CN102766262A - Preparation method for difunctional nanoparticle carrier and preparation method for difunctional nanoparticle preparation - Google Patents
Preparation method for difunctional nanoparticle carrier and preparation method for difunctional nanoparticle preparation Download PDFInfo
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- CN102766262A CN102766262A CN2012102519108A CN201210251910A CN102766262A CN 102766262 A CN102766262 A CN 102766262A CN 2012102519108 A CN2012102519108 A CN 2012102519108A CN 201210251910 A CN201210251910 A CN 201210251910A CN 102766262 A CN102766262 A CN 102766262A
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Abstract
The invention discloses a preparation method for a difunctional nanoparticle carrier and a preparation method for a difunctional nanoparticle preparation. The preparation method for the difunctional nanoparticle carrier comprises the following steps of: synthesizing ester with formyl by using poly(lactic-co-glycolic acid)-COOH (PLGA-COOH) and p-hydroxybenzaldehyde as raw materials in the presence of 4-dimethylaminopyridine and a condensing agent; synthesizing a PLGA derivative with an acid-sensitive connecting segment hydrazone bond by using the ester with the formyl and carboxyl phenylhydrazine in the presence of p-toluenesulfonic acid; conjugating NH2-polyethylene glycol (PEG)-NH2 and the PLGA derivative with the acid-sensitive connecting segment hydrazone bond in the presence of N-hydroxysuccinimide (NHS) and the condensing agent; and adding folate, the NHS and the condensing agent, and conjugating again to obtain the difunctional nanoparticle carrier PLGA-PEG-folate. The prepared difunctional nanoparticle carrier shows a good pharmacokinetic behavior in vitro, and has high medicine-loading rate, encapsulation rate and stability.
Description
Technical field
The present invention relates to the preparation method of a kind of nanoparticulate carriers and nano particle preparations, specifically is the preparation method of a kind of difunctional nanoparticulate carriers and difunctional nano particle preparations.
Background technology
Targeted nanometer drug delivery system can be divided into initiatively target and passive target administration nano-drug administration system usually.Initiatively the important directions of targeting drug delivery system research is to utilize the specificity bonded principle of acceptor and aglucon, synthetic nanoparticulate carriers with active target function.Folic acid (Folate) is use always in the active target ligand a kind of, and all there is the folacin receptor over-expresses on many tumor cell membranes surface.Based on this special effect, can be with importing in these tumour cells with folic acid bonded pharmaceutical carrier.An important research direction of passive target administration nano-drug administration system is to develop the drug-carrying nanometer particle of pH responsive type according to the acid base imbalance of tumor tissues microenvironment.The pH value of tumor tissues microenvironment (5.7～7.8, MV is 7.0) is lower than healthy tissues (pH=7.4).Under normal neutral pH; This nanoparticle is more stable, but when it got into the slant acidity environment of tumor tissues, particle can quicken disintegration; Thereby the medicine that is carried by bag in the snap-out release nanoparticle makes medicine in tumour, reach a higher concentration to improve curative effect.The hydrazone key (C=N-N-) very stable under the physiological pH condition, but very fast hydrolysis under solutions of weak acidity is a kind of pH responsive type linkage section commonly used.
In fact; Targeted nanometer drug delivery system is engulfed by phagocytic cell after getting into blood easily, and phagolysis is then protein mediated through lipophilic conditioning in the blood, and the nanoparticle diameter is controlled at below the 300nm; And use hydrophilic material; (PEG) carries out finishing like polyoxyethylene glycol, can reduce phagocytic cell to the catching of nanoparticle, and plays the function of " long circulation ".In addition, poly (lactic acid-glycolic acid) (PLGA) is one of common carrier of nanoparticle preparation, has excellent biological compatibility, and poisonless biological degradable, is included USP through U.S. FDA authentication and quilt, is widely used in pharmacy, medical engineering field of materials.
Retrieval through to prior art finds that folic acid initiatively targeted nanometer drug delivery system treatment tumour appears in the newspapers.Kin SH; Jeong JH, people such as Chun KW disclose and have a kind ofly shown the electropositive polymer P LL-PEG-Folate that is connected to folic acid (Langmuir 2005,21:8852-8857); Experimental result has confirmed the targeting of folic acid; Compare with control group, the KB cell absorbs and improves 5.7 times, and the cell that folacin receptor is expressed has obvious selectivity.In addition, also has Eanaeili F, Ghahremani MH; PLGA folic acid targeted nano granule (the J Drug Target 2008 of the disclosed a kind of carrying docetaxels of people such as Ostad SN; 16:415-423), the cell experiment result shows that nanoparticle has good targeting.In addition, the nanoparticulate carriers that contains acid-sensitive sense linkage section also has report, for example Bae Y; Fukushima S; Human hydrazone keys such as Harada A be connected to Zorubicin on the aspartic acid units of PEO-b-p (Asp) (Angew Chem Int Engl.2003,42:4640-4643), the release test result shows; Along with the pH value reduces, drug release is obviously accelerated.Yet existing research is to connect with acid-sensitive sense key between polymkeric substance and the medicine mostly, big limitations by the kind of bag medicine carrying thing.And; The difunctional nanoparticulate carriers PLGA-PEG-Folate (that is: pH responsive type folic acid targeted nano granule carrier PLGA-PEG-Folate) that has folic acid and acid-sensitive sense key linking group concurrently does not appear in the newspapers, and the development of this Performances of Novel Nano-Porous grain of rice carrier will provide new approaches for the administration nano-drug administration system antineoplaston.
Summary of the invention
To the above-mentioned deficiency that prior art exists, the present invention provides the preparation method of a kind of difunctional nanoparticulate carriers and difunctional nano particle preparations.The particle diameter that the bag of the present invention's preparation carries the difunctional nano particle preparations of vincristine sulphate is 146.5 ± 7.3nm, has good encapsulation rate, drug loading and stability.
First purpose of the present invention realizes through following technical scheme:
A kind of method for preparing difunctional nanoparticulate carriers may further comprise the steps:
Step 1 under the condition of 4-Dimethylamino pyridine and condensing agent existence, is the ester of raw material anamorphic zone carboxaldehyde radicals with PLGA-COOH and PARA HYDROXY BENZALDEHYDE;
Step 3 under the condition inferior and that exist with condensing agent, makes NH at N-hydroxyl succinyl-
2-PEG-NH
2Close with the said PLGA verivate yoke that has acid-sensitive sense linkage section hydrazone key; Add folic acid, NHS and condensing agent again, take place once more that yoke closes, obtain difunctional nanoparticulate carriers PLGA-PEG-Folate.
Preferably, among the said difunctional nanoparticulate carriers PLGA-PEG-Folate, the weight-average molecular weight of said PEG is 4000Da, and the weight-average molecular weight of said PLGA is 15000Da.
Preferably, said condensing agent is N, the N'-NSC 57182.
Another object of the present invention realizes through following technical scheme:
A kind of method for preparing the difunctional nano particle preparations of bag year vincristine sulphate may further comprise the steps:
Step 1 is dissolved in the Tris-HCl damping fluid with vincristine sulphate, gets mixing solutions;
Step 3, under ultrasonic condition of ice bath, the PVA drips of solution that will contain the Tris-HCl damping fluid adds to said Ruzhong just, obtains emulsion;
Preferably, the weight ratio of said vincristine sulphate and said difunctional nanoparticulate carriers is (1.0～1.5): 10.
Preferably, the pH value of said Tris-HCl damping fluid is 5～7.4.
Preferably, the said Tris-HCl damping fluid in Ruzhong just is 1 with the volume of organic solvent ratio: (5～20).
Preferably, said organic solvent is methylene dichloride or acetone.
Preferably, the pH value of said PVA solution is 5～7.4, and the percent weight in volume concentration of said PVA solution is 0.6～2%.
Preferably, the concrete steps of said centrifugal low-temperature freeze drying are: with the rotating speed centrifugal treating of 12000～50000rpm low-temperature freeze drying after 30 minutes.
The application method of above-mentioned nanoparticle provided by the invention is: be positioned over dialysis tubing through the solution with said nanoparticle and be placed in the release medium, realize drug release through the vibration of constant temperature shaking table.Said dialysis tubing molecular weight cut-off is 3000～10000Da; Said constant temperature is 37 ± 0.5 ℃; Said release medium is phosphate buffered saline buffer or Tris-HCl damping fluid.
The present invention passes through four basic building unit: folic acid (Folate), polyoxyethylene glycol (PEG), poly (lactic acid-glycolic acid) (PLGA), pH sensitive group hydrazone key are (C=N-N-); Synthesize difunctional nanoparticulate carriers PLGA-PEG-Folate through acylation reaction, esterification, nucleophilic substitution/addition reaction and condensation reaction; Through compound emulsion method the vincristine sulphate bag is stated among the said difunctional nanoparticulate carriers PLGA-PEG-Folate, makes the difunctional nanoparticle that bag carries vincristine sulphate.
Beneficial effect of the present invention is: the particle diameter that bag provided by the invention carries the difunctional nanoparticle of vincristine sulphate is 146.5 ± 7.3nm, has good encapsulation rate, drug loading and stability.With the vincristine sulphate aqueous solution, the PLGA-PEG nanoparticle of non-modification is compared, and the difunctional nanoparticle that bag carries vincristine sulphate has good cell toxicity, shows good performance in vivo and in vitro.Thereby the difunctional nano particle preparations of difunctional nanoparticulate carriers PLGA-PEG-Folate and bag year vincristine sulphate is a kind of ideal pharmaceutical carrier.
Description of drawings
Fig. 1 is polymkeric substance NH
2-PEG-NH
2Synthetic route chart;
Fig. 2 is polymkeric substance NH
2-PEG-NH
2 1HNMR is figure as a result;
Fig. 3 is the synthetic route chart that is connected with the PLGA verivate of hydrazone key;
Fig. 4 is the PLGA verivate that is connected with the hydrazone key
1HNMR is figure as a result;
Fig. 5 is the synthetic route chart of difunctional nanoparticulate carriers PLGA-PEG-Folate;
Fig. 6 is difunctional nanoparticulate carriers PLGA-PEG-Folate
1HNMR is figure as a result;
Fig. 7 is the transmission electron microscope picture that bag carries the difunctional nanoparticle of vincristine sulphate;
Fig. 8 is the release behavior of three kinds of vincristine sulphate formulations in Tris-HCl damping fluid figure as a result;
Fig. 9 is the release behavior of three kinds of vincristine sulphate formulations in ammonium acetate buffer figure as a result.
Embodiment
Below in conjunction with specific embodiment the present invention is elaborated.Following examples will help those skilled in the art further to understand the present invention, but not limit the present invention in any form.Should be pointed out that to those skilled in the art, under the prerequisite that does not break away from the present invention's design, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1
Present embodiment relates to the preparation method of a kind of difunctional nanoparticulate carriers PLGA-PEG-Folate;
Difunctional nanoparticulate carriers PLGA-PEG-Folate's is synthetic, specifically may further comprise the steps:
(1) with HO-PEG-OH is raw material, through synthetic NH of three steps
2-PEG-NH
2, building-up process is as shown in Figure 1, NH
2-PEG-NH
2 1HNMR result is as shown in Figure 2;
(2) with CH
2Cl
2Be solvent, make the reaction of good PLGA-COOH of activation and PARA HYDROXY BENZALDEHYDE, add the catalyzer tosic acid afterwards; Condensation reaction takes place; Formation gathers and is connected with the hydrazone key (PLGA verivate NH-N=CH-), building-up process is as shown in Figure 3, is connected with the PLGA verivate of hydrazone key
1HNMR result is as shown in Figure 4;
(3) being connected with after the PLGA verivate carboxyl terminal activation of hydrazone key, is solvent with DMF, NHS be catalyzer, with NH
2-PEG-NH
2Acylation reaction takes place, add catalyzer pyridine, DCC and reactant folic acid again, generate difunctional nanoparticulate carriers PLGA-PEG-Folate, building-up process is as shown in Figure 5, difunctional nanoparticulate carriers PLGA-PEG-Folate's
1HNMR result is as shown in Figure 6.
Present embodiment relates to the preparation method that a kind of bag carries the difunctional nano particle preparations of vincristine sulphate;
Bag carries the preparation of the difunctional nano particle preparations of vincristine sulphate, may further comprise the steps:
(1) vincristine sulphate is dissolved in the Tris-HCl damping fluid of pH6.8; Be made into strong solution (being called the phase I); PLGA-mPEG is dissolved in the organic solvent (methylene dichloride or acetone) (being called II mutually) with difunctional nanoparticulate carriers PLGA-PEG-Folate (the two mass ratio is 8:1); The Tris-HCl damping fluid is 1 with the volume of organic solvent ratio: (5～20), vincristine sulphate dosage are 10%～15% (w/w);
(2) under the ultrasonic condition of ice bath, the phase I is added drop-wise in the phase II, obtains colostrum;
(3) under the ultrasonic condition of ice bath, will contain 0.6%～2%PVA (w/v) and pH and be 5～7.4 Tris-HCl damping fluid and be added drop-wise to Ruzhong just, obtain the emulsion of W/O/W;
(4) rotary evaporation is removed the organic solvent in the emulsion;
(5) (12000～50000rpm) 30min remove free VCR, obtain having blue opalescent nanoparticle solution with the solution high speed centrifugation that obtains in the step (4);
(6) with nanoparticle solution low-temperature freeze drying, promptly obtain wrapping the difunctional nano particle preparations NP2 that carries vincristine sulphate, detect with transmission electron microscope, its TEM results is as shown in Figure 7.
Embodiment 3
Present embodiment relates to a kind of preparation method of PLGA-mPEG nanoparticle;
The preparation method obtains PLGA-mPEG nano particle preparations NP1 with embodiment 1 and embodiment 2.
Bag carries the release of the difunctional nanoparticle of vincristine sulphate
Get vincristine sulphate solution (VCR-Sol), vincristine sulphate PLGA-mPEG nanoparticle (VCR-PLGA-mPEG-NPs) and the difunctional nanoparticle of vincristine sulphate (VCR-PLGA-mPEG/PLGA-pH-PEG-Folate-NPs) and place dialysis tubing (3000 ~ 5000Da); In volume is (acetate buffer or Tris-HCl damping fluid) in the 50mL release medium; 37 ℃ of constant temperature shaking table concussions; Timing sampling is measured the content of VCR in the release medium with performance liquid; Calculate total release percentage, release profiles such as Fig. 8 and shown in Figure 9.
Through the research to the releasing properties of sample in two kinds of release medium, the result shows that VCR-Sol release in two media is all fast, and the 8h medicine basically all discharges.In neutral medium; The release behavior of two kinds of nanoparticles is similar basically, being divided into prominent release with slowly-releasing two mutually, but in acid release medium; The release behavior of two kinds of nanoparticles has obvious difference; VCR-PLGA-mPEG/PLGA-pH-PEG-Folate-NPs has significantly prominent releasing before 8h, total release percentage reaches more than 70%, with the nanoparticle that does not add PLGA-Ph-PEG-Folate very big difference is arranged.This explains that difunctional nanoparticulate carriers brought into play the characteristic of acid sensitivity really.
Implementation result
Particle diameter, Zeta potential, medicine Zhi Zailiang and encapsulation rate to two kinds of nanoparticle NP1 and NP2 characterize, and characterization result is as shown in table 1.
Table 1
Visible by table 1, two kinds of prepared nanoparticle particle diameters are at 100～150nm, Zeta potential-below the 4mv.
NP1, NP2, the VCR aqueous solution and the human breast cancer cell of different concns are hatched 24h jointly, detect cell survival rate with MTT then, calculate its IC50 value.NP1, NP2, the former drug solns of VCR is as shown in table 2 to the IC50 value of human breast cancer cell strain.
Table 2
| Pharmaceutical prepn | IC(μg/mL) |
| F-VCR | 9.05±1.02 |
| NP1 | 5.37±0.54 |
| NP2 | 3.97±0.19** |
< 0.05 adopts t check nanoparticle group and F-VCR to carry out statistical analysis to * p.
Can find out that by table 2 under same concentrations, the cytotoxicity of the VCR of two kinds of nanoparticle forms all is better than the former drug solns of VCR, and the difunctional nano particle preparations NP2 that bag carries vincristine sulphate has minimum IC50 value, show the strongest CDCC.Can know that the difunctional nano particle preparations that bag carries vincristine sulphate has good cell toxicity.
In sum, the particle diameter that bag provided by the invention carries the difunctional nanoparticle of vincristine sulphate is 146.5 ± 7.3nm, has good encapsulation rate, drug loading and stability.With the vincristine sulphate aqueous solution, the PLGA-PEG nanoparticle of non-modification is compared, and the difunctional nanoparticle that bag carries vincristine sulphate has good cell toxicity, shows good performance in vivo and in vitro.Thereby the difunctional nano particle preparations of difunctional nanoparticulate carriers PLGA-PEG-Folate and bag year vincristine sulphate is a kind of ideal pharmaceutical carrier.
Claims (10)
1. a method for preparing difunctional nanoparticulate carriers is characterized in that, may further comprise the steps:
Step 1 under the condition of 4-Dimethylamino pyridine and condensing agent existence, is the ester of raw material anamorphic zone carboxaldehyde radicals with PLGA-COOH and PARA HYDROXY BENZALDEHYDE;
Step 2, under the condition that tosic acid exists, the synthetic PLGA verivate that obtains having acid-sensitive sense linkage section hydrazone key of the ester of band carboxaldehyde radicals and carboxyl phenylhydrazine;
Step 3 under the condition inferior and that exist with condensing agent, makes NH at N-hydroxyl succinyl-
2-PEG-NH
2Close with the said PLGA verivate yoke that has acid-sensitive sense linkage section hydrazone key; Add folic acid, NHS and condensing agent again, take place once more that yoke closes, obtain difunctional nanoparticulate carriers PLGA-PEG-Folate.
2. the method for the difunctional nanoparticulate carriers of preparation according to claim 1 is characterized in that, among the said difunctional nanoparticulate carriers PLGA-PEG-Folate, the weight-average molecular weight of said PEG is 4000Da, and the weight-average molecular weight of said PLGA is 15000Da.
3. the method for the difunctional nanoparticulate carriers of preparation according to claim 1 and 2 is characterized in that, said condensing agent is N, the N'-NSC 57182.
4. one kind prepares the method that bag carries the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, may further comprise the steps:
Step 1 is dissolved in the Tris-HCl damping fluid with vincristine sulphate, gets mixing solutions;
Step 2 under ultrasonic condition of ice bath, is added drop-wise to said mixing solutions in the organic solution that contains the said difunctional nanoparticulate carriers of claim 1, obtains colostrum;
Step 3, under ultrasonic condition of ice bath, the PVA drips of solution that will contain the Tris-HCl damping fluid adds to said Ruzhong just, obtains emulsion;
Step 4, said emulsion is through behind the rotary evaporation, and centrifugal low-temperature freeze drying obtains wrapping the difunctional nanoparticle that is loaded with vincristine sulphate.
5. preparation bag according to claim 4 carries the method for the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, the weight ratio of said vincristine sulphate and said difunctional nanoparticulate carriers is (1.0～1.5): 10.
6. preparation bag according to claim 4 carries the method for the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, the pH value of said Tris-HCl damping fluid is 5～7.4.
7. preparation bag according to claim 4 carries the method for the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, the said Tris-HCl damping fluid in Ruzhong just is 1 with the volume of organic solvent ratio: (5～20).
8. preparation bag according to claim 4 carries the method for the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, said organic solvent is methylene dichloride or acetone.
9. preparation bag according to claim 4 carries the method for the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, the pH value of said PVA solution is 5～7.4, and the percent weight in volume concentration of said PVA solution is 0.6～2%.
10. the method for carrying the difunctional nano particle preparations of vincristine sulphate according to each described preparation bag of claim 4 to 9; It is characterized in that the concrete steps of said centrifugal low-temperature freeze drying are: with the rotating speed centrifugal treating of 12000～50000rpm low-temperature freeze drying after 30 minutes.
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| CN103494829A (en) * | 2013-09-29 | 2014-01-08 | 上海交通大学 | Multifunctional nanoparticle preparation capable of preventing drug tolerance and preparation method thereof |
| CN104434792A (en) * | 2013-09-12 | 2015-03-25 | 中国科学院深圳先进技术研究院 | Polymer micelle, preparation method thereof, antitumor pharmaceutical composition, preparation and preparation method thereof |
| CN104961887A (en) * | 2015-07-07 | 2015-10-07 | 河南大学 | pH-sensitive degradable polymer, and preparation method and application thereof |
| CN105153428A (en) * | 2015-07-02 | 2015-12-16 | 天津大学 | PH responsive polymeric micelle for mucus infiltration and preparation method thereof |
| CN106432741A (en) * | 2016-09-09 | 2017-02-22 | 大连大学 | Preparation method of folic acid grafted PLLA-PEG-PLLA copolymer |
| CN108553446A (en) * | 2018-05-16 | 2018-09-21 | 上海交通大学 | A kind of double nanoparticulate carriers and nano particle preparations for carrying medicine of sensitive |
| WO2019019773A1 (en) * | 2017-07-28 | 2019-01-31 | 上海中医药大学附属岳阳中西医结合医院 | Triptolide-folic acid targeted nano-drug, preparation method therefor and use thereof |
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| CN106432741A (en) * | 2016-09-09 | 2017-02-22 | 大连大学 | Preparation method of folic acid grafted PLLA-PEG-PLLA copolymer |
| CN106432741B (en) * | 2016-09-09 | 2019-09-13 | 大连大学 | A kind of preparation method based on folic acid grafting PLLA-PEG-PLLA copolymer |
| WO2019019773A1 (en) * | 2017-07-28 | 2019-01-31 | 上海中医药大学附属岳阳中西医结合医院 | Triptolide-folic acid targeted nano-drug, preparation method therefor and use thereof |
| CN108553446A (en) * | 2018-05-16 | 2018-09-21 | 上海交通大学 | A kind of double nanoparticulate carriers and nano particle preparations for carrying medicine of sensitive |
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