CN102233140A - Chemical composition for radiation and chemotherapy - Google Patents
Chemical composition for radiation and chemotherapy Download PDFInfo
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- CN102233140A CN102233140A CN2010101730357A CN201010173035A CN102233140A CN 102233140 A CN102233140 A CN 102233140A CN 2010101730357 A CN2010101730357 A CN 2010101730357A CN 201010173035 A CN201010173035 A CN 201010173035A CN 102233140 A CN102233140 A CN 102233140A
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Abstract
The invention discloses a chemical composition for radiation and chemotherapy, which is used in the field of radiation chemistry, nuclear imaging, radionuclide therapy and chemical synthesis and comprises a TA2S derivative which is conjugate with a therapeutic or diagnostic ligand and can chelate with metals under certain conditions.
Description
[technical field]
The invention relates to a kind of chemical composition thing of radiochemistry treatment usefulness, particularly relevant for a kind of chemical composition thing for the treatment of usefulness about the field and the radiochemistry of radiochemistry, nucleon radiography, the treatment of radiation nuclear species and chemosynthesis.
[background technology]
Such as the computed tomography art (computed tomography, CT) and the diagnosis shadowgraph technique of magnetic resonance radiography (MRI) anatomy information about disease location is provided.Although these mode are generally used for monitoring the variation of tumor size, it can not assess the functional variation that takes place in cell or the tumor.Therefore, because the progress of molecule shadowgraph technique, experienced flourish such as the function shadowgraph technique of positron emission tomography (PET) and single photon emission computed tomography art (SPECT).Developed the novel molecule radiography target that is used to diagnose and treats with observation morbid state and pathological process under the situation of detecting health without surgery.Detailed speech, the target radiopharmaceutical provides the ability likely of the pathophysiology of Non-Invasive assess disease.Schillaci, O. and Simonetti, G., Cancer Biother.Radiopharm.19:1-10 (2004); People such as Paulino, Semin.Nucl.Med.33:238-43 (2003).Yet, being applicable to that the radiopharmaceutical of clinical application is restricted, it has caused the radiopharmaceutic newly-developed of when chorologic novelty with improvement sensitivity, specificity, signal and background.Srivastava, S.C, Semin.Nucl.Med.26:119-31 (1996); People such as Gatley, Acta.Radiol.Suppl.374:7-11 (1990); Mason, N.S. and Mathis, C.A., NeuroimagingClin.N.Am.13,671-87 (2003).
PET is a Non-Invasive medical science shadowgraph technique, and it can produce the high-res image of the mankind and animal physiological function.Its clinical practice comprises oncology, cardiology and neurological.The PET radiography in the detecting disease and pay a return visit (follow-up) in treatment plan and treatment respectively can be very effective in the stage.The medical importance of PET radiography is the availability owing to multiple radioactive indicator, and the is described radioactive indicator of Denging comprises the radiosiotope that cyclotron produces: 11C, 13N, 15O and 18F.
Radiosiotope often is to produce by cyclotron or by generator base synthetic schemes.Cyclotron is large-scale expensive system, and therefore, many medical science contrast apparatus must obtain its radiosiotope from the cyclotron equipment of wide apart.Synthesis of radiopharmaceuticals and then it is passed to medical science contrast apparatus institute's time spent and makes used radiosiotope be necessary to have the slightly long half-life of half-life than being ideal value in other cases.
Although FDG-PET is the significant notation that is used for the metabolism radiography, limited accessibility and the expensive diagnosis capability of having impelled radiography research to enlarge PET.At present, researcher can use based on the paired generator of mother-son (P/D) nuclear species, and wherein the parent isotope of longer life (obtaining from cyclotron) decay is the short life daughter isotope that is suitable for radiography relatively.Parent isotope can be transported to clinical place and serve as daughter isotope can be easy to from its molten from the source.Expense is easier to bear under general less and the relatively cheap and situation that therefore use at the scene of medical science contrast apparatus of the generator of this type.
Usually the radiation nuclear species (that is 11C, 13N, 15O and 18F) that used cyclotron produces for covalently bound to targeted molecular and do not need to use chelating moiety.The radiation nuclear species that is generally radioactive metal that this and generator produce forms contrast, and is used for radiolabeled chelating agen by existence and uses Coordinative Chemistry.Be called bifunctional chelants (BFCA) with the binding radioactivity metal and with the conjugated chelating agen of biomolecule.Coordination part such as the most of BFCA of atomic building of the electron rich of nitrogen, oxygen, sulfur and phosphorus.The common BFCA that is used for the radioactive metal chelating comprises DTPA, diazanyl nicotianamine (HYNIC), sulfydryl acetyl group three glycines (MAG3), four nitric heterocyclic compounds (that is 1; 4; 7; 10-tetraazacyclododecanand-1; 4; 7,10-tetraacethyl [DOTA] and huge ring derivatives) and ethylene two aminothiopropionic acid (EC).Each BFCA has and is used for the metalchelated various combination that pushes away electronic atom.
Careful design BFCA changes to avoid interference the targeting activity of ligand to produce minimal structure the selection and the conjugation of biomolecule.BFCA serves two main purposes: 1) coordination radioactive metal and 2) provide and can modify to be connected to the molecular backbone of target biology molecule through the functional group.The conjugation of BFCA and biomolecule will change the physics and the biological property of biomolecule.BFCA such as DTPA will sharply increase the hydrophilic feature of biomolecule and produce the renal excretion that increases.On the other hand, can modify huge ring (for example four azepine chelating agen) to obtain permission and lipotropy and the equal conjugation of hydrophilic ligand and suitable drug kinetics that can the multiple radiation nuclear species of chelating.
The radiopharmaceutical that the improvement of scintigraphy art (scintigraphic) diagnosing tumor, prognosis, plan and monitoring cancer therapy is with exploitation has more tumour-specific closely links to each other.The molecule target is applied to cancer radiography, treatment and the prevention principal focal point for the research of molecule radiography.Novel by developing through radioactive label ligand, antibody and therapeutic agent, make PET and SPECT be used for the purposes that tumor characterizes and strengthened.Therefore, by developing and characterize novel radioactive indicator, molecule nucleon medical science is just improveing and is being used to monitor the methodology of tumor to reaction, Differential Diagnosis and the predicted treatment reaction of treatment.
Similarly, therapeutic nucleon medical science has had benefited from finding and verifying novel molecule target.Discern feasible the developing of the specific molecular relevant and carry the therapeutic radiation nuclear species with target biomolecule as payload (payload) with specified disease.This makes the radiant specificity be passed to desired area, makes nonstandard target organ exempt unnecessary radiation dose simultaneously.90Y is the Beta-ray radiosiotope of emission, and it is used to radiate the nuclear species treatment clinically.The main focus of the method is the nephrotoxicity relevant with 90Y and has caused in described field to using different therapeutic radiation nuclear species to shift.Again, although carry out extensively clinical and preclinical study with different 90Y molecules, have a major defect: it is for pure beta emitter and therefore must use 111In as being used for radiography, bio distribution and assessing dosimetric " coupling is to (matching pair) " succedaneum.Use this technology to make many supposition, therefore a large amount of attention have been directed to also has the practical application of measuring the therapeutic radiation nuclear species of the radiography ability of calculating than exact dose.These radiation nuclear species are incorporated into can provide in can the target biomolecule of radioactive metal chelating the radiation selectivity is passed to specific part to reach the chance of diagnosis or therapeutic purpose.
By novel radioactive label strategy being offered the target tissue to be used for radiography, the present invention overcomes about the restriction of PET radiography availability in the place of not having contiguous cyclotron, lacks other shortcomings that target radiates nuclear species treatment and prior art.The invention provides can various radioactivity and the on-radiation metal universal medication conjugate that comes labelling and have the tissue specificity ligand, and make through the radioactive label ligand and with its method in order to radiography and treated tissue specific diseases.
So, be necessary to provide a kind of radiochemistry to treat the chemical composition thing of usefulness, to solve the existing in prior technology problem.
[summary of the invention]
Main purpose of the present invention is to provide a kind of chemical composition thing of radiochemistry treatment usefulness, and it is the field about radiochemistry, nucleon radiography, the treatment of radiation nuclear species, drug development and chemosynthesis.Particular words more, it is about being used for the strategy of radioactive label target ligand.It is about using they to be used for the method for radiography, the treatment of radiation nuclear species and tissue specificity disease radiography through the radioactive label ligand in addition.
For reaching aforementioned purpose of the present invention, the invention provides a kind of chemical composition thing of radiochemistry treatment usefulness, it is characterized in that: the chemical composition thing of described radiochemistry treatment usefulness exist comprise with therapeutic or diagnostic ligand conjugation and according to circumstances with the constituent of metalchelated TA2S derivant, wherein said TA2S derivant has general formula:
A wherein
1, A
2, A
3And A
4Can be identical or different and be selected from by C
2-C
4Alkyl, C
2-C
4Thiazolinyl, C
2-C
4The group that alkynyl and any combination thereof are formed; And, (R wherein
1And R
3) or (R
2And R
4) wherein one identical or different and be hydrogen or dentate, and (R
1And R
3) or (R
2And R
4) another person is-(CH
2)
n-C (O)-R ', wherein each R ' group and other R ' groups are identical or different and be hydroxyl or dentate; And n=1-4 wherein.
In another embodiment of constituent, A
1, A
2, A
3And A
4Respectively be-(CH
2-CH
2)-group, and have following structure:
(R wherein
1With R
3) identical or different and be hydrogen or dentate, and (R
1' with R
2') identical or different and be dentate or hydroxyl, and n=1-4 wherein, and described TA2S derivant is the DO2S derivant.
In another embodiment, constituent has following structure:
(a) (R
1And R
3) be hydrogen and (R
1' with R
2') identical or different and be dentate or hydroxyl; Or, (b) (R
1And R
3) be dentate and (R
1' with R
2') identical or different and be dentate or hydroxyl; And described DO2S derivant is a DO2S derivant-1.
In an embodiment of DO2S derivant constituent, ligand is to be selected from the group who is made up of following each thing: hypertrophy targeting ligand, angiogenesis targeting ligand, tumor cell are carved the targeting ligand of dying, disease receptor target ligand, the ligand based on medicine, microorganism formulation, glucose imitation agent, the agent of hypoxia targeting, intercellular matrix (extracellular matrix) targeting ligand and any combination thereof.In an embodiment of DO2S derivant constituent, the DO2S derivant comprises at least one connexon in addition, and wherein said at least one connexon forms and makes described DO2S derivant and described conjugated connection of targeting ligand.In comprising the embodiment of at least one connexon, at least one connexon is to be selected from the group who is made up of following each thing: ethylenediamine, amido propanol, two stretch ethyl triamine, Radix Asparagi amino acid, poly-Radix Asparagi amino acid, glutamic acid, poly-glutamic acid, from amino acid, Polyethylene Glycol and any combination thereof.In an embodiment of DO2S derivant constituent, ligand is to be selected from the group who is made up of following each thing: glycosamine, tetracetate mannose, octreotide (octreotide), Hedgehog ligand, EGFR targeted molecular, nucleotide, nucleoside, cholesterol, estradiol, how rice granule, nano carbon tubes and any combination thereof.In an embodiment of DO2S derivant constituent, ligand is an anticancer compound.In an embodiment of DO2S derivant constituent, ligand is a carbohydrate.In an embodiment of DO2S derivant constituent, make DO2S derivant and metallics chelating.With an embodiment of the DO2S derivant constituent of metallics chelating in, metallics is copper, cobalt, platinum, ferrum, arsenic, rhenium or germanium.With an embodiment of the DO2S derivant constituent of metallics chelating in, metallics is the radiation nuclear species.With an embodiment of the DO2S derivant constituent of radiation nuclear species chelating in, the radiation nuclear species is
45Ti,
59Fe,
60Cu,
61Cu,
62Cu,
64Cu,
67Cu,
67Ga,
68Ga,
89Sr,
90Y,
94MTc,
99MTc,
111In,
149Pm,
153Gd,
153Sm,
166Ho,
177Lu,
186Re,
188Re,
211At,
212Bi or
225Ac.In another embodiment, the radiation nuclear species is
68Ga or
177Lu.In an embodiment of DO2S derivant constituent, ligand comprises medicine.
[specific embodiment]
For allowing above-mentioned purpose of the present invention, feature and advantage become apparent, preferred embodiment of the present invention cited below particularly is described in detail below:
As used herein, " one " comprises odd number and plural number and means one or more than one.For example, " ligand " means a ligand or an above ligand.
In the field of nucleon medical science, the particular pathologies situation is through the location, or assesses its degree, its be by detect a small amount of inner throw and radioactive labeled tracer compounds's's (being called radioactive indicator or radiopharmaceutical) distribution.Detect these radiopharmaceutic methods and generally be known as radiography or pneumoradiography method.
" alkyl " is meant saturated aliphatic hydrocarbon, and it comprises straight chain, side chain and cyclic alkyl.Alkyl can comprise any combination of non-annularity and ring-type time unit.In addition, term " alkyl " clearly means and wherein has single bonded non-side chain or side chain hydrocarbon chain as used in this article.Described alkyl can be substituted or be unsubstituted.When being substituted, substituent group can be hydroxyl, cyano group, alkoxyl ,=O ,=S ,-NO
2,-N (CH
3)
2, amido or-SH.Alkyl is preferable to have 1 to 12 carbon.It is more preferred from the low-carbon alkyl with 1 to 7 carbon, better 2 to 4 carbon, and it is better to be to be selected from by-CH
2-CH
2-,-CH
2-CH
2-CH
2-and-CH
2-CH
2-CH
2-CH
2The group of-composition.
" thiazolinyl " means non-side chain or the side chain hydrocarbon chain that wherein has one or more pair key." thiazolinyl " can be unsubstituted or replace through one or more group.When being substituted, substituted radical can be hydroxyl, cyano group, alkoxyl, chloro, bromo, iodo, amido, mercapto (thiolo).Thiazolinyl is preferable to have 2 to 4 carbon, better be selected from by-CH=CH-,-CH2-CH=CH-,-CH=CH-CH
2-,-CH
2-CH=CH-CH
2The group that ,-CH=CH-CH-CH-forms.Term " thiazolinyl " comprises the group such as pentenyl, hexenyl, pentadienyl, hexadienyl.
" alkynyl " means non-side chain or the side chain hydrocarbon chain that wherein has one or more ginseng key." alkynyl " can be unsubstituted or replace through one or more group.When being substituted, substituted radical can be hydroxyl, cyano group, alkoxyl, chloro, bromo, iodo, amido, mercapto (thiolo).Alkynyl is preferable to have 2 to 4 carbon, better be selected from by-C ≡ C-,-CH
2-C ≡ C-,-C ≡ C-CH
2-,-CH
2-C ≡ C-CH
2,-C ≡ C-CH=CH
2The group of-composition.Term " alkynyl " comprises the group such as pentynyl, hexin base, pentadiine base, hexadiine base.
As used herein, speech " chemical compound " means free chemical molecular entity or chemical part, that is than the part of macromole entity.Therefore, for example when mentioning that the targeting ligand is anticancer compound, anticancer compound part and the free anticancer compound of incorporating in the big chemical entities contained in described language.
Speech " conjugation " is reached " through conjugation " herein and be defined as chemical bond in same molecular.For example, two or more molecules and/or atom can form single molecule by the covalent bond conjugation together.Two molecules can come each other conjugation or chemical compound to come conjugation by connecting (for example, wherein two chemical compounds and one or more connexon covalent bonding form single molecule) indirectly by directly connecting (for example, wherein chemical compound directly connects by covalent bond).In other cases, metallic atom can interact and molecular conjugation by chelating.
In an aspect of the present invention, have therapeutic and/or diagnostic constituent, described constituent comprises and conjugated four nitric heterocyclic compounds of ligand (or any as hereinafter defined subgenus), described four nitric heterocyclic compounds according to circumstances with the metallics chelating.Ligand can be medicine or target biology molecule or other treatment or diagnostic ligand.Four nitric heterocyclic compounds are defined as the chemical compound that comprises following structure herein:
A wherein
1, A
2, A
3And A
4Can be identical or different and be to be selected from by C
2-C
4Alkyl, C
2-C
4Thiazolinyl, C
2-C
4The group that alkynyl and any combination thereof are formed; And, (R wherein
1-R
4) identical or different and be hydrogen or following group :-(CH
2)
n-C (O) OR ', n=1-4 wherein, wherein OR ' is to form the protecting group of therapeutic and/or diagnostic constituent through the dentate displacement.At (R
1-R
4) any given R group be not under the situation of hydrogen, R group position be called be substituted.When three R groups are hydrogen and a R group when being non-hydrogen, chemical compound is single the replacement.When two R groups are hydrogen and other two R groups when being non-hydrogen, chemical compound is two replacements, etc.Preferably; being substituted by identical and R ' is to be selected from the group who is made up of following each group: methyl; the 2-chloroethyl; the 2-bromoethyl; 2-iodine ethyl; ethyl; pi-allyl; heptyl; 2-N-(morpholinyl) ethyl; 2; 2; the 2-trifluoroethyl; 2; 2; 2-three chloroethyls; the 2-cyano ethyl; ω-chlorine alkyl; tributyl; benzyl; benzhydryl (benzhydryl); benzoyl group (phenacyl); to bromophenyl acyl; the Alpha-Methyl benzoyl group; to the methoxybenzene acyl group; acetone alcohol radical (acetol); the phenyl acetoxy-methyl; desyl,a-phenyl phenacyl (desyl); benzhydryl; 1; 3-dithiane base-2-methyl; adjacent nitrobenzyl; to nitrobenzyl; the carboxamide groups methyl; to diphenyl diimide carboxamide groups methyl; N-phthalimide ylmethyl; TMS; triethyl silyl; the tri isopropyl silane ylmethyl; the tri isopropyl silane base; tributyl diphenyl silane base; the tributyl dimethylsilyl; the isopropyl dimethylsilyl; the phenyl dimethylsilyl; two-Di tributyl-methyl phosphonium silylation; cyano methyl; methoxy; methoxy ethyl; the 'beta '-methoxy ethoxyl methyl; methylthiomethyl; methylmercaptoethyl; to (methyl mercapto) phenyl; benzyloxymethyl; tetrahydrofuran base; the tetrahydrochysene piperazine base of muttering; pivaloyl oxygen methyl; phenyl; 2-(TMS) ethoxyl methyl; TMS; 2-(TMS) ethyl; 2-(p-toluenesulfonyl) ethyl; 2-(p-nitrophenyl sulfenyl) ethyl; 2-(2 '-pyridine radicals) ethyl; 2-(to methoxyl group-phenyl) ethyl; 1-methyl isophthalic acid-phenylethyl; 2-(4-acetyl group-2-nitrobenzophenone) ethyl; 3-methyl-3-amyl group; bicyclic methyl propyl; 2; 4-dimethyl-3-amyl group; cyclopenta; cyclohexyl; 2-methyl fourth-3-alkene-2-base; 3-methylbut-2-prenyl; 3-butene-1-Ji; 4-(TMS)-2-butylene-1-base; Cortex cinnamomi japonici (Ramulus Cinnamomi) base (cinnamyl); Propargyl; 2; the 6-3,5-dimethylphenyl; 2; the 6-diisopropyl phenyl; 2; 6-two tributyl monomethyl phenyl; 2; 6-2 the tributyls-4-methoxyphenyl; pentafluorophenyl group; trityl; two-(ortho-nitrophenyl methyl); 9-anthryl methyl; 2-(9; 10-two side oxygen bases) anthryl methyl; 5-benzocyclohepta base (5-benzosuberyl); 1-pyrenyl methyl; 2-(trifluoromethyl)-6-chromone ylmethyl; 2; 4; the 6-trimethyl benzyl; to bromobenzyl; to methoxy-benzyl; 4-(methylsulfinyl) benzyl; 4-sulfo group benzyl; 4-nitrilo-the methoxy-benzyl that changes; 4-{N-[1-(4; 4-dimethyl-2,6-two side oxygen basic ring hexylidenes)-the 3-methyl butyl]-amido } benzyl; Helianthi base (piperonyl); 4-picolyl (4-picolyl); to benzyl; 9-Fluorene ylmethyl; methacrylic (methallyl); Alpha-Methyl Cortex cinnamomi japonici (Ramulus Cinnamomi) base and any combination thereof.Four nitric heterocyclic compounds partly are characterised in that and have four nitrogen-atoms and also can be described as the N4 chemical compound in a loop systems.At chemical formula-(CH
2)
nAmong-C (O) OR ', should be appreciated that oxygen atom in the bracket for by the ketonic oxygen of two keys with the adjacent carbons bond, and other oxygen atoms be by singly-bound and identical carbon atoms and with R ' group bond, thereby the formation ester group.When having an above protecting group, R ' group can be identical or different.OR ' is to form the protecting group of therapeutic and/or diagnostic constituent through the dentate displacement.Therefore, term " with conjugated four nitric heterocyclic compounds of ligand " means has in metathetical its OR ' group of dentate one or many persons' four nitric heterocyclic compounds, or if four nitric heterocyclic compounds have all R for hydrogen
1-R
4, then described wait in the hydrogen one or many persons replace through dentate.
In some embodiment of constituent, A
1, A
2, A
3And A
4Respectively be-(CH
2-CH
2)-group and described TA2S derivant are the DO2S derivant.The DO2S derivant is a compounds and is the subgenus of TA2S derivant.Term " with the conjugated DO2S derivant of ligand " means it and is with one or more OR '
1Or OR '
2Group or its one or more hydrogen are through the metathetical DO2S derivant of dentate (reference is structure hereinafter).
Contain the DO2S derivant and with the universal architecture of the conjugated DO2S derivant of ligand be as follows:
Wherein n=1-4 and (a) (R
1And R
3) be hydrogen and (R '
1With R '
2) identical or different and be dentate or hydroxyl; Or (b) (R
1With R
3) identical or different and be dentate or hydrogen and (R '
1With R '
2) identical or different and be dentate or hydroxyl.
In some embodiment of DO2S derivant, R
1And R
3Be hydrogen, n=1, and described DO2S derivant is a DO2S derivant-1.DO2S derivant-1 is a compounds and is the subgenus of DO2S derivant.Contain DO2S derivant-1 and with the universal architecture of the conjugated DO2S derivant-1 of ligand be following (R '
1And R '
2As defined above):
DO2S derivant-1 is a compounds and is the subgenus of DO2S derivant.Four nitric heterocyclic compounds can comprise and targeting ligand (passing through covalent bond) and/or connexon (passing through covalent bond) and/or the conjugated DO2S chemical compound of metallo-chelate (interacting by chelating).DO2S and DO2S derivant-1 are the subgenus of four nitric heterocyclic compounds; The DO2S derivant is the subgenus of four nitric heterocyclic compounds.Four nitric heterocyclic compounds as herein described, TA2S derivant and DO2S derivant are huge ring of the present invention (huge cycle compound) when being used for constituent of the present invention, method and cover group.
In other aspects of the present invention, above constituent is used for preparing diagnostic or therapeutic constituent.Diagnostic or therapeutic constituent comprise the cover group that is applicable to the treatment or the diagnostic medicine patient's condition.It below is the limiting examples of the various embodiment of cover group.In the preferred embodiment of cover group, constituent is and metalchelated DO2S derivant.Metal is the radiation nuclear species in certain embodiments.The example of radiation nuclear species is
45Ti,
59Fe,
60Cu,
61Cu,
62Cu,
64Cu,
67Cu,
67Ga,
68Ga,
89Sr,
90Y,
94MTc,
99MTc,
111In,
149Pm,
153Gd,
153Sm,
166Ho,
177Lu,
186Re,
188Re,
211At,
212Bi or
225Ac.The radiation nuclear species is preferably
68Ga or
177Lu.The cover group can comprise in addition such as vitamin C, 2, the antioxidant of 5-protocatechuic acid, tocopherol, pyridoxol, thiamine or rutacultin.The cover group can comprise the conversion chelating agen, stretches second pentaacetic acid or ethylenediaminetetraacetic acid such as gluceptate, gluconate, glucarate, citrate, tartrate, DOTA, two.The cover group can comprise Reducing agent, such as stannic chloride (II) or triphenyl phasphine.Ligand can be the cancer target ligand.Other examples of ligand include, but is not limited to hypertrophy targeting ligand, angiogenesis targeting ligand, tumor cell carving die targeting ligand, disease receptor target ligand, be that ligand, microorganism formulation, the glucose of basic Chu imitated agent, the agent of hypoxia targeting, intercellular matrix targeting ligand and any combination thereof with medicine.The cover group can comprise at least one connexon in addition, and wherein said at least one connexon forms and makes described DO2S derivant and described conjugated connection of targeting ligand.The limiting examples of at least one connexon comprise ethylenediamine, amido propanol, two stretch ethyl triamine, Radix Asparagi amino acid, poly-Radix Asparagi amino acid, glutamic acid, poly-glutamic acid, from amino acid, Polyethylene Glycol and any combination thereof.Other limiting examples of ligand comprise glycosamine, tetracetate mannose, octreotide, glass alduronic acid, Hedgehog ligand, EGFR targeted molecular, nucleotide, nucleoside, cholesterol, estradiol, how rice granule, nano carbon tubes and any combination thereof.In certain embodiments, ligand is an anticancer compound.In certain embodiments, ligand is a carbohydrate.
As used herein, term " radiation nuclear species " is defined as radioactivity nuclear species (a kind of atom that can exist and distinguish with the quantum state of electric charge, quality, number and nuclear with the scalable life-span), and it is fissioned with emission corpuscular radiation or electromagnetic radiation in a particular embodiment.Described term can exchange with term " radiosiotope " and use.
As used herein, term " therapeutic agent " is defined as the medicament that disease or medical condition is provided treatment.The medicament improvement disease in the specific embodiment or at least one symptom or the parameter of medical condition.For example, in oncotherapy, therapeutic agent reduces the size of tumor, the growth or the transfer of inhibition or prophylaxis of tumours, or eliminate tumor.Example comprises medicine, such as cancer therapy drug, gene therapy constituent, radiation nuclear species, hormone, nutritional drugs or its combination.Therapeutic agent can be on four nitric heterocyclic compounds or TA2S or DO2S derivant on ligand.
As used herein, term " tumor " is defined as uncontrolled and the carrying out property growth of cell in the tissue.Those who familiarize themselves with the technology understands other synonymous terms of existence, such as tumor or malignant tumor.In a specific embodiment, tumor is an entity tumor.In other specific embodiments, tumor originates from the cancer of (former or be transfer form) following organ: such as liver, prostate, pancreas, head and neck, breast, brain, colon, gland sample thing (adenoid), mouth, skin, Fei, testis, ovary, cervix uteri, endometrium, bladder, stomach and epithelium.
As used herein, term " medicine " is defined as helps treatment disease or medical condition, or control or the improvement any physiology relevant with disease or medical condition or the chemical compound of the pathology patient's condition.
As used herein, term " cancer therapy drug " is defined as the medicine of treatment cancer (such as entity tumor).The preferable size that reduces tumor of cancer therapy drug, the growth of inhibition or prophylaxis of tumours or transfer and/or elimination tumor.Term " cancer therapy drug " reaches " anticancer compound " and is used interchangeably in this article.
Used in description as this paper, " one " can mean one or more.Used in claim as this paper, when bluebeard compound " comprised " use, speech " " can mean one or more.As used herein, " another " can mean at least the second or more than.
The invention provides a method, can make four nitric heterocyclic compounds (or any subgenus as defined herein) and medicine or biomolecule conjugation can be used for comprising the compounds of radiography and radiocurable purpose with generation for chelating agen by it.Four nitric heterocyclic compounds are preferably TA2S, are more preferred from the DO2S derivant, and the best is a DO2S derivant-1.Being used for its synthetic chemical compound and initial substance can be from (Dallas, commercial sources TX) obtains such as Macrocyclics.United States Patent (USP) 5,880,281 descriptions are made the method for the huge cycle compound of specific four azepines and are to incorporate into by reference, as be disclosed in herein comprehensively.During remaining is discussed at this paper, anywhere mention in the following one or any one of many persons: TA2S derivant, 3 1) four nitric heterocyclic compounds, 2)) DO2S derivant, or 4) DO2S derivant-1, described discussion all also are applicable to and are interpreted as being applicable in other above-mentioned groups of chemical compound any one.Four nitric heterocyclic compounds, TA2S derivant and DO2S derivant all are huge ring.
Four nitric heterocyclic compounds (with and any subgenus or material) can be used as chelating agen.For example, test wrapper draws (cyclam) and other four nitric heterocyclic compounds to alleviate the ability of acute cadmium poisoning (people such as Srivastava, 1996).United States Patent (USP) 4,141,654 to describe to be the specific compound that has structural similarity with four nitric heterocyclic compounds of element ion in order to the chelating actinium.United States Patent (USP) 5,648,063 discloses the chemical compound that has structural similarity with four nitric heterocyclic compounds, but its chelated metal ions and also can be used in the specific NMR diagnotor.United States Patent (USP) 6,071,490 utilize the stupefied amine of modified ring (cyclen) to carry out the PET radiography.United States Patent (USP) 6,613,305 disclose the vitamin B12 that is connected with various four nitric heterocyclic compounds.
The invention provides the constituent that is used for tissue specificity disease radiography and treatment.Constituent of the present invention generally comprises by the diagnostic radiation nuclear species (described four nitric heterocyclic compounds are preferably the DO2S derivant and are more preferred from DO2S derivant-1) of four nitric heterocyclic compound chelatings and and the conjugated tissue specificity ligand of four nitric heterocyclic compounds.In a preferred embodiment, four nitric heterocyclic compounds are DO2S derivant-1, and the tissue specificity ligand by in its sour arm (acid arm) one or both and/or secondary amine in one or both and DO2S derivant-1 conjugation.Four nitric heterocyclic compounds form coordinate bond with the radiation nuclear species.As used herein, term " conjugate " is meant covalency bond chemical compound.When a part and another part conjugation, there is the covalent bond that connects two parts.
DO2S derivant (preferred compounds of the present invention) and DO2S derivant-1 (optimization compound of the present invention) are four azepine ligands.These chemical compounds and transition metal ions and lanthanum are that element forms stabilizer pole misfit thing.With multiple radiation nuclear species, comprise
64/67Cu,
67/68Ga,
86/90Y,
111In reaches
177Lu comes these chelating agen of labelling.Also showed huge ring with
99MTc forms stabilizer pole misfit thing based on side Yang Ji Technetium (oxotechnetium) group to effective combination of three amine-nitrogen-atoms.
Four nitric heterocyclic compounds are used for chelating and have been used for the multiple radiation nuclear species that diagnostic is used.In these persons, 68Ga base PET medicament (t1/2=68min, β +=89% and EC=11%) has important research and clinical potentiality because isotope can by
68Ge/
68Ga generator (t1/2=271 days) scene is made and is provided based on the isotopic facility of the PET of cyclotron and substitutes.The short-half-life of 68Ga allows to have the application of suitable radiant, simultaneously patient dose is remained on acceptable level.In addition,
68Ga
3+Cation can form as the ligand of executing the body atom and stablizes the misfit thing with many aerobic, nitrogen and sulfur of containing, and makes it be applicable to and multiple chelating agen and macromole misfit.
The targeting ligand is for when in introducing mammal or the patient's body, with especially with the chemical compound of the tissue bond of particular type.Envision constituent of the present invention and can comprise in fact any known tissue specific compound.The tissue specificity ligand of using in conjunction with the present invention is preferable will to be anticarcinogen, DNA topoisomerase enzyme inhibitor, antimetabolite, tumor marker, folate receptor targeting ligand, tumor carving die cell-targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, nucleotide, organ specificity ligand, antibacterial, such as antibiotic or antifungal, glutamic acid pentapeptide or imitate the medicament of glucose.Also can will imitate the medicament of glucose to be called " sugar ".
Preferable anticarcinogen comprises the methylamine petrin, amycin (doxorubicin), tamoxifen (tamoxifen), paclitaxel (paclitaxel), topotecan (topotecan), LHRH, ametycin, etoposide (etoposide), appropriate wonderful moral scholar (tomudex), podophyllotoxin (podophyllotoxin), mitoxantrone (mitoxantrone), camptothecine (camptothecin), colchicine (colchicine), endostatin (endostatin), fludarabine (fludarabin) and gemcitabine (gemcitabine).Preferable tumor marker comprises PSA, ER, PR, AFP, CA-125, CA-199, CEA, interferon, BRCA1, cyclophosphamide (cytoxan), p53, VEGF, integration element, endostatin, HER-2/neu, EGF, Hedgehog molecule, antisense labelling or monoclonal antibody.Envision any other known cancer labelling, therapeutic peptide, antibody fragment or any monoclonal antibody in conjunction with use of the present invention all with effectively.Preferable folate receptor targeting ligand comprises folate, methylamine petrin and appropriate wonderful moral scholar.Die cell or tumor hypoxia targeting ligand of preferable tumor carving comprises annexin V (annexin V), colchicine, nitroimidazole, mitomycin or metronidazole (metronidazole).Preferable antibacterial comprises Ampicillin (ampieillin), amoxicillin (amoxicillin), penicillin (penicillin), cephalosporin (cephalosporin), clindomycin (clidamycin), only big mycin (gentamycin), kanamycin (kanamycin), neomycin (neomycin), natamycin (natamycin), nafcillin (nafcillin), rifampicin (rifampin), tetracycline (tetracyclin), vancomycin (vancomycin), bleomycin (bleomycin) and be used for deoxidation hydroxytetracycline (doxycyclin) and two property mycin B (amphotericin B) of gram (gram) positive and negative bacteria, amantadine (amantadine), nystatin (nystatin), ketoconazole (ketoconazole), polymycin (polymycin), acyclovir (acyclovir), and be used for the ganciclovir (ganciclovir) of fungus.Imitate the preferable medicament of glucose, or steamed bun stuffed with sugar is drawn together neomycin, kanamycin, only big mycin, paromomycin (paromycin), amikacin (amikacin), tobramycin (tobramycin), anti-speciomycin (netilmicin), ribostamycin (ribostamycin), uncommon rope mycin (sisomicin), micronomicin (micromicin), lividomycin (lividomycin), dibekacin (dibekacin), isepamicin (isepamicin), astromicin (astromicin), amido glucosides, glucose or glycosamine.
In certain embodiments, to be necessary between following each thing, to comprise connexon: TA2S derivant 1) four nitric heterocyclic compounds, 2), or 3) DO2S derivant (in the present invention, any one or combination can be served as huge ring and be can be described as huge ring among these three groups) is with the tissue specificity ligand.Usually with connexon in order to increase the drug solubility in the aqueous solution and the variation of minimum medication affinity.In fact all can be used in combination with the present invention although anticipation increases the water miscible any connexon of constituent, connexon generally will be poly-amino acid, water-soluble peptide, single amino acid or Polyethylene Glycol.For example, functional group on tissue specificity ligand or medicine, for aliphatic series or phenol be-during OH (such as estradiol, topotecan, paclitaxel, raloxifene or etoposide), connexon can be poly-glutamic acid, and (MW about 750 to about 15,000), (MW about 2 for poly-Radix Asparagi amino acid, 000 to about 15,000), bromoethyl acetate (bromo ethylacetate), glutamic acid or Radix Asparagi amino acid.When the medicine functional group is that aliphatic series or aromatics-NH2 or peptide are when (such as in amycin, ametycin, endostatin, annexin V, LHRH, octreotide and VIP), connexon can be poly-glutamic acid, and (MW about 750 to about 15,000), (MW about 2 for poly-Radix Asparagi amino acid, 000 to about 15,000), glutamic acid or Radix Asparagi amino acid.When the medicine functional group is carboxylic acid or peptide when (such as in methylamine petrin or folic acid), connexon can be ethylenediamine or from amino acid.
Inventor of the present invention has also found second portion is combined with polypeptide, such as organizing targeting moiety, therapeutic part or radiography part, makes medicament be applicable to multi-modal radiography or radiochemistry treatment.This conjugation reaction can (for example) carry out under aqueous or organic solvent condition.The misfit of metal ion and polypeptide improves the medicament water solublity and medicament be can be used in contrast intensification's target radiography.
Although be used for the preferable radiation nuclear species of radiography be
68Ga, but envision other radiation nuclear species also can with TA2S or DO2S derivant-tissue specificity ligand conjugate, or TA2S of the present invention or DO2S derivant-drug conjugate chelating are especially as therapeutic agent.For example, being suitable for the therapeutic radiation nuclear species is
59Fe,
67Ga,
89Sr,
90Y,
111In,
149Pm,
153Gd,
153Sm,
166Ho,
177Lu,
186Re reaches
188Re, wherein
177Lu is best.The constituent that contains these therapeutic radiation nuclear species is applicable to radiation nuclear species treatment target is passed to specific pathological changes in the body, (for example uses such as breast carcinoma, ovarian cancer, carcinoma of prostate
177Lu-DO2S derivant-folate) and head and neck cancer (for example use
177The Lu-DO2S derivant-EGFR).
Specific embodiment of the present invention comprises
68Ga/
177Lu-DO2S derivant-glucose,
68Ga/
177Lu-DO2S derivant-glycosamine,
68Ga/
177Lu-DO2S derivant-tetracetate mannose,
68Ga/
177Lu-DO2S derivant-EGF,
68Ga/
177Lu-DO2S derivant-octreotide,
68Ga/
177Lu-DO2S derivant-hedgehog ligand,
68Ga/
177Lu-DO2S derivant-estradiol
68Ga/
177Lu-DO2S derivant-glutamic acid pentapeptide,
68Ga/
177Lu-DO2S derivant-oligonucleotide,
68Ga/
177Lu-DO2S derivant-amido glucosides,
68Ga/
177Lu-DO2S derivant-Nai Mi granule,
68Ga/
177Lu-DO2S derivant-nano carbon tubes.
The present invention provides the synthetic method through the huge ring-drug conjugate of radioactive label that is used for diagnostic or therapeutic use in addition.For example, described method comprises that obtaining tissue specificity ligand, the described ligand of mixing and DO2S derivant mixes DO2S derivant-tissue specificity ligand derivant and radiate nuclear species to obtain through radioactive label DO2S derivant-tissue specificity ligand derivative to obtain DO2S derivant-tissue specificity ligand derivant, to reach.Make radiation nuclear species and TA2S or DO2S derivant chelating by nitrogen and oxygen atom by coordinate bond.As mentioned above, make the tissue specificity ligand directly or one or two sour arm conjugation by connexon and TA2S or DO2S derivant, and/or direct or by connexon and one or two amido conjugation.Optionally, such as under the situation of 99mTc and 188Re, Reducing agent (preferable hydrosulfurous acid salt ion (dithionite ion), stannous ion or ferrous ion) is used for radioactive label.
The present invention provides labelling to be used for the method for the tissue specificity ligand of diagnostic, therapeutic or prognostic purposes in addition.Labeling method may further comprise the steps: obtain the tissue specificity ligand, mix described tissue specificity ligand and huge ring obtaining huge ring-ligand drug conjugate, and make drug conjugate and
68Ga or
177Lu reaction with huge ring with
68Ga or
177Form coordinate bond between the Lu.
For reaching the purpose of this embodiment, the tissue specificity ligand can be in the ligand above-mentioned or discussed in this article any one.For
99MTc reaches
188The required Reducing agent of Re can be any known Reducing agent, but preferablely will be hydrosulfurous acid salt ion, stannous ion or ferrous ion.
In another embodiment, the invention provides in mammalian body is the method for a position radiography.Angiographic method may further comprise the steps: throw the constituent through radioactive label DO2S derivant-tissue specificity ligand conjugate of comprising with the efficient diagnosis amount, and detecting is from the radiated signal of the radioactive indicator that is positioned described position.The detecting step will be usually carried out after constituent being introduced in the mammalian body in about 10 minutes to about 4 hours.Detecting step the best will be in injection
68Ga constituent about 1 hour afterwards, or in injection
177The Lu constituent carried out in mammalian body afterwards in 24 hours.
In some preferred embodiment, the position will be infection, tumor, heart, lung, brain, liver, spleen, pancreas, intestinal or any other organ.Tumor or infect can be positioned at mammalian body any one, but generally will be at breast, ovary, prostate, endometrium, lung, brain, colon or liver.The position also can be folate positive carcinoma or estrogen positive carcinoma.
The present invention also is provided for preparing the cover group of radiopharmaceuticals preparation.Described cover group generally comprises sealed vial or sack, or the appropriate containers of any other kind, and it contains the TA2S of scheduled volume or DO2S derivant-tissue specificity ligand conjugate constituent with required radiation nuclear species labelling conjugate.In some cases, huge ring-tissue specificity ligand conjugate constituent also will be included in the connexon between huge ring and the tissue specificity ligand.The tissue specificity ligand can be and the bonded any ligand of any particular tissue type (all they persons as discussed in this article) specificity.When comprising connexon in the constituent, described connexon can be any as described herein connexon.
The component of cover group can be any appropriate format, such as liquid, freezing or dry form.In a preferred embodiment, provide cover group component with lyophilized form.The cover group also can comprise antioxidant and/or conversion chelating agen.Antioxidant can be any known antioxidants but is preferably vitamin C.Also can provide the conversion chelating agen to radiate nuclear species in conjunction with unreacted.Most of commercially available cover group contains gluceptate as the conversion chelating agen.Yet, gluceptate not with typical case's cover group component complete reaction, stay about 10-15% material.This residue gluceptate will arrive tumor and make radiography deflection as a result.Therefore, the preferable use of inventor DTPA, EDTA or DOTA are as the conversion chelating agen, because it is cheap and reaction is more complete.
Another aspect of the present invention is to be used to measure the prognostic method that candidate compound is treated the potential utility of specific tumors.At present, in chemotherapy, treat most of tumor, and in several months subsequently and spent before thousands of dollars, no anyly effectively indicate described specific tumors is whether actual about described medicine with " common selected medicine (usual drug of choice) ".Radiography constituent of the present invention is applicable to certain drug is passed to tumor locus with the form through the huge ring-drug conjugate of labelling, and then in a few hours for described position radiography to measure certain drug and whether be absorbed and to keep.
Given this, prognostic method of the present invention may further comprise the steps: to measure tumor locus, to reach to body of mammals throwing and constituent with the conjugated huge ring of tumor particular cancers chemotherapeutic agent material standed for is that described position radiography is to measure the effectiveness of drug candidate to tumor.The radiography step is carried out in about 10 minutes to about 4 hours after constituent being injected in the mammalian body usually.The radiography step is preferable carries out in about 1 hour after constituent being injected in the mammalian body.
Treat with the prognostic constituent in the conjugated cancer chemotherapeutic drug candidates of huge ring optional from known or still untapped cancer chemotherapeutic medicine.Known these medicines of general technology person.There are many known anticarcinogen specific to some types of cancer.Yet, be not each to be used for the anticarcinogen of specific types of cancer all effective each patient.Therefore, the invention provides the method for the possible effectiveness of the preceding mensuration drug candidate in treatment in consumption plenty of time and money.
Another embodiment of the present invention is the reagent that is used to prepare scintigraphy art contrast agent.Reagent of the present invention comprises the tissue specificity ligand, and it has the affinity that is enough to produce the image that can detect with the scintigraphy art to target site in vivo, and it is covalently bound to radiating the nuclear species bound fraction.Radiation nuclear species bound fraction is directly connected in the tissue specificity ligand or is connected in ligand by aforesaid connexon.Radiation nuclear species bound fraction is preferably four nitric heterocyclic compounds.For example, the tissue specificity ligand can be directly or is covalently attached to one or two sour arm of TA2S derivant or DO2S derivant by connexon, and/or directly or by aforesaid connexon be covalently attached in the secondary amine one or both.The tissue specificity ligand can be as mentioned above in the ligand any one.
Two main purposes of the general service of suitable bifunctional chelants: 1) coordination radioactive metal and 2) provide and to modify to be connected to the molecular backbone of target biology molecule through the functional group.The conjugation of radioactive metal chelating agen can be applicable to following multiclass chemical compound.In certain embodiments, can then use device of the present invention to come these follow-up bioconjugates of radioactive label, to produce the radioactive indicator of final form by automatization's synthesis flow.
Can be in order to target tumor (for example with TA2S derivant or DO2S derivant, carcinous, property precancer, optimum), tumor-blood-vessel growth, hypoxia, cell carving (for example die defective, disease receptor, the cell receptor of indication cancer), function of diseases approach (for example, the metabolic pathway that has changed because of the disease patient's condition) and disease cell cycle.In addition, TA2S derivant or DO2S derivant can be used for assessing the effectiveness of pharmaceutical reagent to these biochemical processes.
TA2S derivant or DO2S derivant also can be used as diagnostic tool and/or are used to predict the reaction that some kind is treated.For example, the conjugate of TA2S derivant or DO2S derivant and tamoxifen (estrogen receptor targeting ligand) can be in order to the radiography cancerous tumour; In this example, radiography can provide the important information about disease, such as the cancerous cell performance degree that estrogen receptor reached, it can will be how (for example be reacted to the treatment of the cell of targeting performance estrogen receptor in order to the prediction disease, when identification cancerous tumour selectivity performance high-load estrogen receptor, this information shows that cancerous cell may react to the anticarcinogen of the cell of the targeting performance estrogen receptor of therapeutic dose).The method is called " image-guided treatment (image guided therapy) ".
Make TA2S derivant or DO2S derivant and tissue target be that to the conjugated advantage of ligand tissue target can concentrate emission signal on the zone of being paid close attention to the specificity binding characteristic of ligand.The derivant that anticipation is used for radiography and/or treatment can comprise with through being designed to conjugated TA2S derivant of targeting ligand or the DO2S derivant that targeting cancerous tumour, precancer tumor, disease receptor, hypoxia tissue (hypoxia), cell are carved die approach, disease cell cycle and/or function of diseases approach.TA2S derivant or DO2S derivant also can be used for assessing the effectiveness of pharmaceutical reagent to various metabolism and/or bio-chemical pathway or indivedual reactions.In certain embodiments, cancer therapy drug can be used as the targeting ligand.In this technology, know cancer therapy drug (for example Connors, 1996).For example, United States Patent (USP) 6,692, the tabular in 724 goes out some examples of the cancer therapy drug that can be used as the targeting ligand in various embodiments of the invention.United States Patent (USP) 6,692,724th is incorporated into by reference, as being disclosed in herein fully.
The present invention is described by above-mentioned related embodiment, yet the foregoing description is only for implementing example of the present invention.Must be pointed out that disclosed embodiment does not limit the scope of the invention.On the contrary, being contained in the spirit of claims and the modification and impartial setting of scope is included in the scope of the present invention.
Claims (9)
1. the chemical composition thing of radiochemistry treatment usefulness is characterized in that: described chemical composition thing comprise with therapeutic or diagnostic ligand conjugation and according to circumstances with metalchelated TA2S derivant, wherein said TA2S derivant has general formula:
A wherein
1, A
2, A
3And A
4Can be identical or different, and be to be selected from by C
2-C
4Alkyl, C
2-C
4Thiazolinyl, C
2-C
4The group that alkynyl and any combination thereof are formed; And (R wherein
1And R
3) or (R
2And R
4) wherein one identical or different and be hydrogen or dentate, and (R
1And R
3) or (R
2And R
4) another person then be-(CH
2)
n-C (O)-R ', wherein each R ' group and other R ' groups are identical or different and be hydroxyl or dentate; Reach wherein n=1-4.
2. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 1 is characterized in that: A
1, A
2, A
3And A
4Respectively be-(CH
2-CH
2)-group and have following structure:
(R wherein
1And R
3) be hydrogen, and (R
1' with R
2') identical or different and be dentate or hydroxyl; And described DO2S derivant is a DO2S derivant-1.
3. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 1 is characterized in that: A
1, A
2, A
3And A
4Respectively be-(CH
2-CH
2)-group and have following structure:
(R wherein
1And R
3) be dentate, and (R
1' with R
2') identical or different and be dentate or hydroxyl; And described DO2S derivant is a DO2S derivant-1.
4. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 1 is characterized in that: described ligand is to be selected from the group who is made up of following each thing: hypertrophy targeting ligand, angiogenesis targeting ligand, tumor cell are carved the targeting ligand of dying, disease receptor target ligand, the ligand based on medicine, microorganism formulation, glucose imitation agent, the agent of hypoxia targeting, intercellular matrix targeting ligand and any combination thereof.
5. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 1, it is characterized in that: described DO2S derivant comprises at least one connexon in addition, and wherein said at least one connexon forms and makes described DO2S derivant and described conjugated connection of targeting ligand.
6. the chemical composition thing of radiochemistry as claimed in claim 1 treatment usefulness is characterized in that: described at least one connexon is to be selected from the group who is made up of following each thing: ethylenediamine, amido propanol, two stretch ethyl triamine, Radix Asparagi amino acid, poly-Radix Asparagi amino acid, glutamic acid, gather glutamic acid, from amino acid, Polyethylene Glycol and any combination thereof.
7. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 1, it is characterized in that: described DO2S derivant is and the metallics chelating.
8. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 7, it is characterized in that: described metallics is copper, cobalt, platinum, ferrum, arsenic, rhenium or germanium.
9. the chemical composition thing of radiochemistry treatment usefulness as claimed in claim 8 is characterized in that: described metal species is the radiation nuclear species.
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|---|---|---|---|---|
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2010
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|---|---|---|---|---|
| CN117088825A (en) * | 2023-10-12 | 2023-11-21 | 成都威斯津生物医药科技有限公司 | Ionizable lipid, pharmaceutical composition containing same and application thereof |
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Application publication date: 20111109 |