CN1846691A - Integrin ligand-modified anticancer drug-loaded long-circulating liposomes for injection - Google Patents
Integrin ligand-modified anticancer drug-loaded long-circulating liposomes for injection Download PDFInfo
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Abstract
The present invention relates to integrin ligand modified long circulation liposome carrying anticarcinogen for injection, and is especially one kind of injected anticarcinogen carrying targeting liposome administration system. The efficient administration system is obtained through modifying the surface of liposome simultaneously with both polyethylene glycol and integrin containing arginine-glycine-asparagic acid sequence or RGD analogue.
Description
Technical field
The present invention relates to technical field of medicine, be particularly related to a kind of targeting liposome administration system of loaded with anti-cancer medicine of injection, this system is that the integrin of Polyethylene Glycol (PEG) being used on the surface of liposome simultaneously and being contained arginine-glycine-aspartic acid sequence (RGD) or RGD analog is modified a kind of efficient liposome administration system that obtains.
Background technology
Malignant tumor is the human important diseases of puzzlement always, does not still have the method for cancer of healing at present.For the traditional remedies of malignant solid tumor is that the reuse antitumor drug carries out chemotherapy after the ocal resection.Most chemotherapeutics does not have selectivity, and these medicines also can produce lethal effect to normal cell in killing tumor cell, therefore can produce serious adverse, as the cardiac toxicity effect of amycin etc.Antitumor drug is carried out Bao Zaihou with liposome can obviously prolong its circulation time in vivo, help antitumor drug and accumulate, thereby increased the therapeutic index of cancer therapy drug, promptly increase curative effect, reduced toxic and side effects to tumor area.Launch such as at present existing Evacet, daunorubicin liposome, Paclitaxel liposome.
Though conventional liposome can improve the curative effect of cancer therapy drug, because it is easily eliminated rapidly by the picked-up of the macrophage in liver, the spleen, medicine is the holdup time weak point in vivo.The surface of conventional liposome further uses hydrophilic Polyethylene Glycol (PEG) to modify, and can be made into long circulating liposomes.Thereby long circulating liposomes can be escaped opsonic conditioning in the blood plasma and avoid by macrophage picked-up (so being also referred to as recessive liposome), significant prolongation its holdup time in blood circulation, blood drug level also obviously improves.Long circulating liposomes can increase by bag medicine carrying thing accumulating in tumor tissues through strengthening delay and osmosis (EPR), thereby has improved the targeting that cancer therapy drug transmits.The recessive liposome listing of at present existing amycin (DOXIL
, CAELYX
).
Long circulating liposomes can prolong drug circulation time in vivo, strengthens antitumor drug accumulating in tumor, but and does not mean that the curative effect that necessarily can improve antitumor drug.One of its reason is to be positioned at endonuclear DNA in the target spot of most of antitumor drug, and medicine must overcome this barrier of cell membrane and enter into competence exertion effect in the cell.Liposomal encapsulated medicine enters and mainly contains three kinds of approach in the cell, i.e. diffusion, and film merges and is engulfed by tumor cell.If the medicine that is encapsulated in the liposome bimolecular film can not be discharged in the intercellular substance, the medicine that enters in the tumor cell by diffusion path can be restricted so.Because most liposome material can not merge with cell membrane, so it is also limited to enter into intracellular medicine through the film amalgamation mode.Many evidences, common recessive liposome can not enter into tumor cell through cytophagy, so although long circulating liposomes can increase the concentration in the tumor tissues, curative effect not necessarily increases to some extent.To intracellular transhipment a lot of limitation are arranged owing to increase antitumor drug, just become the important means that improves the cancer therapy drug targeting with ligand modified long circulating liposomes by the mode that increases the fusion of diffusion and film.Have the scholar to use folic acid abroad, transferrins and monoclonal antibody are modified recessive liposome in order to increase the targeting of drug delivery, and the animal experiment proof can significantly improve the treatment of cancer therapy drug, but still do not have this series products listing at present.
There is report to modify the carrier of long circulating liposomes as cancer therapy drug, the tripeptides that RGD is made up of three seed amino acids (arginine, glycine and aspartic acid are arranged in this order) with the ring type polypeptide that contains RGD.The target spot that has proved this kind ring RGD peptide is tumor neogenetic blood vessels and non-tumor cell.Its principle is that the RGD cyclic peptide can be specifically combines with the expressed integrin alpha v beta 3 of tumor neogenetic blood vessels, thereby cuts off the nutrition of tumor and the supply performance antitumor action of oxygen by the new vessels that destroys tumor.The used polypeptide fragment of the present invention is the linear polypeptide that contains the RGD sequence, and its target spot is tumor cell itself, can be by the plain identification of the integration of tumor cell surface, the adhesion of mediation and tumor cell.The long circulating liposomes that the linear polypeptide of RGD sequence is modified can be to tumor tissue accumulation, then by the expressed plain identification of one or more integration of tumor cell surface, stick to tumor cell surface, cytophagy through mediated by integrin enters into cell then, thereby the drug release that bag is loaded in the liposome is brought into play antitumaous effect in endochylema.
Integrate, the principle that the present invention improves the antitumor drug targeting is as follows: 1, owing to tumor vascular high-permeability, the long circulating liposomes that PEG modifies can be accumulated in tumor tissues by strengthening infiltration and delay effect.2, the savings pastille long circulating liposomes that the linear polypeptide through containing the RGD sequence is modified in tumor tissues is discerned by the expressed integration element of tumor cell surface, sticks to tumor cell surface, in endocytosis enters into tumor cell.Briefly, passive accumulating with active transport makes the final cancer therapy drug that arrives in the tumor cell significantly increase, thereby improved the targeting that cancer therapy drug transmits.
Summary of the invention
The objective of the invention is surface of liposome is modified with the linear polypeptide that contains the RGD sequence with PEG simultaneously, the long circulating liposomes that contains the linear polypeptide modification of RGD sequence has concurrently by trend tumor tissue accumulation and the characteristics of initiatively transporting in tumor cell.The end that the linear polypeptide that contains the RGD sequence is connected the PEG chain makes it not to be subjected to the interference of PEG chain, can be discerned by the integrin receptor of tumor cell surface expression better.The cancer therapy drug that is encapsulated in liposome finally arrives in the tumor cell through passive accumulating with two processes of active transport, and brings into play cytotoxicity after the targeted integration.The present invention combines the long circulating liposomes technology and promotes the strategy of liposome to intracellular transport, thereby has improved the targeting of long circulating liposomes, can improve the utilization rate of antitumor drug.
The present invention proposes the long circulating liposomes drug-supplying system of the loaded with anti-cancer medicine that a kind of linear polypeptide that contains the RGD sequence of injection modifies, the theory that it is characterized in that its foundation is that medicine enters cell and is divided into two steps, promptly from blood vessel be diffused into the tumor tissues gap and from the tumor gap to intracellular transport.Realized this purpose with the long circulating liposomes that the linear polypeptide that contains the RGD sequence is modified.
The linear polypeptide fragment of the said RGD of the containing sequence of the present invention is any linear polypeptide fragment that contains arginine-glycine-aspartic acid sequence, comprise the tripeptides, tetrapeptide, pentapeptide, six peptides, seven peptides, octapeptide, nonapeptide and the decapeptide that contain the RGD sequence, or contain the linear fragment of RGD analog (RGDm), as contain the linear fragment of arginine-6-aminocaprolc acid and derivant thereof.Preferably tripeptides, tetrapeptide, pentapeptide, six peptides, seven peptides, octapeptide, nonapeptide and decapeptide.Tripeptides most preferably.The linear polypeptide of RGD sequence can obtain by prior art, also can buy on market.
The said long circulating liposomes of the present invention refers to that the molecular weight of the Polyethylene Glycol of use (PEG) is 200-50000 preferably, is more preferably 1000-5000 with the surface of Polyethylene Glycol (PEG) modified liposome.
The said entrapped medicine of the present invention comprises any antitumor drug or tumour diagnostic reagent that is fit to make the liposome dosage form, preferably comprises amycin, epirubicin, cisplatin, daunorubicin, paclitaxel or Docetaxel etc.
The method of attachment of the said polypeptide of the present invention comprises the end of the linear polypeptide that contains the RGD sequence being linked PEG, or is directly connected to the surface of liposome.
The said liposome of the present invention is meant that main is the made lipid bilayer vesicle of material with phospholipid and cholesterol; all types of phospholipid have been comprised; be selected from soybean phospholipid, two lauroyl lecithin; two myristoyl lecithin; DPPC; distearoylphosphatidylcholine; distearoylphosphatidylcholine; 1-myristoyl-2-palmityl lecithin; 1-palmityl-2-myristoyl lecithin; 1-palmityl-2-stearoyl lecithin; 1-stearoyl-2-palmityl lecithin; Ovum Gallus domesticus Flavus lecithin; hydrogenated soybean lecithin; dioleoyl lecithin; two lauroyl phosphatidyl glycerols; two Petiolus Trachycarpi acyl glycerol; the distearyl phosphatidyl glycerol; DOPG; two myristoyl phosphatidic acid; two palmityl phosphatidic acid; two myristoyl PHOSPHATIDYL ETHANOLAMINE; two palmityl PHOSPHATIDYL ETHANOLAMINE; two myristoyl Phosphatidylserine; two palmityl phosphatidyls, two serines; cephalin acyl serine; the cranial nerve sphingomyelins; two palmityl sphingomyelins; the distearyl sphingomyelin; DSPE a kind of or their combination.
Liposome of the present invention is characterized in that, wherein the ratio of phospholipid and cholesterol is arbitrarily.The ratio of phospholipid and cholesterol is 0-1000 preferably: 1, be more preferably 1-10: 1.
Described liposome of the present invention can be dispersed in solution, solid or the semisolid medium.Preferably make the pharmaceutical dosage forms of drug administration by injection, particularly injection for intravenous.
The linear polypeptide of the RGD of containing sequence of the present invention or contain the long circulating liposomes that the linear fragment of RGD analog modifies and can prepare by the following method:
At first obtain the phospholipid (as DSPE-PEG) that PEG modifies, again the terminal activation of PEG is formed Acibenzolar, obtain the phospholipid (as DSPE-PEG-BTC) that terminal activatory PEG modifies, the linear fragment (representing with * RGDm*) that contains the linear polypeptide (representing with * RGD*) of RGD sequence or contain the RGD analog reacts in the HEPES buffer with the phospholipid that terminal activatory PEG modifies, form lead compound, promptly contain the linear polypeptide and the common phospholipid of modifying of PEG of RGD sequence, or contain the linear fragment and the common phospholipid of modifying (can represent with DSPE-PEG-*RGD* and DSPE-PEG-*RGDm* respectively) of PEG of RGD analog.
Get phospholipid, cholesterol, DSPE-PEG, DSPE-PEG-*RGD*, or DSPE-PEG-*RGDm* is as the raw material of preparation liposome, put in the round-bottomed flask, after adding organic solvent dissolution, prepare the long circulating liposomes that contains the linear polypeptide of RGD sequence or contain the linear fragment modification of RGD analog by method for preparing lipidosome; Also can prepare long circulating liposomes earlier, lead compound is inserted into form the long circulating liposomes that RGD modifies in the liposome for preparing.Be controlled at about 120nm with pushing poly-carbon ester film or ultransonic method particle diameter liposome.Cancer therapy drug can add before preparation or in the preparation process, perhaps is loaded in the liposome that has prepared by additive method.
The invention has the advantages that the present invention with containing the linear polypeptide of RGD sequence or containing long circulating liposomes that the linear fragment of RGD analog the modifies carrier as antitumor drug, has further improved the therapeutic index of antitumor drug.
The present invention and the liposome of having reported of modifying with the specific RGD cyclic peptide of integrin alpha v beta 3 are that as the carrier difference of cancer therapy drug the kind of two kinds of peptides is different, and mechanism of action is also different.The liposome that the RGD cyclic peptide is modified is that the target tumor new vessels is brought into play the effect that suppresses tumor growth by destroying tumor neogenetic blood vessels, and this carrier is a direct target tumor cell itself, by increasing tumor cell the picked-up of cancer therapy drug is reached antitumor action.
The linear polypeptide that contains the RGD sequence that the present invention is used or to contain the linear fragment molecular weight of RGD analog little, thereby antigenicity is less is difficult for being discerned by immunocyte and causes eliminating and accelerate.
This law is produced simple, can be directly recessive liposome of bag loaded with anti-cancer medicine and the lead compound that contains the linear polypeptide of RGD sequence or contain the linear fragment of RGD analog is hatched and is got.Therefore need only get final product with the synthetic lead compound of chemical method, be suitable for big commercial production.
Description of drawings:
Fig. 1 tail vein injection amycin solution (Free DOX, FD), amycin long circulating liposomes (SSL-DOX), RGD modify the plasma concentration curve behind amycin long circulating liposomes (RGD-SSL-DOX) and the RGDm modification amycin long circulating liposomes (RGDm-SSL-DOX).RGDm wherein represents arginine-6-aminocaprolc acid (annotate: RGDm and the RGDm in the embodiment of the invention in other accompanying drawings represent arginine-6-aminocaprolc acid)
Fig. 2 tail vein injection amycin solution (Free DOX, FD), amycin long circulating liposomes (SSL-DOX), RGD modify amycin long circulating liposomes (RGD-SSL-DOX) and RGDm and modify amycin long circulating liposomes (RGDm-SSL-DOX) doxorubicin concentration curve in the tumor tissues afterwards
Fig. 3 tail vein injection physiology salt water (Saline), amycin solution (Free DOX, FD), amycin long circulating liposomes (SSL-DOX), RGD modifies amycin long circulating liposomes (RGD-SSL-DOX) and RGDm modifies amycin long circulating liposomes (RGDm-SSL-DOX) the survival rate curve of mice afterwards.
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1, bag carry the long circulating liposomes of the RGD modification of amycin
(mol ratio is 20: 10: 2: 1) to get soybean phospholipid, cholesterol, DSPE-PEG2000 and DSPE-PEG-RGD, place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make and on flask walls, form phospholipid membrane, add the ammonium sulphate solution of 123mM, water-bath is ultrasonic to blue opalescence occurring.Pushed the poly-carbon ester film 5 times of 200nm again.The liposome that makes is crossed the SephadexG50 post, as the mobile phase eluting, collect the liposome part, the liposome of collecting is put in 40 ℃ of water-baths heated, add the amycin powder and hatch 20 minutes with PBS buffer (pH7.4), and jolting constantly, this product promptly got.The above-mentioned particle diameter that makes Evacet should be controlled at about 120nm.
(mol ratio is 20: 10: 2: 1) to get soybean phospholipid, cholesterol, DSPE-PEG2000 and DSPE-PEG-RGDm, place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make and on flask walls, form phospholipid membrane, add the ammonium sulphate solution of 123mM, water-bath is ultrasonic to blue opalescence occurring.Pushed the poly-carbon ester film 5 times of 200nm again.The liposome that makes is crossed Sephadex G50 post, as the mobile phase eluting, collect the liposome part, the liposome of collecting is put in 40 ℃ of water-baths heated, add the amycin powder and hatch 20 minutes with PBS buffer (pH7.4), and jolting constantly, this product promptly got.The above-mentioned particle diameter that makes Evacet should be controlled at about 120nm.
Embodiment 3, bag carry the RGD of amycin and the long circulating liposomes that analog is modified
Get soybean phospholipid, cholesterol, DSPE-PEG2000 (mol ratio is 20: 10: 2), place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make and on flask walls, form phospholipid membrane, add the ammonium sulphate solution of 123mM, water-bath is ultrasonic to blue opalescence occurring.Pushed the poly-carbon ester film 5 times of 200nm again.The liposome that makes is crossed polydextran gel (Sephadex G50) post, as the mobile phase eluting, collect the liposome part with PBS buffer (pH7.4), the liposome of collecting is put in 40 ℃ of water-baths heated, add the amycin powder and hatch 20 minutes, and jolting constantly.The lead compound DSPE-PEG-RGD or the DSPE-PEG-RGDm that add recipe quantity again continued to hatch 30 minutes, and jolting constantly, then above-mentioned liposome is put 4 ℃ refrigerator overnight, guidingization body thing is inserted into automatically in the phospholipid bilayer of liposome and promptly gets this product.The above-mentioned particle diameter that makes Evacet should be controlled at about 120nm.
Embodiment 4, bag carry the RGD of amycin and the long circulating liposomes that analog is modified
Get commodity Evacet DOXIL
, it is an amount of to add lead compound DSPE-PEG-RGD or DSPE-PEG-RGDm, put in 40 ℃ the water-bath to hatch 30 minutes, and jolting constantly.Put 4 ℃ refrigerator overnight again, lead compound is inserted into automatically in the phospholipid bilayer of liposome and promptly gets this product.
Embodiment 5, bag carry the long circulating liposomes of the RGD modification of daunorubicin
(mol ratio is 20: 10: 2: 1) to get soybean phospholipid, cholesterol, DSPE-PEG2000 and DSPE-PEG-RGD, place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make and on flask walls, form phospholipid membrane, add the ammonium sulphate solution of 123mM, water-bath is ultrasonic to blue opalescence occurring.Pushed the poly-carbon ester film 5 times of 200nm again.The liposome that makes is crossed the SephadexG50 post, as the mobile phase eluting, collect the liposome part with PBS buffer (pH7.4), the liposome of collecting put in 40 ℃ of water-baths heat, add the daunorubicin powder and hatch 20 minutes, and jolting constantly, this product promptly got.The above-mentioned particle diameter that makes daunorubicin liposome should be controlled at about 120nm.
Embodiment 6, bag carry the long circulating liposomes of RGD analog (RGDm) modification of epirubicin
(mol ratio is 20: 10: 2: 1) to get soybean phospholipid, cholesterol, DSPE-PEG2000 and DSPE-PEG-RGDm, place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make and on flask walls, form phospholipid membrane, add the ammonium sulphate solution of 123mM, water-bath is ultrasonic to blue opalescence occurring.Pushed the poly-carbon ester film 5 times of 200nm again.The liposome that makes is crossed Sephadex G50 post, as the mobile phase eluting, collect the liposome part with PBS buffer (pH7.4), the liposome of collecting put in 40 ℃ of water-baths heat, add the epirubicin powder and hatch 20 minutes, and jolting constantly, this product promptly got.The above-mentioned particle diameter that makes the epirubicin liposome should be controlled at about 120nm.
Embodiment 7, bag carry the RGD of paclitaxel and the long circulating liposomes that analog is modified
Utilize film dispersion method preparation bag to carry the RGD of paclitaxel and the long circulating liposomes that analog is modified.Get soybean phospholipid, cholesterol, DSPE-PEG2000, DSPE-PEG-RGD or DSPE-PEG-RGDm and paclitaxel (mol ratio is 20: 10: 2: 1: 0.5), place round-bottomed flask, after adding an amount of chloroform dissolving, put the heating in water bath rotary evaporation in vacuo and remove organic solvent, make on flask walls, to form phospholipid membrane.Add 0.02mol/LrTris-HCL buffer (pH 7.0, contain the NaCl of 0.15mol/L), round-bottomed flask is shaken in rotation, obtains the liposome suspension.Behind nitrogen wash, sealed under the room temperature balance 1 day, probe sonication 15 minutes, and then pushed the poly-carbon ester film 5 times of 200nm, with 5.4% glucose solution dialysis desalination, promptly get this product at last.The above-mentioned particle diameter that makes Paclitaxel liposome should be controlled at about 120nm.
Embodiment 8, bag carry the long circulating liposomes of the RGD modification of cisplatin
Get cisplatin and be dissolved in 0.9% the sodium chloride solution, concentration is 8.5mg/ml, and incubation is 1 hour to 45 ℃ the water-bath.(mol ratio is 20: 10: 2: 1), place round-bottomed flask, add an amount of dissolve with ethanol, join then in the solution of said medicine to get soybean phospholipid, cholesterol, DSPE-PEG2000 and DSPE-PEG-RGD.The ultimate density that makes fat material in the gained mixed solution is 150mg/ml, and concentration of ethanol is 10%.Solution continue was stirred under 45 ℃ of conditions of temperature 1 hour, and under 45 ℃ of conditions, pushed the poly-carbon ester film 11 times of 200nm, cross the poly-carbon ester film of 100nm at last.The liposome that makes put be chilled to room temperature, in cooling procedure, have the precipitation of buff to form, abandoning supernatant at room temperature leaves standstill the longer time with sample, regathers supernatant, so repeatedly.To reach balance with containing the dialysis of 1mM sodium chloride 10% sucrose solution until solution behind 2 times of the diluted samples at last.Adding histidine buffering liquid (pH6.5) to the ultimate density of cisplatin at last is 10mM, promptly gets white transparently, and particle diameter is the cisplatin liposome of 100nm.
Embodiment 9, bag carry the pharmacokinetics and the experiment of the distribution in tumor tissues of the RGD of amycin or the long circulating liposomes that RGDm modifies.
Because the present invention combines the long circulating liposomes technology and promote the method for intracellular transport to improve the curative effect of cancer therapy drug, thus require its feature that possesses long circulating liposomes, promptly prolong drug in blood circulation half-life and in tumor tissues, accumulate.Be necessary the distribution in its pharmacokinetics and the tumor is investigated for this reason.Below be with C57BL/6 mouse inoculation melanoma, the experimental result behind the tail vein injection doxorubicin formulations:
Reference preparation: amycin long circulating liposomes, amycin solution.
Test preparation: bag carries the RGD of amycin or the long circulating liposomes that RGDm modifies.
Experimental animal: the melanomatous C57BL/6 mice of inoculation Mus source property, body weight 18-22 gram, each time point is 5, the tail vein injection administration, dosage is the 5mg/kg body weight.
Result of the test: blood drug level and tumor Chinese medicine concentration data are over time seen accompanying drawing 1 and accompanying drawing 2 respectively.
Experimental result shows that the long circulation Evacet that RGD or RGDm modify possesses the feature of amycin long circulating liposomes, can keep the long time in blood circulation, and can accumulate in tumor tissues.Four kinds of doxorubicin formulations AUC in blood are respectively: amycin solution, 22.7; The amycin long circulating liposomes, 392.4; The amycin long circulating liposomes that RGD modifies, 139.4; The amycin long circulating liposomes that RGDm modifies, 198.8.Four kinds of doxorubicin formulations AUC in tumor tissues are respectively: amycin solution, 27.4; The amycin long circulating liposomes, 67.4; The amycin long circulating liposomes that RGD modifies, 44.3; The amycin long circulating liposomes that RGDm modifies, 54.3.
The pharmacodynamics test of the amycin long circulating liposomes that embodiment 10, RGD or RGDm modify.
Reference preparation: amycin long circulating liposomes, amycin solution
Test preparation: bag carries the RGD of amycin or the long circulating liposomes that RGDm modifies
Experimental animal: the melanomatous C57BL/6 mice of inoculation Mus source property, body weight 18-22 gram, every group of number of mice is 12, the tail vein injection administration, once the administration single dose was the 5mg/kg body weight in per seven days, was administered four times altogether, investigating index is the mice survival rate.
Result of the test: result of the test is seen accompanying drawing 3.
The result shows, the survival rate that the amycin long circulating liposomes that RGD or RGDm modify can obviously prolong tumor-bearing mice.
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| US11260068B2 (en) | 2017-05-25 | 2022-03-01 | Beijing Greatsun Bto-Pharm. Tech. Co., Ltd | Long-circulating liposome modified with c(RGD-ACP-K) |
| CN107365354A (en) * | 2017-08-02 | 2017-11-21 | 安徽工程大学 | Amphiphilic peptide DGRGGGAAAA and preparation method thereof, new anticancer drug transmission system and preparation method thereof |
| CN107365354B (en) * | 2017-08-02 | 2020-06-30 | 安徽工程大学 | Amphiphilic polypeptide DGRGGGAAAA and preparation method thereof, and anticancer drug delivery system and preparation method thereof |
| CN116891516A (en) * | 2023-07-11 | 2023-10-17 | 中山大学附属第三医院 | Preparation and application of exosome-pseudointegrin short peptide-target cell system for high expression of specific type of integrin |
| CN116891516B (en) * | 2023-07-11 | 2024-06-28 | 中山大学附属第三医院 | Preparation and application of an exosome-pseudointegrin short peptide-target cell system that highly expresses a specific type of integrin |
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