CN102766262B - 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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- CN102766262B CN102766262B CN201210251910.8A CN201210251910A CN102766262B CN 102766262 B CN102766262 B CN 102766262B CN 201210251910 A CN201210251910 A CN 201210251910A CN 102766262 B CN102766262 B CN 102766262B
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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 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 conventionally.Initiatively the important directions of targeting drug delivery system research is the principle of utilizing acceptor to be combined with the specificity of aglucon, the synthetic nanoparticulate carriers with active target function.Folic acid (Folate) is conventional one in active target ligand, and there is folacin receptor overexpression on many tumor cell membranes surface.Based on this special effect, the pharmaceutical carrier of being combined with folic acid can be imported in these tumour cells.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 (5.7～7.8, mean value is 7.0) of tumor tissues microenvironment is lower than healthy tissues (pH=7.4).Under normal neutral pH, this nanoparticle is more stable, but in the time that it enters the slant acidity environment of tumor tissues, particle can accelerate disintegration, thereby discharge fast the medicine being carried by bag in nanoparticle, make medicine in tumour, reach a higher concentration to improve curative effect.Hydrazone key (C=N-N-) is very stable under physiological pH condition, but hydrolysis very soon under solutions of weak acidity is a kind of conventional pH responsive type linkage section.
In fact, targeted nanometer drug delivery system is easily engulfed by phagocytic cell after entering blood, phagolysis is protein mediated by lipophilic conditioning in blood, by nanoparticle diameter control below 300nm, and with hydrophilic material, as polyoxyethylene glycol (PEG) carries out finishing, can reduce phagocytic cell to the catching of nanoparticle, play the function of " long circulation ".In addition, poly (lactic acid-glycolic acid) (PLGA) is one of common carrier of preparing of nanoparticle, has good biocompatibility, and poisonless biological degradable, authenticates and be included American Pharmacopeia by U.S. FDA, is widely used in pharmacy, medical engineering Material Field.
Through the retrieval of prior art is found, folic acid initiatively targeted nanometer drug delivery system treatment tumour appears in the newspapers.KinSH, Jeong JH, the people such as Chun KW disclose a kind of aobvious electropositive polymer P LL-PEG-Folate(Langmuir 2005 that is connected to folic acid, 21:8852-8857), experimental result has confirmed the targeting of folic acid, compared with control group, KB Cell uptake improves 5.7 times, and the cell that folacin receptor is expressed has obvious selectivity.In addition, also has Eanaeili F, Ghahremani MH, PLGA folate-targeted nanoparticle (the JDrug Target 2008 of the disclosed a kind of carrying docetaxels of people such as Ostad SN, 16:415-423), the demonstration of cell experiment result, nanoparticle has good targeting.In addition, nanoparticulate carriers containing acid-sensitive sense linkage section also has report, for example Bae Y, Fukushima S, the people such as Harada A are connected to Zorubicin with hydrazone key in the aspartic acid units of PEO-b-p (Asp) (Angew Chem Int Engl.2003,42:4640-4643), and release test result shows, along with pH value reduces, drug release is obviously accelerated.But existing research is to connect with acid-sensitive sense key between polymkeric substance and medicine mostly, has greatly limited by the kind of bag medicine carrying thing.And, have the difunctional nanoparticulate carriers PLGA-PEG-Folate(of folic acid and acid-sensitive sense key linking group concurrently: pH responsive type folate-targeted nanoparticulate carriers PLGA-PEG-Folate) have no report, the development of this Performances of Novel Nano-Porous grain of rice carrier will provide new approaches for administration nano-drug administration system antineoplaston.
Summary of the invention
For prior art above shortcomings, the invention provides the preparation method of a kind of difunctional nanoparticulate carriers and difunctional nano particle preparations.The particle diameter that bag prepared by the present invention carries the difunctional nano particle preparations of vincristine sulphate is 146.5 ± 7.3nm, has good encapsulation rate, drug loading and stability.
First object of the present invention is achieved through the following technical solutions:
A method of preparing difunctional nanoparticulate carriers, comprises the following steps:
Step 1, under the condition existing at DMAP and condensing agent, the ester taking PLGA-COOH and p-Hydroxybenzaldehyde as raw material anamorphic zone carboxaldehyde radicals;
Step 2, under the condition existing at tosic acid, the synthetic PLGA derivative obtaining with acid-sensitive sense linkage section hydrazone key of the ester with carboxaldehyde radicals and carboxyl phenylhydrazine;
Step 3, at N-hydroxyl succinyl-sub-and and the condition that exists of condensing agent under, make NH
2-PEG-NH
2close with the described PLGA derivative yoke with acid-sensitive sense linkage section hydrazone key; Add again folic acid, NHS and condensing agent, yoke again occurs and close, obtain difunctional nanoparticulate carriers PLGA-PEG-Folate.
Preferably, in described difunctional nanoparticulate carriers PLGA-PEG-Folate, the weight-average molecular weight of described PEG is 4000Da, and the weight-average molecular weight of described PLGA is 15000Da.
Preferably, described condensing agent is N, N'-dicyclohexylcarbodiimide.
Another object of the present invention is achieved through the following technical solutions:
Prepare the method that bag carries the difunctional nano particle preparations of vincristine sulphate, comprise the following steps:
Step 1, is dissolved in Tris-HCl damping fluid by vincristine sulphate, obtains mixing solutions;
Step 2, under ultrasonic condition of ice bath, is added drop-wise to described mixing solutions in the organic solution that contains described difunctional nanoparticulate carriers, obtains colostrum;
Step 3, under ultrasonic condition of ice bath, by drop to described just Ruzhong containing the PVA solution of Tris-HCl damping fluid, obtains emulsion;
Step 4, described emulsion is after rotary evaporation, and centrifugal low-temperature freeze drying, obtains wrapping the difunctional nanoparticle that is loaded with vincristine sulphate.
Preferably, the weight ratio of described vincristine sulphate and described difunctional nanoparticulate carriers is (1.0～1.5): 10.
Preferably, the pH value of described Tris-HCl damping fluid is 5～7.4.
Preferably, the described just Tris-HCl damping fluid in Ruzhong and the volume ratio of organic solvent are 1:(5～20).
Preferably, described organic solvent is methylene dichloride or acetone.
Preferably, the pH value of described PVA solution is 5～7.4, and the percent weight in volume concentration of described PVA solution is 0.6～2%.
Preferably, the concrete steps of described 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 placed in release medium by the solution of described nanoparticle is positioned over to dialysis tubing, realize drug release through constant-temperature table vibration.Described dialysis tubing molecular weight cut-off is 3000～10000Da; Described constant temperature is 37 ± 0.5 DEG C; Described 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 (C=N-N-); synthesize difunctional nanoparticulate carriers PLGA-PEG-Folate through acylation reaction, esterification, nucleophilic substitution/addition reaction and condensation reaction; by compound emulsion method, vincristine sulphate bag is loaded in described difunctional nanoparticulate carriers PLGA-PEG-Folate, makes the difunctional nanoparticle of bag year 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, non-modified PLGA-PEG nanoparticle is compared, and the difunctional nanoparticle that bag carries vincristine sulphate has good cytotoxicity, shows in vivo and in vitro good performance.Thereby the difunctional nano particle preparations of difunctional nanoparticulate carriers PLGA-PEG-Folate and bag year vincristine sulphate is a kind of desirable pharmaceutical carrier.
Brief description of the drawings
Fig. 1 is polymkeric substance NH
2-PEG-NH
2synthetic route chart;
Fig. 2 is polymkeric substance NH
2-PEG-NH
2's
1hNMR result figure;
Fig. 3 is the synthetic route chart that is connected with the PLGA derivative of hydrazone key;
Fig. 4 is the PLGA derivative that is connected with hydrazone key
1hNMR result figure;
Fig. 5 is the synthetic route chart of difunctional nanoparticulate carriers PLGA-PEG-Folate;
Fig. 6 is difunctional nanoparticulate carriers PLGA-PEG-Folate
1hNMR result figure;
Fig. 7 is the transmission electron microscope picture that bag carries the difunctional nanoparticle of vincristine sulphate;
Fig. 8 is the release behavior result figures of three kinds of vincristine sulphate formulations in Tris-HCl damping fluid;
Fig. 9 is the release behavior result figures of three kinds of vincristine sulphate formulations in ammonium acetate buffer.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1
The 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 comprises the following steps:
(1) taking HO-PEG-OH as raw material, through the synthetic NH of three steps
2-PEG-NH
2, building-up process as shown in Figure 1, NH
2-PEG-NH
2's
1hNMR result as shown in Figure 2;
(2) with CH
2cl
2for solvent, the PLGA-COOH having activated is reacted with p-Hydroxybenzaldehyde, add afterwards catalyzer tosic acid, there is condensation reaction, form the poly-PLGA derivative that is connected with hydrazone key (NH-N=CH-), building-up process as shown in Figure 3, is connected with the PLGA derivative of hydrazone key
1hNMR result as shown in Figure 4;
(3) after being connected with the PLGA derivative carboxyl terminal activation of hydrazone key, taking DMF as solvent, DCC NHS be catalyzer, with NH
2-PEG-NH
2there is acylation reaction, then add catalyzer pyridine, DCC and reactant folic acid, generate difunctional nanoparticulate carriers PLGA-PEG-Folate, building-up process as shown in Figure 5, difunctional nanoparticulate carriers PLGA-PEG-Folate's
1hNMR result as shown in Figure 6.
Embodiment 2
The present embodiment relates to a kind of bag and carries the preparation method of the difunctional nano particle preparations of vincristine sulphate;
Bag carries the preparation of the difunctional nano particle preparations of vincristine sulphate, comprises the following steps:
(1) vincristine sulphate is dissolved in the Tris-HCl damping fluid of pH6.8, be made into strong solution (being called phase I), PLGA-mPEG and difunctional nanoparticulate carriers PLGA-PEG-Folate (the two mass ratio is 8:1) are dissolved in organic solvent (methylene dichloride or acetone) (being called phase II), the volume ratio of Tris-HCl damping fluid and organic solvent is 1:(5～20), vincristine sulphate dosage is 10%～15%(w/w);
(2) under ultrasonic condition of ice bath, phase I is added drop-wise in phase II, obtains colostrum;
(3) under ultrasonic condition of ice bath, be added drop-wise to just Ruzhong by containing the Tris-HCl damping fluid that 0.6%～2%PVA (w/v) and pH are 5～7.4, obtain the emulsion of W/O/W;
(4) rotary evaporation, removes the organic solvent in emulsion;
(5) by solution high speed centrifugation (12000～50000rpm) 30min obtaining in step (4), remove free VCR, obtain the nanoparticle solution with blue-opalescent;
(6) by nanoparticle solution low-temperature freeze drying, obtain the difunctional nano particle preparations NP2 of bag year vincristine sulphate, with transmission electron microscope detection, its transmission electron microscope results is as shown in Figure 7.
Embodiment 3
The present embodiment relates to a kind of preparation method of PLGA-mPEG nanoparticle;
Preparation method, with embodiment 1 and embodiment 2, obtains PLGA-mPEG nano particle preparations NP1.
Embodiment 4
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 be placed in dialysis tubing (3000 ~ 5000Da), be (acetate buffer or Tris-HCl damping fluid) in 50mL release medium in volume, 37 DEG C of constant-temperature table concussions, timing sampling is measured the content of VCR in release medium with high performance liquid phase, calculate total release percentage, release profiles as shown in Figure 8 and Figure 9.
By the research of the releasing properties in two kinds of release medium to sample, result shows, VCR-Sol release in two media is all fast, and 8h medicine substantially all discharges.In neutral medium, the release behavior of two kinds of nanoparticles is substantially similar, be divided into prominent releasing and slowly-releasing two-phase, 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, and total release percentage reaches more than 70%, has very big difference with the nanoparticle that does not add PLGA-Ph-PEG-Folate.This illustrates 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
From table 1, two kinds of prepared nanoparticle particle diameters are at 100～150nm, Zeta potential-below 4mv.
The NP1 of different concns, NP2, the VCR aqueous solution and human breast cancer cell are hatched to 24h jointly, then detect cell survival rate with MTT, 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 preparation | IC(μg/mL) |
| F-VCR | 9.05±1.02 |
| NP1 | 5.37±0.54 |
| NP2 | 3.97±0.19** |
* p<0.05 adopts t inspection nanoparticle group and F-VCR to carry out statistical analysis.
As can be seen from Table 2, under same concentrations, the cytotoxicity of the VCR of two kinds of nanoparticle forms is all better than the former drug solns of VCR, and bag carries the difunctional nano particle preparations NP2 of vincristine sulphate and have minimum IC50 value, shows the strongest cytotoxicity.Known, the difunctional nano particle preparations that bag carries vincristine sulphate has good cytotoxicity.
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, non-modified PLGA-PEG nanoparticle is compared, and the difunctional nanoparticle that bag carries vincristine sulphate has good cytotoxicity, shows in vivo and in vitro good performance.Thereby the difunctional nano particle preparations of difunctional nanoparticulate carriers PLGA-PEG-Folate and bag year vincristine sulphate is a kind of desirable pharmaceutical carrier.
Claims (9)
1. a method of preparing difunctional nanoparticulate carriers, is characterized in that, comprises the following steps:
Step 1, under the condition existing at DMAP and condensing agent, the ester taking PLGA-COOH and p-Hydroxybenzaldehyde as raw material anamorphic zone carboxaldehyde radicals;
Step 2, under the condition existing at tosic acid, the synthetic PLGA derivative obtaining with acid-sensitive sense linkage section hydrazone key of the ester with carboxaldehyde radicals and carboxyl phenylhydrazine;
Step 3, under the condition of N-hydroxy-succinamide NHS and condensing agent existence, makes NH
2-PEG-NH
2close with the described PLGA derivative yoke with acid-sensitive sense linkage section hydrazone key; Add again folic acid, NHS and condensing agent, yoke again occurs and close, 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, in described difunctional nanoparticulate carriers PLGA-PEG-Folate, the weight-average molecular weight of described PEG is 4000Da, and the weight-average molecular weight of described PLGA is 15000Da.
3. the method for the difunctional nanoparticulate carriers of preparation according to claim 1 and 2, is characterized in that, described condensing agent is N, N'-dicyclohexylcarbodiimide.
4. prepare the method that bag carries the difunctional nano particle preparations of vincristine sulphate, it is characterized in that, comprise the following steps:
Step 1, is dissolved in Tris-HCl damping fluid by vincristine sulphate, obtains mixing solutions;
Step 2, under ultrasonic condition of ice bath, is added drop-wise to described mixing solutions in the organic solution that contains difunctional nanoparticulate carriers described in claim 1, obtains colostrum;
Step 3, under ultrasonic condition of ice bath, by drop to described just Ruzhong containing the PVA solution of Tris-HCl damping fluid, obtains emulsion;
Step 4, described emulsion is after rotary evaporation, and centrifugal low-temperature freeze drying, obtains wrapping the difunctional nanoparticle that is loaded with vincristine sulphate;
The weight ratio of described vincristine sulphate and described difunctional nanoparticulate carriers is (1.0～1.5): 10.
5. the method that preparation bag according to claim 4 carries the difunctional nano particle preparations of vincristine sulphate, is characterized in that, the pH value of described Tris-HCl damping fluid is 5～7.4.
6. the method that preparation bag according to claim 4 carries the difunctional nano particle preparations of vincristine sulphate, is characterized in that, the described just Tris-HCl damping fluid in Ruzhong and the volume ratio of organic solvent are 1:(5～20).
7. the method that preparation bag according to claim 4 carries the difunctional nano particle preparations of vincristine sulphate, is characterized in that, described organic solvent is methylene dichloride or acetone.
8. the method that preparation bag according to claim 4 carries the difunctional nano particle preparations of vincristine sulphate, is characterized in that, the pH value of described PVA solution is 5～7.4, and the percent weight in volume concentration of described PVA solution is 0.6～2%.
9. carry the method for the difunctional nano particle preparations of vincristine sulphate according to the preparation bag described in any one in claim 4 to 8, it is characterized in that, the concrete steps of described 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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| CN104434792B (en) * | 2013-09-12 | 2018-03-23 | 中国科学院深圳先进技术研究院 | Polymer micelle and preparation method thereof and antineoplastic pharmaceutical compositions, preparation and preparation method thereof |
| 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 |
| CN105153428B (en) * | 2015-07-02 | 2018-02-16 | 天津大学 | A kind of pH response macromolecule micelles for mucus infiltration and preparation method thereof |
| CN104961887B (en) * | 2015-07-07 | 2016-10-12 | 河南大学 | A kind of pH sensitivity degradable polymer, its preparation method and application |
| 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 |
| CN107281165A (en) * | 2017-07-28 | 2017-10-24 | 上海中医药大学附属岳阳中西医结合医院 | A kind of triptolide folate-targeted Nano medication and its preparation method and application |
| CN108553446B (en) * | 2018-05-16 | 2020-06-19 | 上海交通大学 | Double-sensitive double-drug-loading nanoparticle carrier and nanoparticle preparation |
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| CN101732723A (en) * | 2009-12-30 | 2010-06-16 | 上海市肿瘤研究所 | Polyethylene glycol-poly(lactic-co-glycolic acid)-polylysine nano-delivery system, preparation method and application thereof |
| CN101926775A (en) * | 2010-09-07 | 2010-12-29 | 上海交通大学 | Preparation and application methods of difunctional naonparticle preparation entrapping vincristine sulphate |
| CN102343099A (en) * | 2011-09-30 | 2012-02-08 | 中国人民解放军第四军医大学 | Preparation method and application of folacin mediated tumor targeting adriamycin prodrugs |
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| CN101732723A (en) * | 2009-12-30 | 2010-06-16 | 上海市肿瘤研究所 | Polyethylene glycol-poly(lactic-co-glycolic acid)-polylysine nano-delivery system, preparation method and application thereof |
| CN101926775A (en) * | 2010-09-07 | 2010-12-29 | 上海交通大学 | Preparation and application methods of difunctional naonparticle preparation entrapping vincristine sulphate |
| CN102343099A (en) * | 2011-09-30 | 2012-02-08 | 中国人民解放军第四军医大学 | Preparation method and application of folacin mediated tumor targeting adriamycin prodrugs |
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