CN107519497A - Application of the polymer of the oxidation tertiary amine group containing N as medicine or carrier - Google Patents

Application of the polymer of the oxidation tertiary amine group containing N as medicine or carrier Download PDF

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CN107519497A
CN107519497A CN201610451500.6A CN201610451500A CN107519497A CN 107519497 A CN107519497 A CN 107519497A CN 201610451500 A CN201610451500 A CN 201610451500A CN 107519497 A CN107519497 A CN 107519497A
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polymer
tertiary amine
drug
carrier
fragment
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CN107519497B (en
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申有青
钟寅
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HAINAN POLY PHARMACEUTICAL Co.,Ltd.
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Zhejiang University ZJU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Abstract

Application of the polymer of the oxidation tertiary amine group containing N as medicine or carrier.The invention discloses a kind of application of polymer of the oxidation tertiary amine group containing N as antineoplastic, antineoplastic drug carrier or gene delivery carrier, the polymer has following structural framing：Wherein：A1For the fragment containing N oxide structure units；A2For the fragment for the fragment for connecting drug molecule, containing N oxide structure units or it is connected with the fragment of drug molecule；X=0 1, n0=3~300, m=3~300, n=3~300.The polymer of the oxidation tertiary amine group containing N of the present invention both has good water solubility and biocompatibility and blood disguised, and can rapidly enters cell, and tumor hypoxia region can be entered in vivo, therefore as carrier can medicine be effectively transported to tumor hypoxia region and play efficient antitumor action.This N oxidations three-level amine polymer is a kind of excellent drug conveying carrier material.

Description

Application of the polymer of the oxidation tertiary amine group containing N- as medicine or carrier
Technical field
The present invention relates to pharmaceutical technology field, and in particular to the polymer of the oxidation tertiary amine group containing N- is as medicine Or the application of carrier.
Background technology
Many drug molecules it is water-soluble very poor, it is difficult to direct injection application.Delivery vehicles are used as using hydrophilic macromolecule Drug delivery, can increase insoluble medicine water solubility, reduce drug molecule toxic side effect, improve Drug bioavailability And improve curative effect.This macromolecule carrier needs itself have high-hydrophilic or the upper hydrophilic radical of modification, internal to avoid Immune system is removed, extends blood halflife, so as to swollen by the super penetrating and cumulative effect (EPR effects) of tumor tissues It is enriched with knurl, reaches the effect of more preferable and lower toxic side effect.
Poly- (2- hydroxypropyls (methyl) acrylamide) (PHPMA), polyethylene glycol (PEG) are the most commonly used hydrophilic polymerics Thing, its medicine modified have the water solubility significantly improved, removing (the i.e. hidden ability of blood of effective protected from immune system (stealthy)).The medicine of some PEG modifications has come into clinical test, such as polyethylene glycol camptothecin therapy Locally Advanced The clinical second phase (Scott LC, Yao JC, III ABB, et al.A is had been enter into metastatic gastric carcinoma and Carcinoma of gastroesophageal junction phase-II study of pegylated-camptothecin(pegamotecan)in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma；Cancer Chemother Pharmacol 2009；63:363-70).
The water-soluble polymers such as PEG, PHPMA can be itself and albumen, cell membrane the reason for ability hidden with blood Interaction is very weak, so as to be capable of the removing of protected from immune system in hematological system.But this ability assigns its hidden energy While power, also bring one it is serious the shortcomings that：It is exactly phase with cell after medicine or carrier molecule connection PEG or PHPMA Interaction is very weak, thus even if reach also be difficult to after diseased region such as tumor tissues to enter cells play drug effect (Zahr, A.S.；Davis,C.A.；Pishko,M.V.,Macrophage uptake of core-shell nanoparticles surface modified with poly(ethylene glycol).Langmuir 2006,22 (19),8178- 8185.).Therefore, the hidden ability of the blood of pharmaceutical carrier and to rapidly enter between cell be conflict at present.
Therefore, a kind of carrier that can solve the problem that this to contradiction is needed badly, it had both possessed good water solubility and biocompatibility Can be circulated for a long time in vivo with the hidden ability of good blood, again have tumor microenvironment response, can be quick Ground conducts drugs into tumour cell makes it play drug effect into the cell.
The content of the invention
The invention provides containing one or more N- oxidation tertiary amine group polymer be applied to drug delivery or Person's gene transportation art.They have the water solubility similar to PEG, biocompatibility and long blood circulation time, while have again There is the ability for quickly entering cell, and target tumor low oxygen area, the targeting for realizing medicine can be conveyed in tumor tissues, The medicine of conveying is set to play high active anticancer.
It is antitumor present invention also offers being used as after the medicament-carried molecule of polymer of the above-mentioned oxidation tertiary amine group containing N- The application of medicine, step is simple, easy to implement.
Present invention also offers the polymer of another oxidation tertiary amine group containing N- in field of gene as one The application of the genophore of kind high-efficiency low-toxicity.
A kind of polymer of the oxidation tertiary amine group containing N-, it is linear, branched or dendrimer structure, is contained One or more N- aoxidizes tertiary amine group unit.
Molecular weight can be 100-2000
R1、R2、R3、R4For virtues such as alkyl derivative, aromatic radical, the substituted aromatic bases such as alkyl independently, substitution alkyl Perfume base derivative or polymer body structure；Such as methyl, ethyl, the chloroethyl either alkyl such as ethoxy or alkyl derivative Thing；It can also be macromolecular agent structure, can be polymethacrylate backbone structure, hyperbranched polyethyleneimine (PEI), The various polymer architectures such as branched polyethylene imine (BPEI), polylysine (PLL).As further preferred, the R1、R2For Methyl, ethyl independently, R3And R4For one or more hydrogen, methyl.
The nitrogen oxides construction unit is present in or is present in simultaneously the main chain of polymer, side chain, branch or end End position, form the polymer with following structure：
In above formula, D1、D2、D3It is separate for polymer body structure；R1-R5For alkyl, substitution alkyl, aromatic radical, Substituted aromatic base；Or alkyl, substitution alkyl, aromatic radical, substituted aromatic base with N- oxidation tertiary amine groups.As further It is preferred that the R1、R2For methyl independently, ethyl, R3And R4For one or more hydrogen, methyl.
Methyl, ethyl, propyl group, isopropyl etc. may be selected in abovementioned alkyl, and chloro may be selected in above-mentioned substitution alkyl, hydroxyl takes Generation, the methyl of cyano group substitution, ethyl, propyl group, isopropyl etc.；Phenyl, naphthyl etc. may be selected in above-mentioned aromatic radical；Above-mentioned substituted aroma Base can be tolyl, xylyl etc..
According to difference functionally, following important method is illustrated respectively：
A kind of polymer of the oxidation tertiary amine group containing N- conveys as antineoplastic, antineoplastic drug carrier or gene The application of carrier, the polymer have following structural framing：
Wherein：
A1For the fragment containing N- oxide structure units；
A2For the fragment for the fragment for connecting drug molecule, containing N- oxide structure units or it is connected with medicine point The fragment of son；
X=0-1, n0=3~300, m=3~300, n=3~300.
Preferably, the N- oxide structures unit includes at least one of following nitrogen oxides construction unit：
In above formula, R1、R2、R3、R4For hydrogen independently, alkyl, substitution alkyl, aromatic radical, substituted aromatic base or polymerization Thing agent structure.
Preferably, the polymer is antineoplastic；X=0.2~0.95；A2To be connected with the fragment of drug molecule Or DNA with therapeutic effect, RNA molecule；
The drug molecule is antineoplastic.For example described medicine can be anti-tumor drug molecule, such as adriamycin, happiness Set alkali derivant, curcumin, Irinotecan, methotrexate (MTX), matrine, danshinolic acid, one kind in the drug molecule such as taxol or Person is a variety of；The DNA with therapeutic effect, RNA molecule can also be carried.The method of carrying medicament can by covalent key connection, Can also be other interactions commonly used in the art such as hydrophobic interaction, electrostatic interaction.
Can be poly- (methyl) esters of acrylic acid, poly- (methyl) propylene preferably, containing N- oxidation three-level amine unit polymer Amide-type, polyethyleneimine amine, polyvinyl pyridine class, poly N-vinyl pyridines etc.；It is described as further preferred For the polyacrylate of side chain oxide group containing N-, polymethacrylates, polyacrylic acid amide, polymethylacrylic acid acid amides, Polyethyleneimine amine, N- oxidic polyethylenes yl pyridines, N- oxidic polyethylene base imidazoles.
It is preferably, describedStructural formula is as follows：
Preferably, it is SN38 that the drug molecule, which is antineoplastic, the drug containing and N- oxidation tertiary amine groups Polymer formulae be：
Preferably, the polymer formulae of the drug containing and N- oxidation tertiary amine groups is：
Preferably, x=0.8~0.95
OrM=3-300, n=3-300.
Preferably, the polymer is genophore, its structure is：
Wherein z=0.1~1, n2=3~300.
The chemical synthesis of method selection this area routine of the N- oxidation three-level amine polymer connection drug molecules of the present invention Method synthesizes.
Application process of the polymer of the oxidation tertiary amine group containing N- of the present invention as medicinal carrier material, with medicine point Son can either intermolecular interaction be connected, is attached on carrier molecule or carried by covalent bond, ionic bond, hydrogen bond Body molecule wraps up.
The method of above-mentioned polymer connection drug molecule, from the monomer that three-level amine unit is aoxidized containing N- and medicine can be connected with The monomer of molecule polymerisation known to is polymerize or macromolecular carrier polymer addition drug molecule or modification medicine-feeding It is prepared by the reaction of thing molecule, also can first polymerisation prepare the polymer containing tertiary amine and drug molecule simultaneously and carry out oxidation preparation again Obtain.
A kind of connection side of the polymer connection drug molecule of the oxidation tertiary amine group containing N- described in above-mentioned technical proposal Method, it is characterised in that including：By A1Corresponding monomer and A2Corresponding connecting bridge monomer polymerize to obtain polymeric main chain structure；So It should be reacted afterwards with the backbone structure containing nitrogen oxides construction unit and drug molecule, drug molecule reacts with connecting bridge, obtains To the SN38 key compounds of the oxidation tertiary amine group polymer containing N-.
Specific preparation method includes：
(1) under initiator and/or catalyst existence condition, A1The corresponding monomer containing tertiary amine is (with methacrylic acid Exemplified by 2- (N, N- diethylamino) ethyl ester, DEAEMA) and Tert-butyl Methacrylate (tBMA) progress polymerisation, obtain Copolymer (DEAEMA-co-tBMA random copolymers)；
(2) obtained copolymer is utilized into hydrogen peroxide oxidation, obtains corresponding N- oxidations tertiary amine copolymer；
(3) Tert-butyl Methacrylate in copolymer is hydrolyzed to methacrylic acid using trifluoroacetic acid；
(4) under condensing agent, catalyst existence condition, the methacrylic acid in above-mentioned N- oxidations tertiary amine hydrolyzed copolymer Reacted with n-hydroxysuccinimide, obtain the corresponding N- oxidation three-level amine polymers containing NHS Acibenzolars；
(5) the N- oxidation three-level amine polymers containing NHS Acibenzolars carry out aminolysis reaction with the drug molecule with amino, obtain To the polymer-drug key compound of the final oxidation tertiary amine group containing N-.
With A1The corresponding monomer containing tertiary amine is methacrylic acid 2- (N, N- diethylamino) ethyl ester, and drug molecule is Exemplified by SN38, the polymer architecture of the final obtained oxidation tertiary amine group containing N- is as follows：
Wherein x=0.8~0.95, n=3~300.
Preferably, a kind of medicament-carried molecule is SN38, the polymer formulae of the oxidation tertiary amine group containing N- Can also be block copolymer, structural formula is,
Wherein, m=3~300, n=3~300.
A kind of connection side of the polymer connection drug molecule of the oxidation tertiary amine group containing N- described in above-mentioned technical proposal Method, it is characterised in that including：A2Corresponding connection molecule connect after medicine with A1Corresponding monomer carries out block copolymerization.Two kinds of molecules are embedding Duan Juhe obtains polymeric medicine delivery of molecules；
Specific preparation method includes：
(1)A2Corresponding connection molecule is reacted with drug molecule, the monomer structure of the upper drug molecule of generation connection.
(2) under initiator and/or catalyst existence condition, A1The corresponding monomer containing tertiary amine is (with methacrylic acid Exemplified by 2- (N, N- diethylamino) ethyl ester) it is embedding with the monomer for the being connected drug molecule progress obtained in above-mentioned steps (1) Duan Gongju, and aoxidized, obtain carrying medicine block copolymer.
(3) the method such as solvent displacement commonly used using Nano medication delivery system, dialysis, ultrasonic method and liquid film Micelle-type nanoparticles solution is made in above-mentioned copolymer molecule by method.Nanoparticles solution is used for the application of antineoplaston In.
With A1The corresponding monomer containing tertiary amine is diethyl aminoethyl methacrylate, and drug molecule is that SN38 is Example, the block polymer structures of the final obtained oxidation tertiary amine group containing N- are as follows：
Or
Wherein, m=3~200, n=3~300.
Application process of the polymer of the oxidation tertiary amine group provided by the invention containing N- as pharmaceutical carrier, in connection phase Drug molecule is answered to can be used for treatment disease, prevention disease, the function or this point of the either lesions position tracer of carrying therapeutic gene Son is the precursor molecule of the molecule with treatment disease, prevention disease, carrying therapeutic gene or lesions position tracking function.
Present invention also offers a kind of polymer work of the oxidation tertiary amine group containing N- described in any of the above-described technical scheme For the application of pharmaceutical carrier or antineoplastic.
Present invention also offers polymer the answering as inhibiting tumor medicine molecule of another oxidation tertiary amine group containing N- With its structure is：
Wherein n1=3~300.
The invention provides a kind of polymer of the oxidation tertiary amine group containing N- described in above-mentioned technical proposal as alkyl The application process of change type antineoplastic.
The present invention provides application of the polymer of the oxidation tertiary amine group containing N- as genophore, and its structure is：
Wherein n2=3~300.
The described N- oxidation tertiary amine polymer supports of the present invention can dissolve in water, form emulsion, nano-scale Micella or vesica, required solution discrete form is can obtain using preparation method commonly used in the art.
The present invention has the advantages that：
A variety of polymer with N- oxidation three-level amine functional groups are applied to the present invention into drug molecule or therapeutic gene is defeated Send field.Load medicine molecule obtained by this application process has good water solubility and biocompatibility, and property in this respect Can be suitable with the load medicine molecule made by the golden standard PEG in this area, it can circulate for a long time in vivo so as to easily rich Collect in the irregular tumor region more slipped of blood vessel, reduce the enrichment of medicine in the normal tissue, reduce medicine to normal The toxic side effect of tissue, the pharmaceutical effect of medicine can be significantly improved while improving biocompatibility.
Further, compared with the application process for the pharmaceutical carrier modified with PEG carriers or other hydrophilic radicals, N- oxygen The approach for changing the polymer drug-carried molecule of tertiary amine into cell differs markedly from other common drug carrier systems, into cell Speed is significantly larger than the former, overcomes same carrier and enters the slow-footed shortcoming of tumour cell, greatly improves antineoplastic Concentration of the thing in tumour cell, improve utilization rate of the medicine in tumour cell.With important breakthrough.
Further, compared with the pharmaceutical carrier modified with PEG or other hydrophilic radicals, N- oxidation tertiary amine polymerizations Thing enters anoxic zones in tumour.Inside tumor anoxic zones are enriched the tumour cell and tumor stem cell of resistance, are to draw Play the main reason for metastases and recurrence cause death.The drug-loading system of small-molecule drug, PEG or PHPMAization is all difficult To reach anoxic zones in tumour, cause weak curative effect.Induction system of the three-level amine polymer as carrier is aoxidized using N- in the present invention Drug delivery to anoxic zones can effectively be killed tumour cell, improve curative effect, there is important breakthrough.
The N- oxidation tertiary amine pharmaceutical carrier connections drug molecule preparation method of the present invention is simple to operate, normal using this area Synthetic method.
N- oxidation three-levels amine polymer can pass through free radical etc., activity by the monomer for aoxidizing tertiary amine containing N- accordingly Prepared by the polymerizations such as free radical, also can first be polymerize by the monomer containing tertiary amine accordingly and be prepared into corresponding polymer, then Carry out oxidation acquisition.Polymer has water-soluble well when substituent on containing N- oxidation tertiary amines is little, and its energy By covalent key connection drug molecule, dissolved in water and form solution；By adjusting hydrophily it can also be made to be formed in water The micella or vesica of nano-scale are used for conveying drug molecule；The function that can convey gene can also be introduced on this carrier Group, realizes conveying of the carrier to therapeutic gene.It had both had good water solubility and biocompatibility and blood disguise, again Cell and tumor hypoxia region can be rapidly entered, improves the utilization rate of medicine.Therefore, it is this to answer N- oxidation three-level amine polymers For drug delivery and gene transportation art, a kind of method of excellent macromolecular carrier conveying medicine can be considered as.
Brief description of the drawings
Fig. 1 is that PODEAEMA-SN38 medicines prepared by embodiment 1 resist HepG2 in vitro with control drug PEG-SN38 Human hepatoma cell proliferation design sketch.
Fig. 2 is PODEAEMA-SN38 medicine and blood plasma of the control drug PEG-SN38 in Mice Body prepared by embodiment 1 Remove results contrast.
Fig. 3 is the Zeta electric potential knot in HEPES solution of the PODEAEMA carriers of the preparation of embodiment 1 under condition of different pH Fruit.
Fig. 4 be flow cytometer determine HepG2 cells to PODEAEMA carriers prepared by the embodiment 1 of fluorescence labeling with it is right According to carrier PEG phagocytosis result.
(a) is the PEG of PODEAEMA and the Cy5.5 mark of the Cy5.5 marks of the preparation of embodiment 1 of fluorescence labeling in Fig. 5 Pair of the accumulation ability in the weary oxygen region in globuli cell anoxia model；(b) it is that two polymer are injected intravenously lotus knurl respectively After nude mice, they the weary oxygen region of intra-tumor concentration ratio compared with.It can be seen that PODEAEMA can effectively be focused in Fa Yang areas, And PEG is without secondary ability.
Fig. 6 is that PODEAEMA-SN38 medicines prepared by embodiment 1 and control drug PEG-SN38 are thin to HepG2 human liver cancers Tumor growth curve figure in the Inhibition test of spore load knurl nude mouse tumor.
Fig. 7 is PODEAEMA-b-polySN38 medicines prepared by embodiment 2 and control drug PEG-b-SN38 to HepG2 Tumor growth curve figure in the Inhibition test of human liver cancer cell tumor bearing nude mice tumour.
Fig. 8 is the BPEI nitromins polymeric medicine of the preparation of embodiment 3 to HepG2 liver cancer cells tumor bearing nude mice tumours Inhibition test in tumor growth curve figure.
Fig. 9 is the external to human cervical carcinoma of BPEI oxidation modifications genophore and control vector PEI prepared by embodiment 4 HeLa cell lines serum-free and the result compares figure for thering is serum to transfect 48 hours.
Figure 10 is BPEI oxidation modifications genophore prepared by embodiment 4 and control vector PEI to HepG2 cytotoxicities pair According to result.
Embodiment
The present invention provides some specific implementation cases, but the present invention is not limited by these cases.
Embodiment 1：The synthesis of PODEAEMA-SN38 key compounds
The application based on application of the N- oxidation three-level amine polymers as pharmaceutical carrier, a kind of its embodiment, including It is bonded chemotherapeutics.More specifically, in one embodiment, the medicine of load is SN38 (SN38), synthesize as follows.
Wherein x=0.8~0.95, n=3~300
(1) PODEAEMA-NHS synthesis.
By methacrylic acid 2- (N, N- diethylamino) ethyl ester (DEAEMA, 5.37g) and Tert-butyl Methacrylate (0.37g), 2- different bromobutyrate 0.0041g, 2,2 '-bipyridyl 0.085g, cuprous bromide 0.038g and methanol 2mL are put into After in polymerization bottle, continuously it is passed through nitrogen and removes oxygen in 30 minutes.Then 30 degrees Celsius are sealed to react 6 hours.After reaction terminates Cross alundum (Al2O3) post and remove catalyst, be added in n-hexane and precipitate after resulting solution concentration, gained precipitation is dried in vacuo To copolymerization product.
Take 1.21g copolymer products to be added in 10mL 30% aqueous hydrogen peroxide solution, be stirred overnight at room temperature.Institute Obtain settled solution directly to be dialysed with dialysis membrane, resulting solution is freeze-dried after dialysis.Obtain the product of N- oxidations：
Obtain above-mentioned product and be directly added into dichloromethane 4mL, trifluoroacetic acid 2mL is stirred 3 hours at room temperature.After reaction terminates Reaction solution revolving is dialysed after removing most of solvent and trifluoroacetic acid in methanol solution, and dialysis is dialysed after one day in water, Gained settled solution freezes.Obtain product：
Take above-mentioned product 0.82g, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl) 0.2521g, n-hydroxysuccinimide (NHS) 0.17g, catalytic amount DMAP (DMAP) and 0.3mL triethylamines add Enter into round-bottomed flask, be stirred overnight at room temperature.Directly reaction solution is dialysed with water, the freeze-drying of gained dialyzate, contained There is the product (PODEAEMA-NHS) of NHS Acibenzolars：
(2) synthesis of SN38 key compounds
PODEAEMA-NHS 0.30g, 5mL DMSO, the SN38 drug molecules 7.5mg for being connected with amino are added to round bottom burning In bottle, room temperature lucifuge is stirred overnight, and is dialysed with DMSO, and the dialysis solution directly freezed of gained is dried to obtain PODEAEMA-SN38 Bonding product.
1H-NMR Spectra peak recognitions (d6-DMSO, ppm)：7.1-8.2(m,CHCHC(OH)CH,CHCHC(OH)CH,CHCHC (OH)CH,CONCCHC),5.2-5.5(m,CH2OCOCCH2CH3,CONCH2), C 3.8~4.6 (b, COOCH2CH2N, COOCH2CH2O,CONHCH2COO),3.0-3.6(b,CH2N(CH2CH3)2,CH2N(CH2CH3)2),1.6-1.9 (CH2CCOOCH2CH2N,CH2CCONHCH2,CH2OCOCCH2CH3),1.0-1.4(m,CH3CCOOCH2CH2N,CH3CCONHCH2, CCH2NCO,N(CH2CH3)2),0.6-0.9(b,CH2OCOCCH2CH3)。
Molecular weight (GPC) 2.5 × 104Da。
Embodiment 2：The preparation of PODEAEMA-b-polySN38 block copolymers
The application based on application of the N- oxidation three-level amine polymers as pharmaceutical carrier, a kind of its embodiment, be by Hydrophilic N- oxidation three-level amine polymers are long-chain, are connected on drug molecule or its polymer, form amphiphatic bonding chemical drug Thing, nano particle or micella are formed by its assembling in aqueous.More specifically, in one embodiment, load Medicine is SN38 (SN38), and synthesis is as follows.
Wherein, m=3~200, n=3~300.
By 2- (N, N- diethylamino) the different bromobutyrate 3.9mg of ethylmethyl acrylate 240mg, 2-, pentamethyl After diethylenetriamine 40mg, cuprous bromide 10mg, DMF 1mL are put into polymerization bottle, continuously it is passed through nitrogen and removes for 30 minutes Oxygen.Then 40 degrees Celsius are sealed to react 4 hours.Under argon gas protection, directly noted with syringe into closed reaction system Penetrate the monomer SN38-MA 0.2g that upper SN38 molecules are connected as shown in above-mentioned structural formula, under conditions of keeping closed 30 degrees Celsius after Continuous reaction 8 hours.Reaction uses the dialysis membrane of molecular cut off 3500 to dialyse 6 hours in DMSO immediately in aqueous phase after terminating Middle dialysis 6 hours, resulting solution is directly added into 0.8g metachloroperbenzoic acids and stirred 2 hours, is freezed after resulting solution concentration dry It is dry to obtain block copolymerization product PODEAEMA-b-polySN38.
H-NMR Spectra peak recognitions (d6-DMSO, ppm)：7.1-8.2(m,CHCHC(OH)CH,CHCHC(OH)CH,CHCHC (OH)CH,CONCCHC),5.2-5.5(m,C(OH)COOCH2,CONCH2),3.8-4.6(b,COOCH2CH2N,COOCH2CH2O, COOCH2CH2O),3.0-3.6(b,CH2N(CH2CH3)2,CH2N(CH2CH3)2),2.8-2.95(b,OCH2CH2COOC),2.6- 2.8(b,OCH2CH2COOC),1.6-1.9(CH3C(COOCH2CH2O)CH2,CH3C(COOCH2CH2N)CH2,C(OH)CH2CH3), 1.0-1.4(m,CH3CCOOCH2CH2N,CH3CCOOCH2CH2O,CH2NCO,N(CH2CH3)2),0.6-0.9(b,C(OH) CH2CH3)。
Embodiment 3：
The application's aoxidizes application of the three-level amine polymer as macromolecular drug, a kind of its embodiment, bag based on N- Include using itself as macromolecular trunk structure synthetic macromolecule medicine.More specifically, in one embodiment, obtain a kind of N- oxygen Change the nitrogen mustards polymer macromolecule medicine (OPEI-Cl) of polyethyleneimine (OPEI).
It is 25000g/mol branched polyethylene imines () Aldrich to take weight average molecular weight) 1.16g is dissolved in 10mL formamides, In ice-water bath, expoxy propane 2.5mL is added.Continuation is stirred overnight under 0 degree Celsius of environment, and resulting solution is dialysed in water, Dialyzate freezes, and obtains：
Above-mentioned product 0.14g, the aqueous hydrogen peroxide solutions of 3mL 30% are added, aqueous phase is dialysed after being stirred at room temperature 6 hours, dialysis Liquid freezes, and obtains N- oxidation products：
Above-mentioned product 0.1g is taken, 2mL formamides is added, dissolving is stirred at room temperature, 40 μ L thionyl chlorides are added under ice-water bath. Continuation is stirred 3 hours in ice-water bath, is added suitable quantity of water dilution, is then dialysed, what gained dialyzate freezed arrives nitrogen oxide Mustard polymeric medicine OPEI-Cl.
Product structure is as follows：
Wherein n=3~300.
1H-NMR Spectra peak recognitions (D2O,ppm)：3.4-4.1(b,NOCH2CHCl,NOCH2CH2NO),2.6-3.2(b, CH2CHCl),1.2-1.4(b,CH2CHClCH3)。
Embodiment 4：
The application based on N- oxidation three-level amine polymers and its as pharmaceutical carrier of the application, a kind of its embodiment, Including as genophore, conveying therapeutic gene.More specifically, it is by branch shaped polyethylene imines in one embodiment Cationic genophore (the OPEI-NH that tertiary amine is aoxidized2)。
(1) weight average molecular weight is 25000g/mol branched polyethylene imine 3.1g, sodium acid carbonate 4.03g, sodium carbonate 1.01g, it is dissolved in 30mL water.Boc2O is dissolved in 20mL tetrahydrofurans.In the case where being stirred vigorously, by above-mentioned tetrahydrofuran solution Pour into the aqueous solution.It is stirred overnight at room temperature.Reaction solution revolving removes tetrahydrofuran, centrifugation, and the precipitation of gained is washed with water 4 times, very Sky drying, obtain the branched polyethylene imine after Boc protections.
(2) above-mentioned product is added to the hydrogen peroxide of 10mL 30% and is stirred at room temperature overnight.Reaction solution is directly lyophilized, obtains Branched polyethylene imine is aoxidized to N-.Gained solid is added to 10mL dichloromethane, adds 5mL trifluoroacetic acids, is stirred at room temperature Overnight, protective agent Boc is sloughed.Reaction solution adds methanol and rotated repeatedly removes trifluoroacetic acid and solvent.Solution is obtained to exist Dialysed in aqueous phase.Gained dialyzate is lyophilized to produce final product.
Product structure is as follows：
Wherein n=3~300；
1H-NMR Spectra peak recognitions (D2O,ppm)：3.6-4.0(b,NOCH2CH2NO),3.2-3.4(b,NOCH2CH2NH2, NOCH2CH2NH),2.8-3.2(b,NOCH2CH2NH2,NOCH2CH2NH),2.4-2.7(b,NH2CH2CH2NH,NH2CH2CH2NH)。
Application examples 1PODEAEMA-SN38 parenteral solutions
(1) compound method
The administration concentration calculated according to dosage, the PODEAEMA-SN38 prepared in embodiment 1 is dissolved in PBS water In solution (phosphate buffer solution) or normal saline solution.Shake and ultrasound, the injection for being prepared into homogeneous clear are molten Liquid.I.e. with i.e. use.
Detected exemplified by PODEAEMA-SN38 solution prepared by method described above, detection method is normal using this area Rule method.
(2) cytotoxicity experiment
Water-soluble drug delivery system PEG- after PODEAEMA-SN38 is bonded into SN38 with carrier PEG commonly used in the art SN38 carries out vitro cytotoxicity contrast experiment, and PEG-SN38 structural formulas are shown below：
Two kinds carry medicine molecule extracorporeal anti-tumor cell effect respectively as shown in figure 1, it can be seen that PODEAEMA- SN38 and PEG-SN38 has identical cytotoxicity, and this result shows, PODEAEMA-SN38 can be used as anticarcinogen Thing.
(3) plasma clearance is tested
PODEAEMA-SN38 and PEG-SN38 is subjected to white mouse plasma clearance experiment.The mouse that 8 body weight are about 20g with Machine is divided into two groups, and one group of mouse injects PODEAEMA-SN38 according to dosage of the equivalent in SN38 7.5mg/kg, and another set is pressed According to equivalent PEG-SN38 is injected in SN38 7.5mg/kg dosage.Every group of mouse takes blood at the time point of each setting by eye socket Method gathers blood sample, and takes 50 μ L blood samples to be added to the 1.5mL of the NaOH aqueous solution equipped with 50 μ L 0.1mol/L and centrifuge In pipe and concussion shakes up.After the completion of all time points take blood, all samples centrifuge tube is put into 45 DEG C water bath reclaimed waters and bathed Night.Then, 0.9mL acetonitriles are added in every sample cell, after concussion, the precipitation that sample solidifies is smashed into mixing with refiner, from The heart, the μ L of sample supernatant 50 are taken, shaken up with 50 μ L 0.1mol/L combineds, detected after centrifuging again by HPLC SN38 molecule contents in solution.Each sample measures SN38 peak areas and substitutes into working curve after treatment, you can tries to achieve sample Initial concentration, and be scaled in every milliliter of mouse blood and contain relative to the percentage composition for being injected intravenously total dosage.Blood plasma Removing the method that working curve is established is, the DMSO solution by adding a certain amount of SN38 has prepared 5 into blank blood sample Know the blood sample of parallel 3 samples of each concentration of SN38 concentration.The empirically method processing of group processing blood of each sample, The peak area of the SN38 molecules after each sample treatment is measured, it is relative after the peak area averaging of each three parallel samples of concentration Figure is done in concentration, you can obtains plasma clearance experimental work curve.
Experimental result is as shown in Figure 2.The result show PODEAEMA molecules have with PEG close to inside circulation time, With long circulating property inside similar with PEG.
(4) polymer potential determination
The PODEAEMA carrier molecules that will be prepared in embodiment 1, are dissolved in the HEPES cushioning liquid of different pH condition, The solution of 2 mg/mls is formulated as, potential is determined using zeta potential instrument.As a result it is as shown in Figure 3.The result explanation OPDEAEMA molecules have the property that is under physiological ph conditions presented electroneutral similar with PEG.
(5) cell swallows to polymer and determined
By the intermediate molecule PODEAEMA-NHS obtained in embodiment 1 and control sample PEG molecules connection fluorescence molecule Cy5.5, obtain the carrier molecule PODEAEMA-Cy5.5 of fluorescence molecule mark.Every hole is spread thin into 150,000 HepG2 in 12 orifice plates Born of the same parents, cell attachment culture suck culture medium after one day.Added in three holes of 12 orifice plates and do not contain the fresh of fluorescent marker Culture medium adds the fresh culture containing 30 mcg/ml PODEAEMA-Cy5.5, in addition as blank control in three holes The fresh culture containing 30 mcg/ml PEG-Cy5.5 is added in three holes.12 orifice plates are incubated 6 in cell incubation case Hour.Then washed with the PBS solution containing 0.5mg/mL heparin, and digested with pancreatin and continue to be washed with heparin-PBS solution And centrifuge.The ratio that gained cell is swallowed after being suspended again with PBS with flow cytometer measure cell to fluorescence molecule.
As a result as shown in figure 4,64% cell has swallowed PODEAEMA-Cy5.5 molecules, its cell fluorescence intensity peak has bright Aobvious skew, and PEG groups only have 3% cell to swallow PEG-Cy5.5 molecules.The experimental result can prove PODEAEMA molecules Speed into cell is significantly faster than PEG molecules.
(5) distribution situation detection of the polymer in spherical cell hypoxia model
Solid medium is added in 96 orifice plates using the method for routine, and Bcap37 cells are cultivated on solid medium Spherical anoxia model.The PODEAEMA of 50 μ L Cy7 (1 mg/ml) marks is added after models mature, in hole (PODEAEMA-Cy5.5) PBS solution, and add equivalent in other holes and make with the Cy7 of the concentration PEG marked PBS solution For control.After being incubated 6 hours, washed 3 times with PBS.Model is directly observed under Laser Scanning Confocal Microscope, shoots obtained picture Middle fluorescence labeling shows with white point, as a result as shown in Figure 5.It is observed that PODEAEMA is in spherical anoxia model Layer enrichment distribution annular in shape, is uniformly distributed at other positions in weaker, and this is a kind of typical pharmaceutical carrier to hypoxemia position Performance with compared with strong interaction.And as a comparison, PEG carriers are integrally evenly distributed in spherical anoxia model, do not have Enrichment phenomenon is shown to hypoxic sites, illustrates that PEG does not respond to function to hypoxic sites.
(6) inhibiting tumor assay
Investigate inhibitory action of the PODEAEMA-SN38 to HepG2 human liver cancer cell tumor bearing nude mice tumours.BALB/c nude mice armpits Lower transplanting 1 × 106HepG2 tumour cells, treat tumour length to about 100mm3After start to be administered, carry out tail vein injection every three days. Three groups of nude mices are respectively the PODEAEMA-SN38 (embodiment 1) of the present invention, PEG-SN38 (dosage is SN38 10mg/kg) and sky White control group.Dosage period expires after (12 days), stops administration and continues to observe nude mice 9 days.Nude mice is put to death afterwards, is separated all The averagely total weight in wet base of every group of nude mouse tumor is obtained after tumour, as a result as shown in Figure 6.
This result shows：Contrasted with PBS groups (blank control group), calculating PODEAEMA-SN38 tumour inhibiting rates is 51%, and PEG-SN38 tumour inhibiting rates are 8%.Illustrate that PODEAEMA as pharmaceutical carrier, after drug molecule is connected, carries than PEG Body surface reveals more significant active anticancer.
Application examples 2：PODEAEMA-b-polySN38 parenteral solutions
(1) compound method
It is molten among the PODEAEMA-b-polySN38 solid products 100mg obtained in embodiment 2 is dissolved in into 5mL DMF Solution to solution is clarified.Then in the case of magnetic agitation, pure water 20mL is slowly added dropwise into the solution, after being added dropwise, after Continuous stirring 15 minutes.The subsequent solution is dialysed 4 hours using the dialysis membrane of 3500 interception molecular weight in aqueous phase.Finally give Aqueous solution concentrated by rotary evaporation, the aqueous solution of gained are the nanoparticles solution of PODEAEMA-b-polySN38 molecules.
The administration that PODEAEMA-b-polySN38 nano particle aqueous solutions prepared by the above method calculate according to dosage Concentration, it is diluted in the PBS aqueous solution or normal saline solution.Slight concussion shakes up, i.e., with i.e. use.
(2) inhibiting tumor assay
Investigate inhibitory action of the PODEAEMA-b-polySN38 to HepG2 human liver cancer cell tumor bearing nude mice tumours.BALB/c Nude mice oxter transplanting 1 × 106HepG2 tumour cells, treat tumour length to about 80mm3After start to be administered, carry out tail vein every three days Injection.Three groups are respectively PODEAEMA-b-polySN38 (embodiment 2), PEG-b-SN38 (dosage SN38 of the invention 10mg/kg) and blank control group.Dosage period expires after (12 days), stops administration and continues to observe nude mice 27 days.As a result such as Fig. 7 It is shown.
This result shows：Contrasted with PBS groups, the nude mouse tumor volume of PODEAEMA-b-polySN38 treatment groups Do not increase not only, volume is decreased to the level that naked eyes can not be observed on the contrary.Tumour is not observed obvious multiple after drug withdrawal It was found that as.And although the growth of the nude mouse tumor volume of PEG-b-SN38 administration groups is significantly suppressed, gross tumor volume is still So it is being slowly increased, substantially less than PODEAEMA-b-polySN38 tumor killing effects, and tumour rapid development after drug withdrawal.This Contrast and experiment illustrates that PODEAEMA as pharmaceutical carrier, after drug molecule is connected, is prepared into after nanoparticles solution not More significant active anticancer only is shown than PEG carrier, and does not have recurrence sign after treatment in long-time, therapeutic effect is at this Be in a leading position level in field.
Application examples 3：N- aoxidizes PEI mustargen (OPEI-Cl) medicine
(1) preparation method
Administration concentration is calculated according to dosage, the OPEI-Cl medicines prepared in embodiment 3 are dissolved in the PBS aqueous solution Or in normal saline solution, shake and ultrasonic, homogeneous clear injection solution is prepared into, that is, matches somebody with somebody and uses.
(2) inhibiting tumor assay
OPEI-Cl and same type small-molecule drug Chlorambucil are subjected to antitumous effect contrast experiment.Investigate OPEI- The inhibitory action of Cl and same type small-molecule drug Chlorambucil to HepG2 human liver cancer cell tumor bearing nude mice tumours.Notch graft (tumor average volume is about 80mm to the nude mice of kind HepG2 cells after two weeks3) according to being equal to Chlorambucil 10mg/kg's Dosage tail vein injection OPEI-Cl or Chlorambucil, and by the use of the tumor bearing nude mices of tail vein injection 0.2mL PBS solutions as pair According to.After dosage period expires (12 days), stop being administered and continue to observe nude mice 27 days.Nude mice is put to death afterwards, separates all swell The averagely total weight in wet base of every group of mouse tumour is obtained after knurl, is contrasted with PBS groups.As a result it is as shown in Figure 8.
This result shows, OPEI-Cl is shown and small molecule similar drugs Chlorambucil almost phase during administration Same antitumor activity.But energy continuous exhibition goes out to have tumour obvious inhibitory action after administration stops, and does not occur similar The rebound phenomena of tumour fast-growth after Chlorambucil drug withdrawal.So BPEI nitromins polymeric medicine can be used Make a kind of long-acting antineoplastic.
Application examples 4：OPEI-NH2Type genophore system
(1) rotaring redyeing system preparation method
According to required N/P ratio, the OPEI-NH that will be prepared in the embodiment 4 for being fitted on suitable concn2HEPES solution It is added in 100 μ g/mL DNA or RNA HEPES (N-2- hydroxyethyl piperazine-N'-2- ethyl sulfonic acids) solution, is stood after addition Shake 10 seconds, lucifuge stands 30 minutes, you can obtains OPEI-NH2Contain the carrier nanoparticles of gene.
(2) in-vitro transfection is tested
By OPEI-NH2/ gene nano particle and carrier B PEI commonly used in the art carry out in-vitro transfection experiment with Hela cells Contrast, spread per hole into 30000 cells in 48 orifice plates, cultivate in cell incubation case 24 hours it is adherent, then whole renews fresh training Base is supported, each hole adds the above-mentioned OPEI-NH for containing Luci genes prepared of 50 μ L2/ gene nano particle.Culture 6 hours Afterwards, whole culture mediums are replaced with fresh serum-containing media and continue to cultivate 24 hours.Then, vitellophag, wash and centrifuge, Cracked with cell pyrolysis liquid.Chemical luminous substrate is then added, values of chemiluminescence characterizes its transfection activity under the conditions of measure is each.
As a result such as Fig. 9, in free serum culture and under conditions of having serum free culture system, OPEI-NH2The equal table of/gene nano particle Reveal the transfection activity close with this area golden standard BPEI.And external MTT experiment result figure 10 shows, OPEI-NH2Poison Property is well below BPEI carriers.Two above test result indicates that, BPEI oxidation modification genophores OPEI-NH2Can conduct A kind of genophore of high-efficiency low-toxicity is applied to field of gene, has very high researching value and practical value.

Claims (10)

  1. A kind of 1. application of polymer of the oxidation tertiary amine group containing N- as medicine or carrier, it is characterised in that the polymerization Thing has following structural framing：
    Wherein：
    A1For the fragment containing N- oxide structure units；
    A2For the fragment for the fragment for connecting drug molecule, containing N- oxide structure units or it is connected with drug molecule Fragment；
    X=0-1, n0=3~300, m=3~300, n=3~300.
  2. 2. application according to claim 1, it is characterised in that the N- oxide structures unit includes following nitrogen oxides At least one of construction unit：
    In above formula, R1、R2、R3、R4For hydrogen independently, alkyl, substitution alkyl, aromatic radical, substituted aromatic base or polymerization owner Body structure.
  3. 3. application according to claim 1 or 2, it is characterised in that the polymer is antineoplastic；X=0.2~ 0.95；A2To be connected with the fragment of drug molecule or DNA with therapeutic effect, RNA molecule；
    The drug molecule includes adriamycin, camptothecin derivative, curcumin, Irinotecan, methotrexate (MTX), matrine, red phenol One or more in acid, taxol.
  4. 4. application according to claim 3, it is characterised in that describedFor the polypropylene of side chain oxide group containing N- Acid esters, polymethacrylates, polyacrylic acid amide, polymethylacrylic acid acid amides, polyethyleneimine amine, N- oxidic polyethylene bases Pyridine, N- oxidic polyethylene base imidazoles.
  5. 5. application according to claim 4, it is characterised in that describedStructural formula is as follows：
  6. 6. application according to claim 4, it is characterised in that the drug molecule is that antineoplastic is SN38, described Drug containing and N- oxidation tertiary amine group polymer formulaes are：
  7. 7. application according to claim 6, it is characterised in that the polymer of the drug containing and N- oxidation tertiary amine groups Structural formula is：
  8. 8. application according to claim 6, it is characterised in that x=0.8~0.95.
  9. 9. application according to claim 1, it is characterised in that the polymer is antineoplastic, and its structure is：
    Wherein R5=H or CH3Or other alkyl；X=OH or Cl, y=0-1, n1=3~300.
  10. 10. application according to claim 1, it is characterised in that the polymer is genophore, and its structure is：
    Wherein z=0.1~1, n2=3~300.
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