CN103976954A - Drug-carrying liposome co-modified by folic acid and TAT peptide and preparation method thereof - Google Patents
Drug-carrying liposome co-modified by folic acid and TAT peptide and preparation method thereof Download PDFInfo
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- CN103976954A CN103976954A CN201410214337.2A CN201410214337A CN103976954A CN 103976954 A CN103976954 A CN 103976954A CN 201410214337 A CN201410214337 A CN 201410214337A CN 103976954 A CN103976954 A CN 103976954A
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Abstract
The invention discloses drug-carrying liposome co-modified by folic acid and TAT peptide and a preparation method thereof. The drug-carrying liposome comprises liposome, a long chain targeted membrane material, a short chain targeted membrane material and a drug. Meanwhile, the invention provides the preparation method of the drug-carrying liposome co-modified by folic acid and TAT peptide. The method comprises the following steps: weighing phospholipid, cholesterol, the long chain targeted membrane material, the short chain targeted membrane material and the drug, dissolving the components in an organic solvent, and then carrying out rotary evaporation at 50 DEG C under reduced pressure to remove the organic solvent so as to obtain a medicated liposome membrane; adding a phosphate buffer solution into the medicated liposome membrane for dissolving, carrying out ultrasonic treatment for 2 minutes, and filtering for 10 times by using a 0.22mu m membrane to obtain double-target drug-carrying liposome. According to the drug-carrying liposome disclosed by the invention, the TAT peptide is connected with specific ligands by means of PEG with different weight-average molecular weights to establish a nanometer carrier modified by double ligands, and the prepared drug-carrying liposome can be used for efficiently conveying the drug in tumor cells.
Description
Technical field
The invention belongs to pharmaceutical carrier field, particularly co-modified drug-loaded liposome of a kind of folic acid and tat peptide and preparation method thereof.
Background technology
Nano-carrier demonstrates great potential in chemotherapeutics tumor-selective is sent, it is worth noting, this antitumous effect of obtaining by the mode of nanotechnology treatment is still very limited, its reason is likely because nano-carrier delivers into tumor cell by chemotherapeutics not efficiently, has limited the performance of chemotherapy medicine antitumor activity.Nano-carrier sees through blood vessel and enters mesenchyma stroma of tumors mainly by the mode of convection current and diffusion.Meanwhile, interstitial pressure (IFP) higher in mesenchyma stroma of tumors impels tissue fluid reverse flow in surrounding tissue, thereby has hindered nano-carrier to be penetrated into entity tumor inside.See through the nano-carrier of tumor vessel gap and fenestra if absorbed by tumor cell fast, the caused negatively influencing of IFP will be alleviated so.In view of this, express some specific receptors based on most of tumor cell surface height, ligand modified strategy is widely adopted, and the endocytosis that the nano-carrier of linking ligand can mediate by receptor-ligand is absorbed by tumor cells selectivity.But, the expression of tumor cell surface receptor non-constant, there is saturated phenomenon in the cell endocytic of receptor-ligand mediation in addition, causes ligand modified nano-carrier to improve the effect of oncotherapy still limited.
Tat peptide is cell-penetrating peptides (Cell penetrating peptides, CPPs) one in, the bioactive substance that can carry multiple different size and character enters cell, comprise liposome, phage particle and the particles with superparamagnetism etc. of micromolecular compound, dyestuff, polypeptide, polypeptide-nucleic acid, protein, plasmid DNA, siRNA, 200 nm, realize the cell transmembrane transhipment of medicine.Although the precise mechanism of existing cell-penetrating peptides transmembrane transport effect it be unclear that, much research has shown that the basic amino acid in cell-penetrating peptides aminoacid sequence brought into play Main Function.But, because cell-penetrating peptides lacks enough cell selectives, limit to a certain extent its application aspect targeted drug delivery.
Summary of the invention
Folic acid (Folic acid) is a kind of water miscible vitamin, is the trace element of needed by human, and research shows most of solid tumor tumor cell surface wide expression folacin receptors, and therefore folic acid is often used as the part of cancer target.Pass drug carrier and send middle above shortcomings at drug targeting for overcoming the nanometer of modified with folic acid, the invention provides co-modified drug-loaded liposome of a kind of folic acid and tat peptide and preparation method thereof, send to realizing in the efficient tumor cell of antitumor drug.
Object of the present invention can be achieved through the following technical solutions:
The drug-loaded liposome that folic acid and tat peptide are co-modified, component comprises liposome, long-chain targeting film material, short chain targeting film material and medicine, described liposome main component is phospholipid and cholesterol.
The drug-loaded liposome that described folic acid and tat peptide are co-modified, the component that comprises following weight portion is made:
1 part of liposome;
10 parts of long-chain targeting film material 1-;
Short chain targeting film material 1-5 part;
0.01-0.2 part of medicine.
Described long-chain targeting film material is PEG-DSPE-folic acid (DSPE-PEG-FA), and described short chain targeting film material is PEG-DSPE-TAT(DSPE-PEG-TAT).
PEG weight average molecular weight in described long-chain targeting film material is selected from 1000,2000,3400 or 5000; PEG weight average molecular weight in short chain targeting film material is selected from 750,1000,2000 or 3400; In described long-chain targeting film material, PEG weight average molecular weight is greater than PEG weight average molecular weight in short chain targeting film material.
In described liposome phospholipid be selected from phospholipid fabaceous lecithin, lecithin, hydrogenated soy phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE,
dOPE, one or more in phosphatidyl glycerol, cholesteryl hemisuccinate and Phosphatidylserine.
Described medicine is one or more in paclitaxel, docetaxel, amycin, hydroxy camptothecin, doxorubicin hydrochloride, cisplatin, amphotericin B, daunorubicin, cytosine, cytosine arabinoside, vincristine, etoposide and idarubicin.
The mass ratio of described phospholipid and cholesterol is 4-5:1.
A preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, the method comprises the steps:
(1) take phospholipid, cholesterol, long-chain targeting film material, short chain targeting film material and medicine, with organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent subsequently, obtains pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain two target drug-loaded liposomes.
A preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, the method comprises the steps:
(1) take phospholipid, cholesterol and medicine, with organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain drug-loaded liposome;
(3) take long-chain targeting film material and short chain targeting film material, be dissolved in phosphate buffered solution, targeting film material solution dropwise splashes in the drug-loaded liposome in step (2), and insulation is cooling, obtains two target drug-loaded liposomes.
A preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, the method comprises the steps:
(1) take phospholipid and cholesterol, with organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains not pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane not, ultrasonic 2 minutes, pressurizeed 0.22 μ m film 10 times, obtains blank liposome, further regulates pH to 7.6 with sodium hydrogen phosphate aqueous solution, add medicine, at 70 DEG C, mix 30 min, be cooled to room temperature, free drug is removed in dialysis, makes drug-loaded liposome;
(3) subsequently, take long-chain targeting film material and short chain targeting film material, be dissolved in phosphate buffered solution, dropwise splash in the drug-loaded liposome of step (2), be incubated 1h at 55 DEG C, cooling, prepare two target drug-loaded liposomes.
Described organic solvent is chloroform: ethanol=2:1; Described phospholipid is 0.8-0.83 weight portion; Described cholesterol is 0.17-0.2 weight portion; Described long-chain targeting film material is 1-10 weight portions; Described short chain targeting film material is 1-5 weight portion; Described medicine is 0.01-0.2 weight portion; The mass ratio of described phospholipid and cholesterol is 4-5:1.
The purposes of the co-modified drug-loaded liposome of described folic acid and tat peptide in treatment ovarian cancer, pulmonary carcinoma, colon cancer, carcinoma of endometrium, the brain cancer, breast carcinoma and tumor of kidney disease.
compared with prior art, its beneficial effect is in the present invention:
(1) the present invention connects tat peptide and ligands specific by the PEG of different weight average molecular weight, build two ligand modified nano-carriers, to be expected to bring into play the non-specific and ligands specific advantage at intracellular transport medicine simultaneously, promote transport efficacy in the tumor cell of chemotherapeutics.
(2) of the present invention pair of target drug-loaded liposome is easy to preparation, and its surface ligand density is easy to control simultaneously.
(3) for the present invention, folate molecule is connected to surface of liposome by longer chain polyethylene glycols (PEG), connect nonspecific tat peptide with short chain polyalkylene glycol (PEG), after intravenous administration, in blood circulation, the non-selective of tat peptide limited by long-chain PEG, arrive after tumor locus, be exposed to the FA of liposome outermost end can specially recognizing tumor cells the folacin receptor of surface overexpression, and be combined with folacin receptor, shorten the distance between tat peptide and cell membrane, and then the membrane penetration effect of performance tat peptide, effectively liposome is brought in cell.
(4) long-chain PEG connects ligands specific FA and can make it fully be exposed to surface of liposome and the receptor of tumor cell surface overexpression effectively, connect tat peptide by flexible short chain PEG, can reduce sterically hindered that long-chain PEG produces, make the tat peptide can freedom and cell membrane effect.
(5) of the present invention pair of target drug-loaded liposome is in cell, its drug delivery efficiency height depends on the receptor of tumor cell surface overexpression, be different from the nano-carrier connecting by chemical-sensitive key, without any need for additional stimulation or manual operation, can realize in efficient medicine tumor cell and carrying.
Brief description of the drawings
Fig. 1 is the particle size distribution figure of two target drug-loaded liposomes of the embodiment of the present invention 1.
Fig. 2 is transmission electron microscope (TEM) aspect graph of two target drug-loaded liposomes of Evacet and the embodiment of the present invention 1, and wherein A is Evacet, and B is two target liposomees of embodiment 1.
Fig. 3 is two target drug-loaded liposomes and Evacet, PEG liposome and the cell survival rate figure of single target liposome 1 under different doxorubicin concentration of the embodiment of the present invention 1.
Fig. 4 is the test result figure of flow cytometer, and wherein A is PEG liposome, and B is single target liposome 1, and C is single target liposome 2, and D is two target drug-loaded liposomes of the embodiment of the present invention 1.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
method of testing:
particle diameter and Zeta potential method of testing:sample thief, with after pure water dilution, adopts particle diameter and zeta potential instrument to measure respectively particle diameter and current potential, three parts of every kind of sample parallel assays, and test result is in table 1, and particle size distribution is shown in Fig. 1.
the mensuration of envelop rate:adopt ultrafiltration centrifugal determination envelop rate, get respectively the sample of 0.5ml, be placed in 10kD ultra-filtration centrifuge tube, 10000 rpm, centrifugal 15 min, by filtrate dilution, adopt HPLC to analyze, and the results are shown in Table 1.
Envelop rate %=(drop into total dose-free dose)/drop into total dose × 100%
transmission electron microscope (TEM) morphologic observation: testing sample is dropped to special purpose copper online, after being dried, carry out TEM scanning, the results are shown in Figure 2.
liposome cytotoxicity is investigated:kB cell uses the DMEM culture fluid that does not contain folic acid in CO
2in incubator, 37 DEG C, 5%CO
2, cultivate under saturated humidity condition, the trophophase KB cell of taking the logarithm is with after 0.25% trypsinization, with 5 × 10
4cells/mL is inoculated in 96 orifice plates, every hole 100 μ L, 96 orifice plates are moved in incubator and cultivated after 24h, add respectively variable concentrations (0.01,0.1,0.5,1,2,2.5,5,10,20 μ g/mL) dissimilar Evacet solution and corresponding free DOX solution 100 μ L, establish five multiple holes, 37 DEG C, 5% CO for every group
2, cultivate after 48 hours under saturated humidity condition and remove the culture fluid in plate, with twice of PBS cleaning, add 100 μ L Folate-free DMEM(10% 5 mg/mL MTT) mixed liquor, similarity condition continue cultivate 4 h, carefully suck afterwards culture fluid in hole, every hole adds 100 μ L DMSO, 5 min that vibrate gently, fully dissolve crystallization, survey 492 nm place absorbances (OD492) in microplate reader, calculate cell survival rate by OD value, formula is:
Cell survival rate (Cell Viability)=(experimental group OD value-blank group OD value)/(matched group OD value-blank group OD value) × 100%; Cell survival rate is shown in Fig. 3, calculates IC50 value, as table 2.
liposome cellular uptake is investigated:take the logarithm trophophase KB cell taking concentration as 1 × 10
5cells/mL is inoculated in 6 orifice plates, and 2 mL are inoculated in every hole, after adhere-wall culture 24 h, is replaced by containing the culture fluid 100 μ L of various liposomees and cultivates after 1 h, discards culture fluid, with cold PBS cleaning three times; Centrifugal after trypsinization, abandon supernatant, add 0.5 mLPBS to blow and beat into cell suspension, be placed in flow cytometer analysis.
embodiment 1
(1) take phospholipid fabaceous lecithin 0.8g and cholesterol 0.2g, with chloroform: ethanol=2:1(volume ratio) organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains not pastille adipose membrane;
(2) dissolve to adding in pH 7.6 phosphate buffered solution in pastille adipose membrane not, ultrasonic 2 minutes, 0.22 μ m film 10 times pressurizeed, obtain blank liposome, further regulate pH to 7.6 with sodium hydrogen phosphate aqueous solution, add amycin 0.15g, at 70 DEG C, mix 30 min, be cooled to room temperature, make drug-loaded liposome;
(3) subsequently, take DSPE-PEG
5000-FA 10g and DSPE-PEG
2000-TAT 5g, is dissolved in phosphate buffered solution, dropwise splashes in the drug-loaded liposome of step (2), is incubated 1h at 55 DEG C, cooling, prepares two target drug-loaded liposomes.
Two target drug-loaded liposomes to embodiment 1 gained are tested, and particle diameter as shown in Figure 1, can find out that two target drug-loaded liposome particle size distribution evenly and are all less than 200nm, can effectively realize EPR effect; Obtain aspect graph with transmission electron microscope, as shown in Figure 2, can find out this pair of target drug-loaded liposome form rounding, uniform particle diameter, and part successfully inserts in drug-loaded liposome, the positive charge of tat peptide is shielded completely simultaneously; Fig. 3 can find out that two target drug-loaded liposomes, compared with PEG liposome and each single target liposome, all show stronger cytotoxicity under each concentration; Fig. 4 can find out that two target drug-loaded liposomes are compared with PEG liposome, single target liposome 1, single target liposome 2, its fluorescence intensity is the strongest, prove can significantly improve cellular uptake after two targets are modified, show stronger anti-tumor activity, be conducive to bring into play the cytotoxicity of cancer therapy drug.
embodiment 2
(1) take hydrogenated soy phosphatidyl choline 0.8g, cholesterol 0.2g, DSPE-PEG
3400-FA 1g, DSPE-PEG
3000-TAT 1g and hydroxy camptothecin 0.2g, with chloroform: ethanol=2:1(volume ratio) organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent subsequently, obtains pastille adipose membrane;
(2) dissolve to adding in pH 7.6 phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain two target drug-loaded liposomes.
embodiment 3
(1) take lecithin 0.8g, cholesterol 0.2g and paclitaxel 0.01 g, with chloroform: ethanol=2:1(volume ratio) organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains pastille adipose membrane;
(2) dissolve to adding in pH 7.6 phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain drug-loaded liposome;
(3) take DSPE-PEG
1000-FA 10g and DSPE-PEG
750-TAT5g, is dissolved in phosphate buffered solution, dropwise splashes in the drug-loaded liposome in step (2), and insulation, cooling, obtain two target drug-loaded liposomes.
comparative example
The preparation method of PEG liposome, single target liposome 1 and single target liposome 2 is as follows:
Get respectively DSPE-PEG
5000-FA, DSPE-PEG
2000-TAT and DSPE-PEG
5000-NH
2targeting film material, be dissolved in respectively in the phosphate buffer of pH 7.6, be respectively 5%, 2.5% and 5% by the mol ratio of targeting film material and phospholipid, drawing respectively targeting film material solution splashes in the Evacet of equivalent, at 55 DEG C, be incubated 1h, cooling, obtain respectively single target liposome 1, single target liposome 2 and PEG liposome.
The preparation method of single target liposome 3 is: by 5% DSPE-PEG
5000-NH
2and 2.5% DSPE-PEG
2000the film material aqueous solution of-TAT splashes in the Evacet of equivalent, is incubated 1h at 55 DEG C, cooling, obtains single target liposome 3.
The dissimilar liposome particle diameter of table 1, current potential and envelop rate (
n=3)
The IC50 value of table 2 amycin and different drug-loaded liposomes
The present invention uses broad-spectrum anti-cancer drug amycin (DOX) as model drug, and DOX is written in liposome by pH gradient method, two kinds of part (FA-PEG
5000-DSPE and TAT-PEG
2000-DSPE) be inserted in drug-loaded liposome by rear insertion, obtain two ligand modified DOX drug-loaded liposomes.
In addition, flow cytometer detects and shows, with single ligand modified Evacet (FA-PEG
5000-LP and PEG
5000/ TAT-PEG
2000-LP) relatively, tumor cell shows higher intake to two ligand modified drug-loaded liposomes.Therefore, this pair of ligand modified drug-loaded liposome is hopeful the efficient targeted delivery of drugs for tumor.
The invention is not restricted to above-described embodiment, those skilled in the art are according to announcement of the present invention, and not departing from improvement and the amendment that category of the present invention makes all should be within protection scope of the present invention.
Claims (9)
1. the co-modified drug-loaded liposome of folic acid and tat peptide, is characterized in that, component comprises liposome, long-chain targeting film material, short chain targeting film material and medicine, and described liposome main component is phospholipid and cholesterol.
2. the co-modified drug-loaded liposome of folic acid and tat peptide according to claim 1, is characterized in that, the component that comprises following weight portion is made:
1 part of liposome;
Long-chain targeting film material 1-10 part;
Short chain targeting film material 1-5 part;
0.01-0.2 part of medicine.
3. the co-modified drug-loaded liposome of folic acid and tat peptide according to claim 1, it is characterized in that, described long-chain targeting film material is PEG-DSPE-folic acid, and described short chain targeting film material is PEG-DSPE-TAT; PEG weight average molecular weight in described long-chain targeting film material is selected from 1000,2000,3400 or 5000; PEG weight average molecular weight in short chain targeting film material is selected from 750,1000,2000 or 3400; In described long-chain targeting film material, PEG weight average molecular weight is greater than PEG weight average molecular weight in short chain targeting film material.
4. according to folic acid described in claim 1 and the co-modified drug-loaded liposome of tat peptide, it is characterized in that, in described liposome, phospholipid is selected from one or more in phospholipid fabaceous lecithin, lecithin, hydrogenated soy phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, DOPE, phosphatidyl glycerol, cholesteryl hemisuccinate, Phosphatidylserine; Described medicine is one or more in paclitaxel, docetaxel, amycin, hydroxy camptothecin, doxorubicin hydrochloride, cisplatin, amphotericin B, daunorubicin, cytosine, cytosine arabinoside, vincristine, etoposide and idarubicin; The mass ratio of described phospholipid and cholesterol is 4-5:1.
5. a preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, is characterized in that, the method comprises the steps:
(1) take phospholipid, cholesterol, long-chain targeting film material, short chain targeting film material and medicine, with organic solvent dissolution, under 50 DEG C of conditions, decompression is spin-dried for organic solvent subsequently, obtains pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain two target drug-loaded liposomes.
6. a preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, is characterized in that, the method comprises the steps:
(1) take phospholipid, cholesterol and medicine, with organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane, ultrasonic 2 minutes, with 0.22 μ m film, filter 10 times, obtain drug-loaded liposome;
(3) take long-chain targeting film material and short chain targeting film material, be dissolved in phosphate buffered solution, targeting film material solution dropwise splashes in the drug-loaded liposome in step (2), and insulation is cooling, obtains two target drug-loaded liposomes.
7. a preparation method for the co-modified drug-loaded liposome of folic acid and tat peptide, is characterized in that, the method comprises the steps:
(1) take phospholipid and cholesterol, with organic solvent dissolution, under 40 DEG C of conditions, decompression is spin-dried for organic solvent, obtains not pastille adipose membrane;
(2) dissolve to adding in phosphate buffered solution in pastille adipose membrane not, ultrasonic 2 minutes, pressurizeed 0.22 μ m film 10 times, obtains blank liposome, further regulates pH to 7.6 with sodium hydrogen phosphate aqueous solution, add medicine, at 70 DEG C, mix 30 min, be cooled to room temperature, free drug is removed in dialysis, makes drug-loaded liposome;
(3) subsequently, take long-chain targeting film material and short chain targeting film material, be dissolved in phosphate buffered solution, dropwise splash in the drug-loaded liposome of step (2), be incubated 1h at 55 DEG C, cooling, prepare two target drug-loaded liposomes.
8. according to the preparation method of the folic acid described in any one in claim 5-7 and the co-modified drug-loaded liposome of tat peptide, it is characterized in that, described organic solvent is chloroform: ethanol=2:1; Described phospholipid is 0.8-0.83 weight portion; Described cholesterol is 0.17-0.2 weight portion; Described long-chain targeting film material is 1-10 weight portions; Described short chain targeting film material is 1-5 weight portion; Described medicine is 0.01-0.2 weight portion; The mass ratio of described phospholipid and cholesterol is 4-5:1.
9. the purposes of the co-modified drug-loaded liposome of the folic acid described in any one and tat peptide in treatment ovarian cancer, pulmonary carcinoma, colon cancer, carcinoma of endometrium, the brain cancer, breast carcinoma and tumor of kidney disease in claim 1-4.
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