM.

[0368] Figure 3 shows the free state of the glioblastoma xenograft mouse model in Experimental Example 3. 99m This shows in vivo SPECT / CT images taken after administering Tc-CB259, including coronal plane images (left) and transverse plane images (right) acquired at 1 hour after injection.

[0369] Figure 4 shows the glioblastoma xenograft mouse model in Experimental Example 3. 99m Tc-CB259 encapsulated standard liposomes ( 99m In vivo SPECT / CT images taken after administration of Tc-CB259@NL. Coronal plane images (left) and transverse plane images (right) acquired at 1 hour after injection are shown. Whole-body maximum-intensity projection images at 0.5, 1, 2, and 4 hours after injection are also shown.

[0370] FIG. 5 shows the glioblastoma xenograft mouse model according to the present invention in Experimental Example 3. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m In vivo SPECT / CT images taken after administration of Tc-CB259@pRL), Fig. 5(A) is a transverse SPECT / CT image passing through the tumor site, and the arrow indicates the tumor site. Fig. 5(B) is a whole-body maximum-intensity projection image acquired at the same time, and the dotted circle indicates the tumor site.

[0371] Figure 6 shows the free state of the glioblastoma xenograft mouse model in Experimental Example 3. 99m Tc-CB259, 99m Tc-CB259 encapsulated standard liposomes ( 99m Tc-CB259@NL), and according to the present invention 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99mThis shows an in vivo SPECT / CT coronal plane image acquired at 1 hour after administration of Tc-CB259@pRL.

[0372] Figure 7 shows the glioblastoma xenograft mouse model in Experimental Example 3. 99m Tc-CB259 encapsulated standard liposomes ( 99m This is a graph showing the change in radioactivity distribution (%ID / g) in major organs and tumors over time after administration of Tc-CB259@NL).

[0373] FIG. 8 shows the glioblastoma xenograft mouse model according to the present invention in Experimental Example 3. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m This is a graph showing the change in radioactivity distribution (%ID / g) in major organs and tumors over time after administration of Tc-CB259@pRL.

[0374] FIG. 9 shows the prostate cancer xenograft mouse model according to the present invention in Experimental Example 4. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m In vivo SPECT / CT images after administration of Tc-CB259@pRL, Fig. 9(A) shows coronal plane images acquired at 1 hour and 4 hours after injection, and Fig. 9(B) shows cross-sectional plane images.

[0375] FIG. 10 shows the colorectal cancer xenograft mouse model according to the present invention in Experimental Example 5. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL) and control group 99m Tc-CB259, or 99m Tc-CB259 encapsulated standard liposomes ( 99m This is a graph showing the change in radioactivity distribution (%ID / g) over time in the tumors, liver, and lungs of mice after administration of Tc-CB259@NL).

[0376] Figure 11 is a graph showing the change in radioactivity distribution (%ID / g) over time in the tumors and liver of mice after administering the pH-responsive liposomes of Example 3 and the pH-responsive liposomes of Example 7 to a colorectal cancer xenograft mouse model in Experimental Example 7.

[0377] Figure 12 is a graph showing the change in radioactivity distribution (%ID / g) over time in the tumors and liver of mice after administering the pH-responsive liposomes of Example 3 and the pH-responsive liposomes of Example 8 to a colorectal cancer xenograft mouse model in Experimental Example 8.

[0378] FIG. 13 is a phospholipid (mPEG2k-Hz-DPPE) containing a pH-responsive functional group prepared in Preparation Example 1. 1 This shows the results of the H NMR analysis.

[0379] FIG. 14 is a phospholipid (mPEGk-Hz-DPPE) containing a pH-responsive functional group prepared in Preparation Example 2. 1 This shows the results of the H NMR analysis.

[0380] FIG. 15 is a phospholipid (mPEG550-Hz-DPPE) containing a pH-responsive functional group prepared in Preparation Example 3. 1 This shows the results of the H NMR analysis.

[0381] FIG. 16 is a phospholipid (mPEG350-Hz-DPPE) containing a pH-responsive functional group prepared in Preparation Example 4. 1 This shows the results of the H NMR analysis.

[0382] FIG. 17 is a phospholipid (mPEGk-di(Hz-DPPE)) containing a pH-responsive functional group prepared in Preparation Example 6. 1 This shows the results of the H NMR analysis.

[0383] FIG. 18 is the one prepared in Preparation Example 2 99m A chromatogram showing the HPLC analysis results of Tc-CB259, which is a non-radioactive standard material 188The formation of the product was confirmed through simultaneous injection with Re-CB259.

[0384] According to one embodiment of the present invention, the invention relates to a radioactive drug delivery composition comprising a radioactive drug to be delivered to a target and a pH-responsive liposome.

[0385] The above pH-responsive liposome may comprise a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1:

[0386] [Chemical Formula 1]

[0387]

[0388] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0389] m is an integer from 1 to 3, and

[0390] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and

[0391] [Chemical Formula 2]

[0392]

[0393] In the above chemical formula 2, * represents the part where the bond is formed, and

[0394] R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It is a residue derived from phospholipids selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0395] The pegylated phospholipid containing the above pH-reactive functional group may be represented by the following chemical formula 3 or 4:

[0396] [Chemical Formula 3]

[0397]

[0398] [Chemical Formula 4]

[0399]

[0400] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

[0401] The above n may be an integer from 350 to 1,000.

[0402] The above pH-responsive liposome may further include a second phospholipid.

[0403] The above second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;It may be one or more selected from the group consisting of POPG), phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0404] The above pH-responsive liposomes may further include cholesterol or cholesterol analogs.

[0405] The above pH-responsive liposomes may further include pegylated phospholipids bound to mannose.

[0406] The pegylated phospholipid with the mannose group attached above may be represented by the following chemical formula 5:

[0407] [Chemical Formula 5]

[0408]

[0409] In the above chemical formula 5,

[0410] p is an integer from 1,000 to 5,000.

[0411] The average diameter of the liposomes is 20 to 150 nm, and the polydispersity index (PDI) may be 0.3 or less.

[0412] The above radiopharmaceutical may be included at a concentration of 1 pmol to 100 nmol.

[0413] The encapsulation rate of the radiopharmaceutical in the above liposome may be 50% or more.

[0414]

[0415] According to another embodiment of the present invention, the invention relates to an imaging composition comprising, as an active ingredient, a pH-responsive liposome encapsulated therein with a radiopharmaceutical represented by the following chemical formula 7 or 8:

[0416] [Chemical Formula 7]

[0417]

[0418] [Chemical Formula 8]

[0419]

[0420] In the above chemical formulas 7 and 8, M is 99m Tc and M 1 silver 18 It is F.

[0421] The above pH-responsive liposome may comprise a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1:

[0422] [Chemical Formula 1]

[0423]

[0424] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0425] m is an integer from 1 to 3, and

[0426] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and

[0427] [Chemical Formula 2]

[0428]

[0429] In the above chemical formula 2, * represents the part where the bond is formed, and

[0430] R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.A residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0431]

[0432] According to another embodiment of the present invention, the invention relates to a pharmaceutical composition for the diagnosis or treatment of TSPO-related diseases comprising, as an active ingredient, a pH-responsive liposome encapsulated therein with a radiopharmaceutical represented by the following chemical formula 7 or 8:

[0433] [Chemical Formula 7]

[0434]

[0435] [Chemical Formula 8]

[0436]

[0437] In the above chemical formulas 7 and 8, M is 99m Tc or 188 Re and M 1 silver 18 F, 125 I or 131 I am.

[0438] The above pH-responsive liposome comprises a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1, and

[0439] A pharmaceutical composition for TSPO overexpression diseases that are neuroinflammation, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer:

[0440] [Chemical Formula 1]

[0441]

[0442] In the above chemical formula 1, n is an integer from 300 to 2,000, and

[0443] m is an integer from 1 to 3, and

[0444] R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and

[0445] [Chemical Formula 2]

[0446]

[0447] In the above chemical formula 2, * represents the part where the bond is formed, and

[0448] R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It may be a residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

[0449] The present invention will be described in more detail below through examples. These examples are intended solely to explain the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the invention.

[0450]

[0451] Examples

[0452]

[0453] [Preparation Example 1] Preparation of pegylated phospholipids having pH-reactive functional groups

[0454] A phospholipid represented by the following chemical formula 3 (where n is 2,000) was prepared by the following method:

[0455] [Chemical Formula 3]

[0456]

[0457] 1. Preparation of mPEG2k-4-formylbenzoate (mPEG2k-aldehyde)

[0458] Methoxy-polyethylene glycol (Mn=2,000; hereinafter referred to as "mPEG2k", 0.75 mmol) was placed in a 250 mL round-bottom flask under argon and dissolved in anhydrous dichloromethane (DCM, 20 mL). Subsequently, a solution of 4-dimethylaminopyridine (DMAP, 2.0 equivalents) dissolved in DCM (4 mL) was added, and the mixture was stirred at room temperature for 15 minutes. Separately, 4-formylbenzoic acid (2.5 equivalents) was dissolved in DCM (120 mL) and added to the flask. Then, a solution of N,N'-dicyclohexylcarbodiimide (DCC, 10 equivalents) dissolved in DCM (10 mL) was added dropwise while stirring. The reaction mixture was stirred under argon at room temperature for 18 hours. After 18 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to produce an amber color. Crude yellow oil was obtained. The residue was slowly added to cold diethyl ether to precipitate it. The white solid product obtained during the precipitation process was recovered by centrifugation and then dried.

[0459] 2. Preparation of mPEG2k-EMCH (Maleimide Functionalized mPEG2k)

[0460] mPEG2k-4-formylbenzoate (0.0456 mmol) was dissolved in chloroform (CHCl3, 2 mL) under argon. N-ε-maleimidocaproic acid hydrazide (EMCH; 1.20 equivalents) was dissolved in CHCl3 (2 mL). The EMCH solution was added to the mPEG2k-aldehyde solution. The mixed solution was stirred at room temperature for 18 hours. After the reaction was complete, the solvent was removed under reduced pressure. The product was obtained as a white solid precipitated by cold diethyl ether (-20 °C).

[0461] 3. Manufacture of mPEG2k-Hz-DPPE

[0462] mPEG2k-EMCH (95 mg, 0.0416 mmol) was dissolved in methanol (MeOH, 1.0 mL) under argon. DPPE-SH (1.50 equivalents) was dissolved in MeOH (2.0 mL) and immediately added to the mPEG2k-EMCH solution. Triethylamine (2.0 equivalents) was added, and the mixture was stirred at room temperature for 18 hours.

[0463] 4. Purification process after reaction

[0464] After 18 hours, the reaction mixture was rotary evaporated to remove MeOH. A small amount of acetone was added, and the solution was crystallized at -20 °C. The resulting precipitate was separated by centrifugation and redissolved in 1.0 mL of acetone. Subsequently, the precipitate was dissolved in 12 mL of 60% aqueous methanol. The solution was purified by ultrafiltration. The recovered filtrate was concentrated, frozen at -80 °C, and lyophilized to obtain a yellow solid of mPEG2k-Hz-DPPE with a yield of 94%.

[0465] 5. Analysis of Final Product

[0466] The final product is 1 It was analyzed by H NMR (Fig. 13). 1 In the ¹H NMR (CDCl3) spectrum, DPPE alkyl chains could be identified at δ 0.90 ppm and 1.25 ppm. Methyl and methylene of the phospholipid could be identified at ~0.9 ppm and 1.25 ppm.

[0467]

[0468] [Preparation Example 2] Radiolabeling and purification of CB259 with 99mTc

[0469] [Reaction Equation 2]

[0470]

[0471] As in the above reaction equation 2 99m Radiolabeling of CB259 with Tc was performed. First,99m Tc-Tricabonyl Technetium([ 99m Tc(CO)3(H2O)3] + ) was prepared using a kit. 370 ~ 740 MBq of eluted in physiological saline 99m TcO4 - Add to the kit vial and heat at 100°C for 30 minutes [ 99m Tc(CO)3(H2O)3] + was generated. In the precursor [ 99m Tc(CO)3(H2O)3] + The labeling reaction involves 500 μg of CB259 dissolved in DMF and [in physiological saline 99m Tc(CO)3(H2O)3] + The components were mixed to achieve a final DMF:physiological saline ratio of 7:3 (v / v), and the mixture was reacted at 70°C for 30 minutes. The reaction mixture was separated using HPLC, and the separated components were separated 99m Tc-CB259 is tC 18 It was eluted with a solvent for biological experiments using a Sep-Pak cartridge and used in the experiment. Labeled 99m It was confirmed that Tc-99m was labeled by comparing the retention times of Tc-CB259 with the reference substance Re-CB259 through HPLC co-injection (Fig. 18, 99m HPLC results of simultaneous injection of Tc-CB259 and reference substance Re-CB259).

[0472]

[0473] [Example 1] Preparation of pH-responsive liposomes (99mTc-CB259@pRL) encapsulated with 99mTc-CB259

[0474] PEG2k-Hz-DPPE, a pH-reactive phospholipid prepared in Preparation Example 1, was prepared with DSPC and cholesterol in a molar ratio of 1:3:1, and the radiopharmaceutical prepared in Preparation Example 2 99m Tc-CB259 was included so that the radioactivity / lipid weight ratio was approximately 5 MBq / mg. The above lipid component and99m Tc-CB259 was dissolved in a 30% methanol / chloroform mixed solvent and mixed in a reaction vial. The solvent was removed from the solution to form a thin lipid film. Subsequently, the solution was dried under high vacuum for at least 30 minutes to completely remove any residual solvent. Distilled water was added to the formed lipid film to hydrate it. The resulting suspension was cooled over ice and subjected to ultrasonic treatment in pulse mode using a tip-sonicator (probe sonicator). The ultrasonic treatment was performed for a total of approximately 12 minutes by repeating a cycle of 8 seconds of irradiation followed by 5 seconds of rest under conditions of approximately 24% amplitude.

[0475] The generated liposome suspension was purified using a PD-10 size-exclusion column. The column was eluted with physiological saline, and the fraction exhibiting the highest radioactivity was collected. 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL) was obtained.

[0476]

[0477] [Comparative Example 1] Preparation of a standard liposome (99mTc-CB259@NL) encapsulated with 99mTc-CB259

[0478] To prepare a general liposome that does not contain pH-responsive lipids, liposomes were prepared in the same manner as in Example 1, but the general phospholipid PEG2k-PE was used instead of the pH-responsive phospholipid PEG2k-Hz-DPPE. Specifically, PEG2k-PE, DSPC, and cholesterol were prepared, and the radiopharmaceutical prepared in Preparation Example 2 99m Tc-CB259 was included so that the radioactivity / lipid weight ratio was approximately 5 MBq / mg. Subsequently, the same process as in Example 1 was performed. 99m Tc-CB259 encapsulated standard liposomes ( 99m Tc-CB259@NL) was obtained.

[0479]

[0480] [Experimental Example 1] Measurement of Liposome Particle Size, Polydispersity Index, and Encapsulation Efficiency

[0481] 1. Analysis of physicochemical properties

[0482] The one prepared in Example 1 above 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL) and the general liposome prepared in Comparative Example 1 ( 99m The mean hydrodynamic diameter and polydispersity index (PDI) of Tc-CB259@NL were measured using dynamic light scattering (DLS). The measurements 99m Considering the half-life of Tc, the test was performed at 25°C using a Zetasizer Nano ZS (Malvern Instruments, Malvern, UK) after approximately 3 days had elapsed. To prevent multiple scattering, the sample was diluted to an appropriate concentration with PBS (pH 7.4) before measurement. All measurements were performed in triplicate.

[0483] 2. Measurement of encapsulation efficiency

[0484] Encapsulated within a liposome 99m The encapsulation efficiency (EE) of Tc-CB259 was measured using the ultrafiltration method. Specifically, free-state Tc-CB259 not encapsulated in liposomes 99m Tc-CB259 was separated from the radioligand encapsulated in the liposome using PD-10 size exclusion chromatography. Initial for introduction into the liposome 99m Tc-CB259 radioactive encapsulated within liposomes 99m The encapsulation efficiency was calculated based on the ratio of radioactivity of Tc-CB259.

[0485] As a result, as shown in Fig. 1, it was confirmed that the average particle size of the liposomes of Example 1 was approximately 95 nm, the PDI was approximately 0.3, and the encapsulation efficiency was approximately 60%. Meanwhile, the control liposomes that do not contain pH-responsive lipids ( 99m In the case of Tc-CB259@NL), the average particle size was found to be about 95 nm, the PDI was about 0.3, and the encapsulation efficiency was about 55%.

[0486] Next, the particle size and polydispersity index were measured for the liposomes of Example 2 prepared using a microfluidic method in the same way. The average particle size of the liposomes prepared in Example 2 was approximately 67.18 ± 3.73 nm, the PDI was approximately 0.22473 ± 0.02, and the encapsulation efficiency was approximately 60%. This indicates that liposomes with relatively uniform particle sizes can be reproducibly prepared using a microfluidic process.

[0487]

[0488] [Experimental Example 2] Confirmation of morphological changes in pH-responsive liposomes according to pH changes

[0489] The one prepared in Example 1 above 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99mTc-CB259@pRL) was dispersed in buffer solutions at pH 7.4, pH 6.4, and pH 5.4, respectively, and reacted for a certain period of time. Transmission electron microscopy (TEM) was used to observe the morphological changes of the liposomes treated under each pH condition. Specifically, a drop of the diluted liposome suspension was placed on a carbon-coated copper grid and dried; subsequently, negative staining was performed using a 2% uranyl acetate solution, and the morphology of the liposomes was observed using TEM (JEOL JEM-2100F, Tokyo, Japan).

[0490] As a result, as shown in Figure 2, it was confirmed that the spherical structure of the liposome was stably maintained under pH 7.4 conditions. On the other hand, it was observed that the structure of the liposome gradually changed as the pH decreased, and in particular, under pH 5.4 conditions, it was confirmed via TEM that the liposome structure collapsed as the hydrazine bonds of the pH-responsive lipids decomposed.

[0491] These results suggest that the pH-responsive liposomes of the present invention can selectively disintegrate and release drugs under acidic conditions, such as the tumor microenvironment, while maintaining stability under physiological pH conditions.

[0492]

[0493] [Experimental Example 3] Analysis of In vivo Distribution of pH-Reactive Liposomes in a Glioblastoma Xenograft Mouse Model

[0494] Female athymic nude mice aged 6–8 weeks were used in the experiment. 5 x 10⁶ U87-MG cells were injected into the flank of each mouse. 6Tumors were formed by subcutaneous injection at cell / mouse concentrations. The tumors were grown until they reached a diameter of approximately 5–8 mm and then used in the experiment. In mice, free-state 99m Tc-CB259, a standard liposome prepared in Comparative Example 1 ( 99m Tc-CB259@NL), prepared in Example 1 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL was administered. Images were acquired using a SPECT / CT scanner at 0.5, 1, 2, and 4 hours after injection. Regions of interest (ROIs) were established for the tumor and major organs in the acquired images, and the radioactivity distribution was analyzed as the percentage injected dose per gram of tissue (% ID g). -1 It was quantified as ).

[0495] As seen in Figures 3 and 6, 99m When Tc-CB259 was administered, strong signals were observed in non-target organs such as the liver, lungs, kidneys, and bladder, but no significant signals were observed in tumors.

[0496] As seen in FIGS. 4, 6, and 7, the one prepared in Comparative Example 1 99m Tc-CB259 encapsulated in a standard liposome ( 99m When Tc-CB259@NL was administered, a strong signal was observed in the liver in the SPECT / CT image at 1 hour after injection, but almost no uptake was observed in the tumor. Almost no tumor uptake was observed, and it was confirmed that the radioactivity in the liver continuously increased over time.

[0497] On the other hand, as seen in FIGS. 5, 6, and 8, the one prepared in Example 1 99m Tc-CB259 encapsulated in pH-responsive liposomes ( 99mUpon administration of Tc-CB259@pRL), a distinct localized radioactivity signal was observed at the tumor site in SPECT / CT imaging, and a tendency for the signal to increase over time was confirmed. Quantitative analysis revealed that the tumor uptake rate increased to approximately 1.0% ID / g at 0.5 hours, 3.1% ID / g at 1 hour, and 5.1% ID / g at 2 hours, with high uptake of over 3% ID / g maintained even at the 4-hour mark. Background signals in non-target organs, such as the lungs, were confirmed to be relatively low compared to other formulations. This suggests that pH-responsive liposomes within the acidic conditions of the tumor microenvironment 99m This suggests that Tc-CB259 can bind to TSPO within the tumor by releasing it at the tumor site, and as a result, shows that the delivery of the radiopharmaceutical to the tumor site is significantly improved.

[0498]

[0499] [Experimental Example 4] Analysis of In vivo Distribution of pH-Reactive Liposomes in a Prostate Cancer Xenograft Mouse Model

[0500] According to the present invention in a prostate cancer xenograft mouse model 99m The in vivo distribution of pH-responsive liposomes (99mTc-CB259@pRL) encapsulated with Tc-CB259 was analyzed. In a xenograft mouse model in which LNCaP cells were transplanted to form a tumor, the liposomes prepared in Example 1 99m SPECT / CT images were acquired at 1 hour and 4 hours after intravenous injection of Tc-CB259@pRL.

[0501] As a result, as shown in Figure 9, radioactivity uptake of approximately 1.6% ID / g was observed at the tumor site at 1 hour after injection, and a trend of increasing to approximately 1.8% ID / g was confirmed at 4 hours. In addition, it was observed in SPECT / CT images that the radioactivity signal at the tumor site was maintained over time, confirming that the pH-responsive liposome formulation according to the present invention tends to accumulate and be maintained in the tumor tissue.

[0502]

[0503] [Experimental Example 5] Analysis of In vivo Distribution of pH-Reactive Liposomes in a Colorectal Cancer Xenograft Mouse Model

[0504] In a colorectal cancer xenograft mouse model, the one prepared according to the present invention 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m The in vivo distribution of Tc-CB259@pRL was analyzed. In the tail vein of a colorectal cancer xenograft mouse model in which CT26 cells were transplanted to form a tumor 99m Tc-CB259, a standard liposome prepared in Comparative Example 1 ( 99m Tc-CB259@NL), prepared in Example 1 99m pH-responsive liposomes encapsulated with Tc-CB259 ( 99m Tc-CB259@pRL) was injected. SPECT / CT images were acquired at 30 minutes, 1 hour, 2 hours, and 4 hours after injection. Based on the acquired images, the uptake rate in the tumor and major organs was analyzed.

[0505] As a result, as shown in Fig. 10, 99m In the case of Tc-CB259@pRL, it was confirmed that the uptake rate in tumor tissue reached approximately 2% ID / g about 2 hours after administration and was maintained at a level of approximately 2% ID / g up to 4 hours. On the other hand, 99m Tc-CB259 alone and 99mWhen Tc-CB259@NL was administered, no significant uptake in tumor tissue was observed.

[0506] Also, the uptake rate in the liver 99m In the case of Tc-CB259@pRL, it is maintained at approximately 20 %ID / g levels for up to 4 hours, whereas, 99m Tc-CB259 alone and 99m In the case of Tc-CB259@NL, it was confirmed that the levels increased to approximately 40 %ID / g and approximately 50 %ID / g, respectively.

[0507] From the above results, it was confirmed that the pH-responsive liposomes of the present invention can enhance the delivery of radiopharmaceuticals to tumor tissues and reduce non-specific accumulation in normal organs, particularly the liver.

[0508]

[0509] [Example 2] Preparation of pH-responsive liposomes (RE-CB259@pRL) using a microfluidic device

[0510] pH-responsive liposomes were prepared with the same composition as in Example 1, but the liposome formation process was performed using a microfluidic device. Specifically, PEG2k-Hz-DPPE, DSPC, and cholesterol prepared in Preparation Example 1 were prepared in a molar ratio of 1:3:1, and Re-CB259, the reference material of Preparation Example 2, was dissolved in an ethanol solvent to prepare the organic phase. Subsequently, the prepared organic phase and water were injected into the inlet channel of a microfluidic device (enCell master, enParticle) to mix within the microchannel. As the organic and aqueous phases mixed, the lipid components self-assembled to form pH-responsive liposomes encapsulated with Re-CB259. The suspension produced after liposome preparation was purified through washing and filtration processes.

[0511] As described above, the liposome manufacturing process using a microfluidic device can be performed in a very short time, for example, about 10 minutes for the preparation and dissolution of lipid materials, about 9 to 36 seconds for the liposome formation step, about 15 minutes for the washing step, and about 5 to 10 minutes for the filtration step.

[0512] From this, it was confirmed that using a microfluidic device can reduce the manufacturing time to within tens of minutes compared to the conventional liposome manufacturing process, which takes about 2 hours or more.

[0513]

[0514] [Preparation Examples 3 to 5] Preparation of Pegylated Phospholipids Having pH-Reactive Functional Groups

[0515] To confirm the change in in vivo distribution of the above pH-responsive liposomes according to the PEG chain length, pegylated phospholipids having pH-responsive functional groups with different PEG chain lengths were prepared. mPEGk-Hz-DPPE (Preparation Example 3), mPEG550-Hz-DPPE (Preparation Example 4), and mPEG350-Hz-DPPE (Preparation Example 5) were obtained using the same method as in Preparation Example 1, except that methoxy-PEG with Mn=350, 550, or 1000 was used. For each of the above compounds 1 As a result of performing H NMR analysis, it was confirmed that the target compound was successfully synthesized by identifying the shift value and integration value corresponding to the PEG, aromatic, and DPPE alkyl chains (Figs. 14 to 16).

[0516]

[0517] [Examples 3 to 5] Preparation of pH-responsive liposomes with different PEG lengths

[0518] Except for using the mPEGk-Hz-DPPE, mPEG550-Hz-DPPE, or mPEG350-Hz-DPPE prepared in Preparation Examples 2 to 4, respectively, in the same method as Example 1 above 99m pH-responsive liposomes encapsulated with Tc-CB259 were prepared. As a result, liposomes using mPEGk-Hz-DPPE (Example 3), liposomes using mPEG550-Hz-DPPE (Example 4), and liposomes using mPEG350-Hz-DPPE (Example 5) were obtained, respectively.

[0519] For the pH-responsive liposomes prepared in this way, particle size and polydispersity index (PDI) were measured using the same method as in Experimental Example 1. In addition, for comparison, the results of liposomes prepared using mPEG2k-Hz-DPPE (Example 1) were also presented.

[0520] Example 1 Example 3 Example 4 Example 5 Phospholipid mPEG 2k-Hz-DPPE mPEG 550-Hz-DPPE mPEG 350-Hz-DPPE 550-Hz-DPPE

[0521] As shown in Table 1 above, as the length of the PEG chain decreased, the particle size of the liposomes tended to decrease, and in particular, when the PEG length was 1000 or less, the size of the liposomes was observed to decrease to about 50 nm. In addition, regarding the polydispersity index (PDI), it showed an overall decreasing trend as the PEG length became shorter, which suggests that liposomes with a more uniform particle size distribution are formed.

[0522]

[0523] [Experimental Example 6] Comparison of In vivo Distribution of pH-Reactive Liposomes According to PEG Length

[0524] To compare the in vivo distribution of pH-responsive liposomes according to PEG length in a tumor mouse model, experiments were conducted using liposomes prepared in Examples 3 to 5. The experimental method was performed in the same manner as in Experimental Example 5, and to compare the effects according to PEG length, the results of liposomes containing mPEG2k-Hz-DPPE prepared in Example 1 were also presented.

[0525] Classification Tumor uptake rate (%ID / g) by PEG length and time Example 1 Example 3 Example 4 Example 5 Phospholipid mPEG 2k-Hz-DPPE mPEG k-Hz-DPPE mPEG 5 50-Hz-DPPE mPEG 3 50-Hz-DPPE 0.5 h 2.6 2.1 2.8 0.21 h 3.0 8.8 5.4 0.5

[0526] Classification Liver uptake rate (%ID / g) by PEG length and time Example 1 Example 3 Example 4 Example 5 Phospholipid mPEG 2k-Hz-DPPE mPEG k-Hz-DPPE mPEG 5 50-Hz-DPPE mPEG 3 50-Hz-DPPE 0.5 h 32.23 1.45 3.43 7.51 h 32.14 4.04 8.72 2.8

[0527] First, when comparing the uptake rates in tumor tissue, a relatively higher tumor uptake rate was observed in liposomes using mPEGk-Hz-DPPE (Example 3) or mPEG550-Hz-DPPE (Example 4) at 1 hour after injection compared to liposomes using mPEG2k-Hz-DPPE (Example 1).

[0528] Meanwhile, when comparing the uptake rates in the liver, liposomes using mPEGk-Hz-DPPE (Example 3) or mPEG350-Hz-DPPE (Example 5) showed an uptake rate equivalent to that of liposomes using mPEG2k-Hz-DPPE (Example 1).

[0529] From the above results, it was found that the uptake rate in tumor tissue compared to normal tissue was the best when the PEG chain length was 1000, which implies that the in vivo distribution of liposomes varies depending on the PEG length. In particular, liposomes containing mPEGk-Hz-DPPE showed significantly improved tumor accumulation compared to the existing mPEG2k-Hz-DPPE, confirming that PEG length regulation is an important factor in improving tumor target delivery efficiency.

[0530]

[0531] [Examples 6 and 7] Preparation of pH-responsive liposomes containing mannose-conjugated pegylated phospholipids

[0532] According to the methods of Examples 1 and 3 99m pH-responsive liposomes encapsulated with Tc-CB259 were prepared, but DSPE-PEG(2000)-Mannose (CAS No. 1829524-73-3), a pegylated phospholipid bound to mannose, was additionally included during liposome preparation. At this time, cholesterol, DSPC, pH-responsive phospholipid, and mannose-bound lipid were included in a molar ratio of 2:6:1:1.

[0533] For the pH-responsive liposomes prepared in this way, the particle size and polydispersity index (PDI) were measured using the same method as in Experimental Example 1 above. As shown in Table 4 below, when liposomes were prepared by additionally including mannose-conjugated pegylated phospholipids, the average particle size of the PEG2000-based liposomes was approximately 136.4 nm and the PDI was approximately 0.246, while the average particle size of the PEG1000-based liposomes was approximately 69.8 nm and the PDI was approximately 0.178.

[0534] Example 6 Example 7 Phospholipid mPEG 2k-Hz-DPPE mPEG k-Hz-DPPES Size 136.469.8 PDI 0.2460.178

[0535]

[0536] [Experimental Example 7] Analysis of In vivo distribution of pH-responsive liposomes containing mannose-conjugated pegylated phospholipids

[0537] To compare the in vivo distribution of pH-responsive liposomes following the addition of mannose-linked pegylated phospholipids in a tumor mouse model, an experiment was performed using the liposomes prepared in Examples 3 and 7 in the same manner as in Experimental Example 5.

[0538] Tumor uptake rate (%ID / g) over time according to the presence or absence of mannose phospholipids Example 3 Example 7 0.5 h 2.1 2.11 h 8.8 3.22 h 9.0 3.1

[0539] Liver uptake rate (%ID / g) over time according to the presence or absence of mannose phospholipids Example 3 Example 7 0.5 h 3 1.4 3 0.11 h 4 4.0 2 7.5 2 h 3 7.6 1 4.2

[0540] As shown in Tables 5 and 6 and Figure 11, the tumor uptake rate was very high in liposomes that did not introduce mannose-conjugated pegylated phospholipids, but at the same time, uptake in the liver, a non-target organ, also increased. However, in the case of liposomes that introduced mannose-conjugated pegylated phospholipids, it was confirmed that the uptake rate in the tumor was maintained at 3% ID / g while the uptake rate in the liver, a non-target organ, was reduced by more than twofold.

[0541] From the above results, it was confirmed that by using a liposome composition containing mannose-bound pegylated phospholipids, non-specific uptake in normal organs such as the liver can be reduced while maintaining selective accumulation characteristics in tumor tissue.

[0542]

[0543] [Preparation Example 6] Preparation of pegylated phospholipids containing two pH-reactive functional groups

[0544] A phospholipid represented by the following chemical formula 4 (where n is 1000) was prepared by the following method:

[0545] [Chemical Formula 4]

[0546]

[0547] After dissolving methoxy-polyethylene glycol (mPEGk, 100 mg) in DCM, DMAP (2 equivalents) was added and stirred at room temperature for 15 minutes. Then, 3,5-diformylbenzoic acid (0.8 equivalents) was dissolved in DCM and added, followed by the addition of DCC (10 equivalents). The mixture was stirred at room temperature for 18 hours, after which DCU was removed by filtration. The product, mPEGk-diformyl benzoate, was obtained through purification using silica gel column chromatography. The obtained mPEGk-diformyl benzoate was dissolved in chloroform, followed by the addition of EMCH (2 equivalents) and stirring at room temperature for 18 hours. After removing the solvent from the reaction mixture, the product was precipitated in diethyl ether to obtain the product mPEGk-di(EMCH) as a white solid. The obtained mPEGk-(EMCH)2 was dissolved in methanol under argon, after which DPPE-SH (2 equivalents) and TEA (2 equivalents) were added and stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture, acetone was added to induce a precipitate. The resulting precipitate was purified through the same precipitation and washing process to obtain the final compound, mPEGk-di(Hz-DPPE). The final product is 1 It was analyzed by H NMR (Fig. 17).

[0548]

[0549] [Example 8] Preparation of pH-responsive liposomes using pegylated phospholipids containing two pH-responsive functional groups

[0550] Except for using the mPEGk-di(Hz-DPPE) prepared in Preparation Example 6, in the same method as in Example 1 above 99m pH-responsive liposomes encapsulated with Tc-CB259 were prepared.

[0551] For the pH-responsive liposomes prepared in this way, particle size and polydispersity index (PDI) were measured using the same method as in Experimental Example 1 above. As shown in Table 7 below, in the case of liposomes with two pH-responsive functional groups introduced, the average particle size was approximately 135.4 nm and the PDI was approximately 0.170, confirming that the size of the liposomes increased by about twofold.

[0552] Example 7 Example 8 Phospholipid mPEGk-Hz-DPPE mPEGk-di(Hz-DPPE) Size 69.8 135.4 PDI 0.17 80.170

[0553]

[0554] [Experimental Example 8] Analysis of In vivo distribution of liposomes according to an increase in the number of pH-reactive functional groups

[0555] In order to compare the in vivo distribution of pH-responsive liposomes according to the number of pH-responsive functional groups in a tumor mouse model, experiments were performed using the pH-responsive liposomes prepared in Examples 3 and 8 in the same manner as in Experimental Example 5.

[0556] Tumor uptake rate (%ID / g) over time according to pH, reactive functional group number Example 3 Example 8 0.5 h 2.1 2.31 h 8.8 2.5 2 h 9.0 3.0

[0557] Classification pH Reactivity Number of Functional Groups Liver uptake rate (%ID / g) over time Example 3 Example 8 0.5 h 3 1.4 3 1.11 h 4 4.0 3 0.62 h 3 7.6 1 4.9

[0558] As shown in Tables 8 and 9 and Figure 12, it was confirmed that liposomes containing two pH-responsive functional groups maintained an uptake rate of about 3% ID / g in tumors, while the uptake rate in the liver, a non-target organ, was significantly reduced compared to liposomes containing one functional group.

[0559] From these results, it was confirmed that by increasing the number of pH-responsive functional groups, non-specific uptake in normal organs such as the liver can be reduced while maintaining the selective accumulation characteristics in tumor tissue.

[0560]

[0561] Specific parts of the present invention have been described in detail above. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

[0562] The present invention relates to a pH-responsive liposomal pharmaceutical composition loaded with a radiopharmaceutical and a method for manufacturing the same. The pharmaceutical composition of the present invention can be used for imaging or targeted therapy aimed at diagnosing a disease or tracking disease progression by increasing the uptake rate of the radiopharmaceutical in target lesions rather than in normal organs.

Claims

1. As a composition for delivering radiopharmaceuticals, A radiopharmaceutical to be delivered to a target; and comprising pH-responsive liposomes, A composition wherein the above pH-responsive liposome comprises a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, n is an integer from 300 to 2,000, and m is an integer from 1 to 3, and R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and [Chemical Formula 2] In the above chemical formula 2, * represents the part where the bond is formed, and R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.It is a residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

2. In Paragraph 1, A composition in which the pegylated phospholipid containing the above pH-reactive functional group is represented by the following chemical formula 3 or 4. [Chemical Formula 3] [Chemical Formula 4] In the above chemical formulas 3 and 4, n is an integer from 300 to 2,000.

3. In Paragraph 2, A composition in which n is an integer from 350 to 1,000.

4. In Paragraph 1, The above pH-responsive liposome is a composition further comprising a second phospholipid.

5. In Paragraph 4, The above second phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol;A composition comprising one or more selected from the group consisting of POPG, phosphatidylethanolamine, bis(1,2-dimethylphosphino)ethane (DMPE), 1,2-bis(diphenylphosphino)ethane (DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS).

6. In Paragraph 4, The above pH-responsive liposomes are a composition further comprising cholesterol or a cholesterol analog.

7. In Paragraph 1, The above pH-responsive liposome is a composition further comprising a pegylated phospholipid bound to mannose.

8. In Paragraph 7, A composition wherein the pegylated phospholipid to which the mannose is bonded is represented by the following chemical formula 5: [Chemical Formula 5] In the above chemical formula 5, p is an integer from 1,000 to 5,000.

9. In Paragraph 1, A composition in which the average diameter of the liposomes is 20 to 150 nm and the polydispersity index (PDI) is 0.3 or less.

10. In Paragraph 1, A composition comprising the above radiopharmaceutical at a concentration of 1 pmol to 100 nmol.

11. In Paragraph 1, A composition having an encapsulation rate of the radiopharmaceutical within the liposome of 50% or more.

12. An imaging composition comprising, as an active ingredient, a pH-responsive liposome encapsulated with a radiopharmaceutical represented by the following chemical formula 7 or 8, wherein A composition wherein the above pH-responsive liposome comprises a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, n is an integer from 300 to 2,000, and m is an integer from 1 to 3, and R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and [Chemical Formula 2] In the above chemical formula 2, * represents the part where the bond is formed, and R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.A residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). [Chemical Formula 7] [Chemical Formula 8] In the above chemical formulas 7 and 8, M is 99m Tc and M 1 silver 18 It is F.

13. A pharmaceutical composition for the diagnosis or treatment of TSPO-related diseases comprising, as an active ingredient, a pH-responsive liposome encapsulated therein with a radiopharmaceutical represented by the following chemical formula 7 or 8, wherein The above pH-responsive liposome comprises a pegylated phospholipid containing a pH-responsive group represented by the following chemical formula 1, and A pharmaceutical composition for TSPO-related diseases, which are neuroinflammation, pancreatic cancer, lung cancer, thyroid cancer, ovarian cancer, uterine cancer, colorectal cancer, stomach cancer, bladder cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, kidney cancer, or brain cancer: [Chemical Formula 1] In the above chemical formula 1, n is an integer from 300 to 2,000, and m is an integer from 1 to 3, and R1 is a group represented by the following chemical formula 2, and if there are multiple R1s, they are identical or different from each other, and [Chemical Formula 2] In the above chemical formula 2, * represents the part where the bond is formed, and R2 is hydrogenated soy phosphatidylcholine (HSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), phosphatidylcholine, dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (distearoyl Phosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), diethyl phosphorocyanidate (DEPC), phosphatidylglycerol, dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl-phosphatidylglycerol (DPPG), dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis(1.A residue derived from a phospholipid selected from the group consisting of 2-dimethylphosphino)ethane (bis(1,2-dimethylphosphino)ethane; DMPE), 1,2-bis(diphenylphosphino)ethane (1,2-Bis(diphenylphosphino)ethane; DPPE), dioleoylphosphatidylethanolamine (DOPE), phosphatidylserine, and dioleoyl phosphatidylserine (DOPS). [Chemical Formula 7] [Chemical Formula 8] In the above chemical formulas 7 and 8, M is 99m Tc or 188 Re and M 1 silver 18 F, 125 I or 131 I am.

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