CN102716495A - Multifunctional poly(malic acid) carried drug for targeting treatment of tumors - Google Patents
Multifunctional poly(malic acid) carried drug for targeting treatment of tumors Download PDFInfo
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Abstract
The invention discloses a poly(malic acid) carried drug, which is prepared by fixing drug on poly(malic acid) carriers. The drug incudes antitumor drug and derivatives thereof, wherein the antitumor drug contains amino groups or can be introduced with amino groups. The poly(malic acid) carriers are connected with cell-penetrating peptides, and targeting groups Ligand or targeting groups modified with flexible chains are connected to the poly(malic acid) carriers through breakable bonds. Structural characteristics of the poly(malic acid) carriers are utilized sufficiently, activated molecules with different biological characteristics are connected to the poly(malic acid) carriers sequentially, and a polymer drug system with characteristics of targeting and high-efficiency endocytosis drug-delivery for tumor treatment is established by the shielding-deshielding effect. The polymer drug system realizes active targeting to tumor portions by binding of specificities of ligand-receptor and antibody-antigen.
Description
Technical field
The present invention relates to the multi-functional polymalic acid carrier medicament of a kind of target tumor.
Background technology
Chemotherapy is one of main means of malignant tumor Comprehensive Treatment.Antitumor drug has high bio-toxicity usually and rarer biological selectivity in killing tumor cell, also kills and wounds normal tissue cell.Because the multidrug resistance of non-special toxicity, shortage tumor-selective and tumor, most of antitumor drug are also such effective unlike expection, it perplexs the subject matter of chemotherapy especially to the toxic and side effects of normal structure.
Macromolecular material with biocompatibility and biodegradability can optionally discharge medicine at lesions position as the carrier of small-molecule drug, can greatly improve the bioavailability of medicine, reduces the toxic and side effects and the dosage of medicine effectively; Targeted molecular is introduced polymer, also can be with the drug main moving-target to diseased region.Using more macromolecular material in the preparation polymeric prodrugs at present has: polylactic acid (PLA), polyglycolic acid (PGA), polyglutamic acid etc.Polylactic acid, polyglycolic acid are water insoluble, and crosslinked drug molecule discharges very slow in vivo, influences drug effect, and water absorption such as polyglutamic acid are too strong, and so disintegrate easily is all can not be as the selection of optimal drug carrier.(Polymalic acid, PMLA) be is a kind of aliphatic polyester that only monomer is formed by connecting through ester bond each other with the malic acid to polymalic acid.Its relative highly dissoluble, high spontaneous degradation rate and immunologic inertia under physiological condition makes it become the novel pharmaceutical modified release carrier material that is superior to polysaccharide and polypeptide class biopolymer.
β-polymalic acid compound with regular structure has a plurality of active center, can covalently bound a plurality of group with biological function, form the nanometer copolymers as carrying multiple medicine, multiple targeted molecular and fluorescent tracer etc. simultaneously, and be the efficient carrier of antitumor drug.Up to now, be that the foreign scholar of representative is to synthetic, the performance of polymalic acid with should be used as more deep research with Vert, Cammas and Kajiyaina etc.; With its brain targeted polymeric prodrugs of doing preparing carriers, not only have excellent biological compatibility and degradability, and improved pharmaceutical properties.
Although a lot of drug delivery systems have shown goodish tumor-targeting; Combine the drug main moving-target to tumor cell surface through specificity between Ag-Ab, the receptor-ligand; But tumor presents various cell mass usually; Cell surface has not isoacceptor or antigen presentation, and has the phenotype that is different from other tumor cells with tumor recurrence and relevant " cancer stem cell " of transfer.Therefore, the active targeted approach that is generally the design of specific antigen or receptor for kill and wound cancerous cell be not certain effectively.And usually carrier with go into after target cell combines born of the same parents' ability a little less than, sufficiently high born of the same parents can not be provided interior drug level, and cytotoxic drug must get into the effect of cell competence exertion, thereby can't effectively suppress the growth of tumor cell, particularly the drug-resistant tumor cell; And might redistribute normal structure after the drug diffusion that carrier discharges outside born of the same parents, reduce the specificity of targeted drug.Therefore, the intracellular transport of bioactive molecule is still a key issue in the transport of drug.
Cell-penetrating peptide (cell-penetrating peptides; CPP) be one type of small peptide that can carry macromolecular substances entering cell of discovered in recent years; Its membrane penetration effect does not rely on classical endocytosis; Have the cell membrane affinity high, wear fast, the advantage such as can be degraded rapidly of film speed, it is the most ripe to wear the research of film peptide with TAT (transcriptional activator protein) especially.Receptor-mediated through not having, as not have power consumption mode is worn the film peptide and can be brought cell into peptide section, protein even than big a lot of times oligonucleotide, the liposomees of self molecular weight, and the transduction rate almost can reach 100%.But curative effect is unsatisfactory when wearing the film peptide and being used in the body delivery system research, and the subject matter of existence is that CPP lacks target-specific, and it is active that all cells are had an identical transduction; Non-target tissue also can be through nonspecific cell internalizing effect picked-up chimera through the CPP mediation.
Sethuraman etc. are with pH sensitive polymers and cell-penetrating peptide TAT a kind of multifunctional polymer micellar system that has been fundamental construction; This system is made up of two parts: a part is that TAT is the micelle of target head; Polylactic acid (PLLA) constitutes hydrophobic inner core, and TAT is connected in the end of hydrophilic block Polyethylene Glycol (PEG); Another part is that the responsive diblock copolymer of pH gathers madribon-Polyethylene Glycol (PSD-PEG).Under physiological condition, electronegative PSD combines with the TAT of positively charged, and PSD-PEG is covered in the micellar outside of TAT, and target head TAT is hidden, and under the pH of tumor locus environment, PSD-PEG separates with the TAT micelle and the target head is come out.Similar with it, the multi-functional mixed micelle of preparation such as Lee, under physiological environment (pH7.4), TAT is anchored on the hydrophobic inner core through the responsive polyhistidyl (polyHis) of pH.When micelle is exposed to tumor or inflammation part (6.5 < pH < 7.0), polyHis is to a certain degree by protonated, and hydrophilic increases, and TAT comes out and mediates endocytosis.But receive the restriction of micelle stability, wear the film peptide and before arriving target position, can still be faced with challenge by safeguard protection.Therefore, how making up the targeting drug release system that has the cancer target specificity concurrently and efficiently go into born of the same parents' drug release feature dual-use function is to improve the key of cancer target preparation curative effect.
Summary of the invention
The purpose of this invention is to provide a kind of multi-functional polymalic acid carrier medicament that has the cancer target specificity concurrently and efficiently go into born of the same parents' drug release feature.
Another purpose of the present invention provides the method for preparing of above-mentioned polymalic acid carrier medicament.
Implementation procedure of the present invention is following:
A kind of polymalic acid carrier medicament is that medicine is fixed on the polymalic acid carrier, it is characterized in that:
(1) said medicine is to contain amino maybe can introduce amino antitumor drug and derivant thereof;
(2) be connected with on the polymalic acid carrier and wear the film peptide;
(3) the targeting group of targeting group L igand or flexible chain modification is connected on the polymalic acid carrier through easy fracture key (like the hydrazone key).
Said flexible chain can connect for Polyethylene Glycol, and molecular weight is 3000～7000.
The molecular weight of described polymalic acid is 1000 ~ 200,000.
Said antitumor drug or derivatives thereof is amycin (DOX), amino camptothecin (CPT-NH
2), azacitidine or carat Qu Bin.
The said film peptide CPP that wears modifies or is directly connected on the polymalic acid carrier through flexible short chain; Said flexible short chain is that Polyethylene Glycol connects; Molecular weight is 500～3000, and it also comprises having the small peptide that passes nucleus, cell membrane function, like nuclear localization signal peptide (NLS) etc.
Said targeting group is the material with tumor cell targeting; Comprise that all solid tumor tissue surfaces have the part of the receptor of its corresponding relative high expressed; Kind is vitamin, albumen, peptide class, polysaccharide, integration element etc., like folic acid (FA), luteinising hormone-releasing hormo (LHRH), biotin (biotin), transferrins, low density lipoprotein, LDL, enoxolone, agglutinin, antineoplastic amalgamation protein, monoclonal antibody or synthetic part (like Angiopep-2).
The method for preparing of above-mentioned polymalic acid carrier medicament may further comprise the steps:
(1) under the catalysis of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl), N-maloyl imines (NHS) and triethylamine (TEA), polymalic acid (PMLA) obtains PMLA-NH with the hydrazine hydrate prepared in reaction
2, the carboxyl that wherein contains in the polymalic acid and the mol ratio of hydrazine hydrate are between 10 ~ 1;
(2) the Polyethylene Glycol OHC-PEG-Ligand that selects for use the Polyethylene Glycol that contains aldehyde radical and targeting group L igand prepared in reaction to obtain the targeting base group modificationization; The molecular weight of the Polyethylene Glycol of selecting for use that contains aldehyde radical is 3500 ~ 7000, and wherein the reaction mol ratio of Ligand and aldehyde radical Polyethylene Glycol is between 0.1 ~ 10;
(3) with PMLA-NH
2Be dissolved in the DMF solvent with OHC-PEG-Ligand, reacting under the room temperature obtains PMLA-Hz-PEG-Ligand, forms required hydrazone key spacer, wherein PMLA-NH
2The reaction mol ratio of middle amino and OHC-PEG-Ligand is 0.5 ~ 1;
(4) PMLA-Hz-PEG-Ligand with wear film peptide TAT or TAT-PEG reaction and obtain TAT-PMLA-Hz-PEG-Ligand or TAT-PEG-PMLA-Hz-PEG-Ligand, the wherein molecular weight 500 ~ 3000 of short chain PEG;
(5) under the catalysis of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl), N-maloyl imines (NHS) and triethylamine (TEA), TAT-PMLA-Hz-PEG-Ligand or TAT-PEG-PMLA-Hz-PEG-Ligand are obtained polymalic acid carrier medicament TAT-PMLA (drug)-Hz-PEG-Ligand or TAT-PEG-PMLA (drug)-Hz-PEG-Ligand with the antitumor drug or derivatives thereof prepared in reaction that contains amino.
The synthetic route of PMLA-Hz-PEG6-FA is following:
Above-mentioned polymalic acid carrier medicament has the cancer target specificity concurrently and efficiently goes into the application in born of the same parents' drug release feature medicine in preparation.
The present invention connects the targeting group on the long flexible chain at the hydrazone key spacer that adopts easy fracture under the weak acid environment on the polymalic acid main chain, and the spacer groups of short chain connects wears film peptide (TAT) and antitumor drug, forms certain stereovision.In protection during TAT, can be on the polymalic acid main chain targeting group modified of the single flexible chain of bonding (like Polyethylene Glycol) or flexible chain.Wearing the film peptide can directly or indirectly be connected with the polymalic acid main chain through the different molecular weight flexible chain, and the length of this chain is less than the chain length between targeting group (or PEG) and polymalic acid.The present invention uses polymalic acid to be polymer support, with the targeting group bonding, can reach the initiatively effect of targeting through flexible chain; After arriving the tumor tissues position, acid-sensitive linking arm can respond to the tumor tissues sour environment and the polymalic acid main chain breaks off.Through directly or use that short flexible chain connects wear the film peptide, go into born of the same parents fast after can promoting medicine to arrive tumor tissues.
It is base material that the present invention selects polymalic acid for use, can give prodrug excellent biological compatibility and vivo degradation property.On its main chain, distinguish the good ligand modified Polyethylene Glycol (PEG) of bonding hydrophilic, wear film peptide (CPP) and antitumor drug.Employing shields/deshields the bottleneck problem that method solves the CPP lack of specific, and promptly CPP is hidden earlier before arriving target area, avoids the non-specific film of wearing of CPP mediation; After ligand-mediated arrival target area, CPP just exposes fully and promotes effective cell internalizing.
The present invention is with responsive chemical bond (hydrazone key) of pH and polymalic acid a kind of multifunctional nano hybrid system that has been fundamental construction; Utilize different molecular weight soft segment (PEG chain) to deliver part (or monoclonal antibody, agglutinin, biotin etc.) respectively, wear the film peptide; They are not disturbed mutually; Under the tumor sour environment, bring into play targeting accumulation and internalization endocytosis successively.In the regular circulation (pH ~ 7.4), the TAT on the short chain PEG (biotin etc.) is hidden in the protective layer of long-chain PEG; In the tumor sour environment, dissociating in the acid-sensitive position that connects long-chain PEG, loses protective layer, and TAT exposes at microparticle surfaces, thereby realize the internalization to tumor cell.This targeting drug release system can make the specific tumor locus that accumulates in of medicine, and passes target cell membrane medicine efficiently is transported in the tumor cell, and then the release of response lysosomal acid environment (pH ~ 6.0).
Advantage of the present invention and good effect: (1) is integrated in multiple function in the same polymeric system cleverly, makes polymalic acid nanometer graft become better drug delivery vehicle.This delivery system can make the specific tumor locus that accumulates in of medicine, and passes target cell membrane medicine efficiently is transported in the tumor cell, and then the release of response tumor cell endosome sour environment.(2) the present invention makes full use of the polymalic acid construction features, and the bioactive molecule of different biological natures is connected in turn on the polymalic acid, through shielding-deshielding effect, has made up and has had cancer target concurrently, efficiently gone into the polymeric medicine system of born of the same parents' drug release feature.This system realizes the initiatively function at target tumor position through the combination of ligand-receptor, antibody-antigenic specificity.And wear the film peptide in the regular circulation, and being hidden in the protective layer, behind the arrival target position, the sour environment lower protective layer disappears outside tumor cell, wears the film peptide to come out, thereby realizes the quick internalization to tumor cell.This complex function micelle that can make response to the entity tumor environment is for the cancer target drug-supplying system that makes up high-efficiency low-toxicity provides New Policy.(3) the used carrier material polymalic acid of the present invention is a kind of biodegradable material; Its catabolite is the material that human body itself has; Can not produce cumulative toxicity and toxic and side effects, have the characteristics of avirulence, non-immunogenicity and antigenicity, good biocompatibility.
Description of drawings
Fig. 1 is PMLA (A), PMLA-NH
2(B) infrared spectrum
Fig. 2 is O-PEG6-FA (C), the nuclear magnetic spectrum of PMLA-Hz-PEG6-FA (D);
Fig. 3 is the transmission electron microscope picture of polymalic acid carrier micelle;
Fig. 4 be after two hours during different pH the A2780 cell (A:pH 7.4 to the encytosis figure of polymalic acid nano-complex; B:pH 6.8);
Fig. 5 is a polymalic acid carrier medicament structural representation.
The specific embodiment
Below be the embodiment that the inventor provides, the invention is not restricted to these embodiment.
Embodiment 1:TAT-PEG
2-PMLA (DOX)-Hz-PEG
6The foundation of-FA medicine-carried system
(1) aldehyde radical Polyethylene Glycol-folic acid (CHO-PEG
6-FA) preparation
Take by weighing 44 mg folic acid (FA) and be dissolved among an amount of DMSO, add 22mg (Boc) successively
2O, 20 mg triethylamines, the room temperature lucifuge is reacted 4 h, obtains the FA of Boc protection; Add 170 mg HO-PEG then successively
6-CHO (M
n: 6000), 19 mg EDCHCl, 10 mg DMAP, room temperature lucifuge, stirred overnight; Reactant liquor is with DMSO 24 h that dialyse, deionized water 48 h that dialyse, and lyophilization obtains CHO-PEG-FA (Boc); CHO-PEG-FA (Boc) is dissolved in the anhydrous CH of 10 mL
2Cl
2In, Dropwise 5 mL TFA, stirring at room 4 h revolve to steam and remove CH
2Cl
2And TFA, obtain FA-PEG-CHO.
(2) have the polymalic acid (PMLA-NH of hydrazides key
2) preparation
Take by weighing 80 mg PMLA, 88 mg NHS are dissolved among the 20 ml DMF, stir 5 min under the room temperature.Add 192 mg EDC HCl, reaction 2 h in the ice-water bath.Dropwise add 1 ml, 5 % hydrazine hydrate solutions, reaction is spent the night under the room temperature.Reacted solution was with deionized water dialysis two days, and lyophilization gets product.The infared spectrum of PMLA (Figure 1A) is compared, among Figure 1B at 1612 cm
-1New strong absworption peak occurred, be the characteristic absorption peak of carbonyl in the amido link, shown to have formed amido link, PMLA-NH
2Synthesize successfully.NH
2Substitution value is gone up substituted number of amino groups in per 100 construction units (being carboxyl), through being determined as 75.
(3) polymalic acid-Polyethylene Glycol-folic acid (PMLA-Hz-PEG
6-FA) preparation
Take by weighing 6 mg PMLA-NH
2With 126 mg OHC-PEG
6-FA is dissolved among 20 mLDMF, reaction 24 h under the room temperature.Deionized water dialysis 48 hours, lyophilization gets faint yellow solid.PEG
6The percent grafting of-FA (is the PEG that is connected in molar percentage
6The mole ratio of-FA molal quantity and construction unit), recording the product percent grafting through ultraviolet spectrophotometry (280nm) is 8.65 mol%.The characteristic peak of folic acid has all appearred in the 6.7-9.0 ppm place of Fig. 2 A Fig. 2 B, has confirmed the generation of target product.
(4) TAT-PEG
2-PMLA (DOX)-Hz-PEG
6The preparation of-FA
Take by weighing an amount of HO-PEG
2-COOH (Mn:2,000) dissolves among an amount of DMF, adds EDC HCl and TEA, under the ice-water bath condition with TAT-NH
2DMF solution slowly drip room temperature reaction 24 h behind 0 ℃ of reaction 2h.Reactant liquor is dialysed with deionized water, and lyophilization obtains TAT-PEG
2-OH.The product P MLA-Hz-PEG that (3) are obtained
6-FA is dissolved among an amount of DMF, adds 192mg EDC HCl, 0.14mL TEA, and ice-water bath stirs.With the TAT-PEG that is dissolved in DMF in advance
2-OH and quantitative amycin (DOX) solution join in this system gradually, are transferred to room temperature reaction 24 h behind 0 ℃ of reaction 2h.Reaction finishes the back with deionized water 24 h that dialyse, and lyophilization obtains yellow powder shape product.
(5) preparation of polymer micelle
Take by weighing the 10mg end-product and be dissolved among the 20mLDMSO, the 24h that dialyses in the deionized water is self-assembled into nano-micelle (Fig. 3), the form rounding.
(6) take the photograph experiment in the cell
With A2780 is cell model, and the subject cell of exponential phase is mixed with 5 * 10
5The cell suspension of/mL is inoculated on 96 orifice plates by every hole 200 μ L, treats that cell is long when about 80% converges, and outwells original culture medium, changes the TAT-PEG of the 200 μ L (2 μ g/mL) of pH6.6 and pH7.4 respectively
2-PMLA (DOX)-Hz-PEG
6-FA solution is cultivated 2h altogether, earlier rinses sample cell well with PBS afterwards, and 3% glutaraldehyde is fixedly behind the 5min, the hoechst33342 fluorescent dye pair cell 15min that dyes, under the fluorescence microscope observation of cell in take the photograph phenomenon.Take the photograph experimental result in the cell and show, when pH6.6, go into born of the same parents' efficient when this system is gone into born of the same parents' efficient apparently higher than physiological pH 7.4.Explanation after the hydrazone bond fission of connection folic acid, is exposed TAT under acid condition, under the leading who wears the film peptide, get into cell fast.The flow cytometer testing result shows equally: in the identical time, the polymalic acid nano-complex is gone into the matched group (Fig. 4) that born of the same parents' effect is significantly higher than physiological pH under the acid condition.
Adopt same procedure targeting group folic acid to be changed into the TAT-PEG for preparing behind the luteinizing hormone releasing hormone (LHRH)
2-PMLA (DOX)-Hz-PEG
6-LHRH nano-complex has also obtained similar experimental result.
Embodiment 2:TAT-PMLA (CPT-NH
2)-Hz-PEG
6The foundation of medicine-carried system
Take by weighing excessive slightly polymalic acid (PMLA; Mn:5,000) 30mg is dissolved among an amount of DMF, adds EDC HCl 100mg, 2 ml, 5 % hydrazine hydrates, stirred overnight at room temperature.Add 200mg OHC-PEG
6-OH (Mn:6,000) stirring at room 10h.Finish the back with the deionized water 48h that dialyses, to remove unreacted substrate and solvent, lyophilization promptly gets product P MLA-Hz-PEG
6-OH.
With PMLA-Hz-PEG
6-OH is dissolved among an amount of DMF, adds EDC HCl and TEA, and ice-water bath stirs.The DMF solution of an amount of TAT is dropwise joined in this system, add 50mg amino camptothecin (CPT-NH again
2), be transferred to room temperature reaction 24h behind 0 ℃ of reaction 2h, deionized water dialysis 24h, lyophilization obtains yellow powder TAT-PMLA (CPT-NH
2)-Hz-PEG
6
Preliminary biological experiment confirm this protection/go protect the method for TAT can effectively strengthen nano-complex in take the photograph efficient, reach the effect of efficiently going into born of the same parents.Polymalic acid carrier medicament of the present invention can be a graft brush shape structure, also can be polymer micelle (as shown in Figure 5), becomes the mode that also can adopt physical encapsulation in the micellar process that medicine and the sensitizer that some is difficult for connecting is written into.
Claims (10)
1. a polymalic acid carrier medicament is that medicine is fixed on the polymalic acid carrier, it is characterized in that:
(1) said medicine is to contain amino maybe can introduce amino antitumor drug and derivant thereof;
(2) be connected with on the polymalic acid carrier and wear the film peptide;
(3) the targeting group of targeting group or flexible chain modification is connected on the polymalic acid carrier through the easy fracture key.
2. polymalic acid carrier medicament according to claim 1 is characterized in that: said antitumor drug or derivatives thereof is amycin, amino camptothecin, azacitidine or carat Qu Bin.
3. polymalic acid carrier medicament according to claim 1 is characterized in that: the said film peptide CPP that wears modifies or is directly connected on the polymalic acid carrier through flexible short chain, and said flexible short chain is that Polyethylene Glycol connects, and molecular weight is 500～3000.
4. polymalic acid carrier medicament according to claim 1 is characterized in that: the molecular weight of described polymalic acid is 1000 ~ 200,000.
5. polymalic acid carrier medicament according to claim 1 is characterized in that: said flexible chain is that Polyethylene Glycol connects, and molecular weight is 3000～7000.
6. according to claim 1 or 3 described polymalic acid carrier medicaments, it is characterized in that: the said film peptide of wearing also comprises having the nuclear localization signal peptide that passes nucleus, cell membrane function.
7. polymalic acid carrier medicament according to claim 1; It is characterized in that: said targeting group is the material with tumor cell targeting; Comprise that all solid tumor tissue surfaces have the part of the receptor of its corresponding relative high expressed, kind is vitamin, albumen, peptide class, polysaccharide or integrates plain.
8. polymalic acid carrier medicament according to claim 7 is characterized in that: said targeting group is folic acid, luteinising hormone-releasing hormo, biotin, transferrins, low density lipoprotein, LDL, enoxolone, agglutinin, antineoplastic amalgamation protein, monoclonal antibody or synthetic part.
9. the method for preparing of the said polymalic acid carrier medicament of claim 1 may further comprise the steps:
(1) under the catalysis of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-maloyl imines and triethylamine, polymalic acid PMLA and hydrazine hydrate prepared in reaction obtain PMLA-NH
2, the carboxyl that wherein contains in the polymalic acid and the mol ratio of hydrazine hydrate are between 10 ~ 1;
(2) the Polyethylene Glycol OHC-PEG-Ligand that selects for use the Polyethylene Glycol that contains aldehyde radical and targeting group L igand prepared in reaction to obtain the targeting base group modificationization; The molecular weight of the Polyethylene Glycol of selecting for use that contains aldehyde radical is 3500 ~ 7000, and wherein the reaction mol ratio of Ligand and aldehyde radical Polyethylene Glycol is between 0.1 ~ 10;
(3) with PMLA-NH
2Be dissolved in the DMF solvent with OHC-PEG-Ligand, reacting under the room temperature obtains PMLA-Hz-PEG-Ligand, forms required hydrazone key spacer, wherein PMLA-NH
2The reaction mol ratio of middle amino and OHC-PEG-Ligand is 0.5 ~ 1;
(4) PMLA-Hz-PEG-Ligand with wear film peptide TAT or TAT-PEG reaction and obtain TAT-PMLA-Hz-PEG-Ligand or TAT-PEG-PMLA-Hz-PEG-Ligand, the wherein molecular weight 500 ~ 3000 of short chain PEG;
(5) under the catalysis of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-maloyl imines and triethylamine, TAT-PMLA-Hz-PEG-Ligand or TAT-PEG-PMLA-Hz-PEG-Ligand are obtained the polymalic acid carrier medicament with the antitumor drug or derivatives thereof prepared in reaction that contains amino.
10. the described polymalic acid carrier medicament of claim 1 has the cancer target specificity concurrently and efficiently goes into the application in born of the same parents' drug release feature medicine in preparation.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140017329A1 (en) * | 2012-07-10 | 2014-01-16 | Shaker A. Mousa | Nanoformulation and methods of use of thyroid receptor beta1 agonists for liver targeting |
| CN104277209A (en) * | 2013-07-08 | 2015-01-14 | 江南大学 | Polyelectrolyte terpolymer and preparation of nano micelle |
| CN108218932A (en) * | 2017-12-27 | 2018-06-29 | 北京大学 | The cancer pre-targeting medicine of agglutinin receptor mediation |
| CN111182913A (en) * | 2017-10-02 | 2020-05-19 | 西奈医疗中心 | Methods and compositions for effective delivery through multiple biological barriers |
| CN112843251A (en) * | 2021-02-03 | 2021-05-28 | 中国药科大学 | Cell-penetrating peptide modified drug carrier and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879315A (en) * | 2010-08-16 | 2010-11-10 | 中国人民解放军第四军医大学 | Polymalic acid prodrug derivant and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101879315A (en) * | 2010-08-16 | 2010-11-10 | 中国人民解放军第四军医大学 | Polymalic acid prodrug derivant and applications thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140017329A1 (en) * | 2012-07-10 | 2014-01-16 | Shaker A. Mousa | Nanoformulation and methods of use of thyroid receptor beta1 agonists for liver targeting |
| US9956291B2 (en) * | 2012-07-10 | 2018-05-01 | Shaker A. Mousa | Nanoformulation and methods of use of thyroid receptor beta1 agonists for liver targeting |
| CN104277209A (en) * | 2013-07-08 | 2015-01-14 | 江南大学 | Polyelectrolyte terpolymer and preparation of nano micelle |
| CN104277209B (en) * | 2013-07-08 | 2016-08-10 | 江南大学 | A kind of polyelectrolyte terpolymer and the preparation of nano-micelle thereof |
| CN111182913A (en) * | 2017-10-02 | 2020-05-19 | 西奈医疗中心 | Methods and compositions for effective delivery through multiple biological barriers |
| CN108218932A (en) * | 2017-12-27 | 2018-06-29 | 北京大学 | The cancer pre-targeting medicine of agglutinin receptor mediation |
| CN112843251A (en) * | 2021-02-03 | 2021-05-28 | 中国药科大学 | Cell-penetrating peptide modified drug carrier and preparation method and application thereof |
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