CN103006560B - Hyaluronic acid oligosaccharide encased paclitaxel liposome and preparation method thereof - Google Patents
Hyaluronic acid oligosaccharide encased paclitaxel liposome and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a method for preparing a hyaluronic acid oligosaccharide encased paclitaxel liposome. The method comprises the following steps of: weighing phospholipids and paclitaxel to prepare a phospholipids-paclitaxel honeycomb-type thin film; hydrating the prepared thin film; preincubating oligosaccharide and ethyl dimethyl amine propyl carbodiimide in an acetate buffering solution; adding the hydrated suspension into an oligosaccharide-acetate buffering solution for incubation; and separating an obtained mixture to obtain the hyaluronic acid oligosaccharide encased paclitaxel liposome. The oligosaccharide encased paclitaxel liposome is uniform in size, high in encapsulation rate and stable in property; and the solubility of paclitaxel in water is effectively improved. Furthermore, for CD44 high-expression cancer cells (such as the breast cancer), the compound has relatively high targeting (hyaluronic acid is capable of specifically combining with CD44); the concentration of paclitaxel on a tumor part can be effectively increased; the using amount of paclitaxel is reduced; and the toxicity of a medicine on a human body is reduced, and the biological utilization rate is enhanced.
Description
Technical field
The present invention relates to a kind of liposome, relate in particular to Paclitaxel liposome of a kind of hyaluronic acid oligosaccharide parcel and preparation method thereof.
Background technology
Oncotherapy is a current not solution difficult problem, is the significant challenge that medical circle faces always.Drug therapy is an important means of oncotherapy, though traditional antineoplastic thing is obtained certain curative effect, but the toxic and side effects such as its anaphylaxis causing, medulla hematopoietic system inhibition, alopecia, have greatly limited it in clinical practice, become one of difficult problem of clinical treatment.The curative effect that how to improve oncotherapy is problem demanding prompt solution of current medical science.For this shortcoming, targeted therapy becomes the study hotspot of oncotherapy, becomes the focus of medical scholar's research using nanometer as targeting vector.
So-called targeted drug treatment is exactly to make medicine aim at tumor locus, preserves relatively high concentration in part, the time of prolong drug, improve the lethality to tumor, and normal tissue cytosis is less.At present, there is chemotherapeutic (as sustained-release chemotherapy medicine, liposome chemotherapeutic) for the medicine of neoplasm targeted therapy, chemical ablation medicine (as dehydrated alcohol, glacial acetic acid, hydrochloric acid, the protein coagulation agent such as sulphuric acid), gene and molecular targeted medicine, Chinese medicine etc.Medicine can be by many by way of giving, as tumor by local administration under administration in percutaneous puncture administration, art, scope or chamber mirror, blood vessel insertion administration, drug percutaneous ultrasonic electric guide therapeutic, intracavity drug infusion etc.Meanwhile, also derive the new Therapeutic Method such as freezing chemotherapy, thermochemotherapy, Miles' operation therapy, greatly alleviated patient suffering, obviously improved curative effect.
Paclitaxel (Paclitaxel, PTX) be a kind of conventional broad-spectrum anti-tumor medicine, extracted by Chinese yew genus plants, there is unique anticancer mechanism, belong to novel breast cancer, by promoting tubulin polymerization to suppress depolymerization, keep tubulin stable, suppress cell mitogen, the several late cancers such as ovarian cancer, breast carcinoma, pulmonary carcinoma are had to certain curative effect.But because its dissolubility in water is minimum, oral cannot absorption, the PTX injection of existing clinical practice is using polyoxyethylene castor oil and dehydrated alcohol as hydrotropy carrier, but while use, cause multiple toxic and side effects, wherein anaphylaxis is the most serious, adds that it lacks targeting, large usage quantity, more increase its toxic and side effects, make its application seriously limited.
For PTX poorly water-soluble, shortage targeting, in prior art, PTX is made to liposome.Liposome is a kind of Organic Nano-Scale Pharmaceutical Carrier, there is the advantages such as efficient, stable aspect transporting at medicine, that phospholipid relies on hydrophobic association to act on a kind of Molecular Organized Assemblies of spontaneous formation in water, for multilamellar vesicle structure, hydrophobic drug is embedded in the hydrophobic bilayer of liposome by hydrophobic interaction, taking liposome as carrier, not only can reduce the allergy of body, also can improve the meltage of hydrophobic drug in water, reduce the application dose of medicine.Nano-particle connected targeted molecular in recent years, carried out neoplasm targeted therapy, had had very large progress.
If Chinese invention patent application 200610137900.6(publication number is 101176719A), this invention provides a kind of paclitaxel polyene taxol liposome composition of medicine and preparation method thereof, institute's medicine that provides reduces nearly one times of drug dose, and curative effect can improve more than 15%, the toxic and side effects of medicine greatly reduces.
And for example Chinese invention patent application numbers 200710010448.1, this invention provides a kind of Paclitaxel liposome and preparation method thereof, solve paclitaxel water-insoluble shortcoming, paclitaxel thermosensitive long circulation liposome not only has the features such as hypotoxicity, high stability and the minimizing toxic and side effects of paclitaxel conventional liposome preparation, also there is the long cyclicity of long circulating liposomes and the thermal sensitivity of thermal sensitive liposome simultaneously, can extend paclitaxel circulation time in vivo, improve the targeting to tumor, thereby improve its antitumor action.
But domestic and international relevant hyaluronic acid oligosaccharide (hyaluronan oligosaccharides, oHA) is prepared the method for PTX nano material at present, there is not yet report.OHA as the effective killing tumor cell of the molecular targeted tumor cell surface CD44 of target spot time, does not impact normal cell.Compared with conventional liposome, have the advantages that stability is strong, envelop rate is high, be a kind of desirable antitumor drug, therefore, if develop the potentiality of oHA-PTX-Lipid targeting therapy on tumor, will produce tremendous influence to oncotherapy.
Summary of the invention
For the weakness of PTX poorly water-soluble, shortage targeting in prior art, the object of the present invention is to provide a kind of hyaluronic acid oligosaccharide parcel Paclitaxel liposome (oHA-PTX-Lipid) and preparation method thereof.OHA-PTX-Lipid can effectively improve the meltage of PTX in water, by oHA target tumor cell surface CD44 receptor, effectively improves its concentration at tumor locus, reduces the dosage of PTX, strengthens its bioavailability.
According to another aspect of the present invention, provide a kind of preparation method of hyaluronic acid oligosaccharide parcel Paclitaxel liposome, first by thin film aquation method, make drug-loaded liposome with phospholipid, then, by itself and oHA overnight incubation, distilled water is fully dialysed, through high pressure homogenizer homogenizing, obtain hyaluronic acid oligosaccharide parcel Paclitaxel liposome oHA-PTX-Lipid, this method step is simple, easy and simple to handle, the oHA-PTX-Lipid size homogeneous obtaining, envelop rate is high, stable in properties.
Particularly, the invention provides a kind of preparation method of Paclitaxel liposome of hyaluronic acid oligosaccharide parcel, comprise the following steps:
Step 1, takes phospholipid and paclitaxel, prepares the cellular thin film of phospholipid-paclitaxel, and wherein, the mass ratio of phospholipid and paclitaxel is (20 ~ 50)
:1;
Step 2, by the thin film aquation making, the mass percentage concentration that makes phospholipid is 1% ~ 5%;
Step 3,35 ~ 50 DEG C of preincubates in the acetate buffer that is 3 ~ 6 at pH value by hyaluronic acid oligosaccharide and ethyl dimethyl amine propyl carbodiimide diimine, obtain hyaluronic acid oligosaccharide-acetate buffer;
Step 4, the suspension that step 2 is obtained joins in hyaluronic acid oligosaccharide-acetate buffer that step 3 obtains, and hatches for 35 ~ 50 DEG C;
Step 5, the mixture separation that step 4 is obtained, makes the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up;
Wherein, the mass ratio of phospholipid, paclitaxel, hyaluronic acid oligosaccharide and ethyl dimethyl amine propyl carbodiimide diimine is (20 ~ 50)
:1
:(0.25 ~ 1)
:(2.5 ~ 10), the mass volume ratio of hyaluronic acid oligosaccharide and acetate buffer is (2 ~ 8) g
:1mL.
Wherein, prepare method that described cellular thin film can adopt as: phospholipid and paclitaxel are dissolved in solvent, and are preferably and are dissolved in easy volatile solvent, then solvent evaporates makes the Paclitaxel liposome of hyaluronic acid oligosaccharide parcel.
Described easy volatile solvent can be selected from least one in chloroform, ethanol, dichloromethane, ethyl acetate, acetone, tertbutyl ether, normal heptane, ether, methanol, toluene, benzene etc.
Preferably, described effumability solvent is the mixture of chloroform and methanol, and both volume ratios are 65
:35.
Preferably; in step 1, described phospholipid is selected from least one in dioxane acyl phospholipids phatidylcholine, dioleyl phosphatidyl choline (DOPC), dioxane acyl phospholipids acyl hydramine, dioleoyl phosphatidyl hydramine, dioxane acyl phospholipids acyl glycerol and dioxane acyl phospholipids amic acid etc.
Preferably, described dioxane acyl phospholipids phatidylcholine is two C
10~ C
20alkanoyl phosphatidylcholine, as two C
12alkanoyl phosphatidylcholine (DLPC), two C
14alkanoyl phosphatidylcholine (DMPC), two C
16alkanoyl phosphatidylcholine (DPPC), two C
18alkanoyl phosphatidylcholine (DSPC) etc.
Preferably, described dioxane acyl phospholipids acyl hydramine is dioxane acylphosphatidyl ethanolamine.
Preferably, described dioxane acylphosphatidyl ethanolamine is two C
10~ C
20alkanoyl PHOSPHATIDYL ETHANOLAMINE, as two C
12alkanoyl PHOSPHATIDYL ETHANOLAMINE (having another name called is two lauroyl PHOSPHATIDYL ETHANOLAMINE, DLPE), two C
14alkanoyl PHOSPHATIDYL ETHANOLAMINE (DMPE), two C
18alkanoyl PHOSPHATIDYL ETHANOLAMINE (DSPE) etc.
Preferably, described dioleoyl phosphatidyl hydramine is DOPE (DOPE).
Preferably, described dioxane acyl phospholipids acyl glycerol is two C
10~ C
20alkanoyl phosphatidyl glycerol, as two-C
12alkanoyl phosphatidyl glycerol (having another name called for PE DLPG) etc.
Preferably, described dioxane acyl phospholipids amic acid is dioxane acyl phospholipids acyl serine.
Preferably, described dioxane acyl phospholipids acyl serine is two C
10~ C
20alkanoyl Phosphatidylserine, as two C
18alkanoyl Phosphatidylserine (DSPS) etc.
Preferably, described phospholipid is the mixture of DLPE and DLPG, and wherein, the mass ratio of DLPE and DLPG is (9 ~ 1)
:1.
Preferably, in step 2, aquation is 2h at least.
Preferably, in step 2, thin film is at 45 DEG C of at least 2h of rotation aquation.
Preferably, in step 3, the pH of described acetate buffer is 4.5.
Preferably, preincubate at least 1 ~ 3h in step 3, hatches in step 4 as at least 4 ~ 12h.
Preferably, at least 2h of preincubate in step 3, hatches in step 4 as 8h at least.
Preferably, in step 3, preincubate temperature is 37 DEG C, and in step 4, incubation temperature is 37 DEG C.
Preferably, in step 5, the mixture dialysis that step 4 is obtained, homogenizing, dry, make the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up.
Preferably, described dialysis is specially: it is in 10000 bag filter that step 4 gained mixture is transferred to molecular cut off, the distilled water 24h that fully dialyses.
Preferably, described homogenizing is specially: adopt high pressure homogenizer homogenizing, pressure 1.5-2 ten thousand PSI, cycle-index 5-10 time.
The present invention also provides the Paclitaxel liposome of hyaluronic acid oligosaccharide parcel prepared by a kind of above-mentioned preparation method.
Preferably, in the Paclitaxel liposome of described hyaluronic acid oligosaccharide parcel, the content of paclitaxel is 2 ~ 5wt%, and hyaluronic acid oligosaccharide content is 0.8 ~ 1.2wt%.
Preferably, described hyaluronic acid oligosaccharide content is 1wt%.
The Paclitaxel liposome size homogeneous of hyaluronic acid oligosaccharide parcel provided by the invention, envelop rate is high, stable in properties, can preserve for a long time and overcome the shortcoming such as PTX poorly water-soluble, shortage targeting, can be used for breast carcinoma, ovarian cancer, the targeted therapy of the malignant tumor of the CD44 high expresseds such as head and neck cancer, effectively improves the bioavailability of PTX.Experimental studies results shows, oHA-PTX-Lipid prepared by the present invention in vitro, show good antitumous effect in body, compared with traditional PTX, obviously improves its antitumous effect.
Detailed description of the invention
By specific embodiment, technical scheme of the present invention is further described below, to understand better the present invention.
embodiment 1
Take 820mg DLPE, 380mg DLPG and 40mg PTX, add 20ml organic solvent and be dissolved in 250ml round-bottomed flask, 50 DEG C mix 10-20min, and vacuum is drained 4h,-80 DEG C of refrigerator 2h, after lyophilized overnight, by 26ml distilled water aquation, 45 DEG C, 150r/min, at least 2h; 10mg hyaluronic acid oligosaccharide (oHA) and 200mg ethyl dimethyl amine propyl carbodiimide diimine (EDAC) are dissolved in 5ml acetate buffer simultaneously, 37 DEG C, 150 r/min, preincubate 2h; After aquation is completed, suspension joins after preincubate in buffer, and 37 DEG C, 150 r/min, overnight incubation; Then distilled water dialysis 24h; High pressure homogenize, pressure 1.5 ten thousand left and right, circulate 10 times; Super-clean bench 0.22 μ m filter filters; Subpackage ,-80 DEG C freeze and spend the night, and drain powdered, make the Paclitaxel liposome (oHA-PTX-Lipid) of hyaluronic acid oligosaccharide parcel.
The mean diameter of the oHA-PTX-Lipid that measurement the present embodiment makes is in 120nm left and right, big or small homogeneous, stable in properties.The content that high-efficient liquid phase technique is measured calculating PTX is 3wt%, and the content that carbazole method is measured calculating oHA is 1wt%.Acted on breast tumor cell MDA-MB-231, detect its lethal effect to breast tumor cell, result shows: its lethal effect strengthens 2 times compared with the commercially available medicine taxol of simple PTX-of same concentrations, illustrate that oHA-PTX-Lipid prepared by the present embodiment has reached the effect of target killing tumor cell, reduce the using dosage of PTX, effectively improved the bioavailability of PTX.
embodiment 2
Take 1440.3mgDLPE, 175.0mgDLPG and 50.0mgPTX, add 15ml organic solvent and be dissolved in 250ml round-bottomed flask, 50 DEG C mix 10-20min, and vacuum is drained 2h,-80 DEG C of refrigerator 2h, after lyophilized overnight, by 35ml distilled water aquation, 45 DEG C, 150 r/min, at least 2h; 14mg oHA and 240mg EDAC are dissolved in 7ml acetate buffer simultaneously, 37 DEG C, 150 r/min, preincubate 2h; After aquation is completed, suspension joins after preincubate in buffer, and 37 DEG C, 150 r/min, overnight incubation; Distilled water dialysis 24h; High pressure homogenize, pressure 1.5 ten thousand left and right, circulate 10 times, and super-clean bench 0.22 μ m filter filters, subpackage ,-80 DEG C freeze and spend the night, and drain powdered, make the Paclitaxel liposome (oHA-PTX-Lipid) of hyaluronic acid oligosaccharide parcel.
The mean diameter of the oHA-PTX-Lipid that measurement the present embodiment makes is in 120nm left and right, big or small homogeneous, stable in properties.The content that high-efficient liquid phase technique is measured calculating PTX is 5wt%, and the content that carbazole method is measured calculating oHA is 1wt%.Acted on breast tumor cell MDA-MB-231 upper, detected its lethal effect to breast tumor cell.Result shows: its lethal effect strengthens 2 times compared with the commercially available medicine taxol of simple PTX-of same concentrations, illustrate that oHA-PTX-Lipid prepared by the present embodiment has reached the effect of target killing tumor cell, reduce the using dosage of PTX, effectively improved the bioavailability of PTX.
embodiment 3
Take 600.0mg DLPE, 600.0mg DLPG and 40.0mg PTX, add 15ml organic solvent and be dissolved in 250ml round-bottomed flask, 50 DEG C mix 10-20min, and vacuum is drained 2h,-80 DEG C of refrigerator 2h, after lyophilized overnight, by 35ml distilled water aquation, 45 DEG C, 150 r/min, at least 2h; 14mg oHA and 240mg EDAC are dissolved in 7ml acetate buffer simultaneously, 37 DEG C, 150 r/min, preincubate 2h; After aquation is completed, suspension joins after preincubate in buffer, and 37 DEG C, 150 r/min, overnight incubation; Distilled water dialysis 24h, high pressure homogenize, pressure 1.5 ten thousand left and right, circulates 10 times, and super-clean bench 0.22 μ m filter filters, subpackage ,-80 DEG C freeze and spend the night, and drain powdered, make the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up.
The mean diameter of the oHA-PTX-Lipid that measurement the present embodiment makes is in 120nm left and right, big or small homogeneous, stable in properties.The content that high-efficient liquid phase technique is measured calculating PTX is 2wt%, and the content that carbazole method is measured calculating oHA is 1wt%.Acted on breast tumor cell MDA-MB-231 upper, detected its lethal effect to breast tumor cell.Result shows: its lethal effect strengthens 2 times compared with the commercially available medicine taxol of simple PTX-of same concentrations, illustrate that oHA-PTX-Lipid prepared by the present embodiment has reached the effect of target killing tumor cell, reduce the using dosage of PTX, effectively improved the bioavailability of PTX.
embodiment 4
Take 800.0mg DLPE, 600.0mg DLPG and 40.0mg PTX, add 15ml organic solvent and be dissolved in 250ml round-bottomed flask, 50 DEG C mix 10-20min, and vacuum is drained 2h,-80 DEG C of refrigerator 2h, after lyophilized overnight, by 35ml distilled water aquation, 45 DEG C, 150 r/min, at least 2h; 16mg oHA and 280mg EDAC are dissolved in 8ml acetate buffer simultaneously, 37 DEG C, 150 r/min, preincubate 2h; After aquation is completed, suspension joins after preincubate in buffer, and 37 DEG C, 150 r/min, overnight incubation; Distilled water dialysis 24h, high pressure homogenize, pressure 1.5 ten thousand left and right, circulates 10 times, and super-clean bench 0.22 μ m filter filters, subpackage ,-80 DEG C freeze and spend the night, and drain powdered, make the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up.
embodiment 5
Take 900.0mg DLPE, 600.0mg DLPG and 40.0mg PTX, add 15ml organic solvent and be dissolved in 250ml round-bottomed flask, 50 DEG C mix 10-20min, and vacuum is drained 2h,-80 DEG C of refrigerator 2h, after lyophilized overnight, by 35ml distilled water aquation, 45 DEG C, 150 r/min, at least 2h; 20mg oHA and 300mg EDAC are dissolved in 10ml acetate buffer simultaneously, 37 DEG C, 150 r/min, preincubate 2h; After aquation is completed, suspension joins after preincubate in buffer, and 37 DEG C, 150 r/min, overnight incubation; Distilled water dialysis 24h, high pressure homogenize, pressure 1.5 ten thousand left and right, circulates 10 times, and super-clean bench 0.22 μ m filter filters, subpackage ,-80 DEG C freeze and spend the night, and drain powdered, make the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up.
The big or small homogeneous of the oHA-PTX-Lipid that measurement embodiment 4 ~ 5 makes, stable in properties, and experimental result shows that embodiment 4 ~ 5 acts on breast tumor cell MDA-MB-231 and also can reach the effect of target killing tumor cell, reduce the using dosage of PTX, effectively improved the bioavailability of PTX.
Liposome is a kind of Organic Nano-Scale Pharmaceutical Carrier, there is the advantages such as efficient, stable aspect transporting at medicine, that phospholipid relies on hydrophobic association to act on a kind of Molecular Organized Assemblies of spontaneous formation in water, for multilamellar vesicle structure, hydrophobic drug is embedded in the hydrophobic bilayer of liposome by hydrophobic interaction, taking liposome as carrier, not only can reduce the allergy of body, also can improve the meltage of hydrophobic drug in water, reduce the application dose of medicine.In oHA-PTX-Lipid of the present invention, liposome can strengthen the dispersion of PTX in water, on liposome, connect oHA can targeting in conjunction with cell surface CD44 receptor.CD44 receptor is a kind of transmembrane glycopeptide polymeric immunoglobulin receptor that is distributed widely in cell surface, belongs to adhesion factor family, and mediated cell and extracellular matrix adhere to, the multiple physiology such as lymphocyte homing and pathological process.Research discovery, CD44 receptor is highly expressed on many tumor cells, and its main part is hyaluronic acid (HA).OHA is the catabolite of HA, has similar alduronic acid structure to HA, and just disaccharidase unit's number of oHA is less, and oHA has the ability that specificity is combined with CD44 equally.But compared with HA, oHA has the biological function advantages such as metabolic clearance rate is low, releasing tumor cell surface sugar coat, and oHA dissolubility, higher than HA, is better than HA as targeted molecular in succession in fabrication techniques simultaneously.Can be combined with oHA based on tumor cell surface CD44, make oHA can become the targeting part for the treatment of CD44 high expression tumour cell.Use oHA to carry chemotherapeutics, can reduce tumor size in CD44 high expressed animal model for tumour, improve tumor locus drug level, reach the effect of targeting therapy on tumor.Nano-particle connected targeted molecular in recent years, carried out neoplasm targeted therapy, had had very large progress.The oHA of surface of liposome of the present invention is target tumor cell surface CD44 receptor directly, removes tumor cell surface HA sugar coat, improves tumor locus PTX concentration, strengthens its killing activity and bioavailability, for neoplasm targeted therapy opens up a new way.At present domestic and international relevant oHA prepares the method for PTX nano material, there is not yet report.
And when in oHA-PTX-Lipid of the present invention, oHA is as the effective killing tumor cell of the molecular targeted tumor cell surface CD44 of target spot, normal cell is not impacted.Compared with conventional liposome, have the advantages that stability is strong, envelop rate is high, be a kind of desirable antitumor drug.OHA-PTX-Lipid of the present invention has the potentiality of the clinical practice of entering as targeting antineoplastic medicine thing, aspect oncotherapy, can produce very big breakthrough.
Above specific embodiments of the invention be have been described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and alternative also all among category of the present invention.Therefore, equalization conversion and the amendment done without departing from the spirit and scope of the invention, all should contain within the scope of the invention.
Claims (10)
1. a preparation method for the Paclitaxel liposome of hyaluronic acid oligosaccharide parcel, is characterized in that, comprises the following steps:
Step 1, takes phospholipid and paclitaxel, prepares the cellular thin film of phospholipid-paclitaxel;
Step 2, by the thin film aquation making, making the mass percentage concentration of phospholipid is 1% ~ 5%, obtains suspension;
Step 3,35 ~ 50 DEG C of preincubates in the acetate buffer that is 3 ~ 6 at pH value by hyaluronic acid oligosaccharide and ethyl dimethyl amine propyl carbodiimide diimine, obtain oligosaccharide-acetate buffer;
Step 4, the suspension that step 2 is obtained joins in hyaluronic acid oligosaccharide-acetate buffer that step 3 obtains, and hatches for 35 ~ 50 DEG C;
Step 5, the mixture separation that step 4 is obtained, makes the Paclitaxel liposome that hyaluronic acid oligosaccharide wraps up;
Wherein, the mass ratio of phospholipid, paclitaxel, hyaluronic acid oligosaccharide and ethyl dimethyl amine propyl carbodiimide diimine is (20 ~ 50)
:1
:(0.25 ~ 1)
:(2.5 ~ 10), the mass volume ratio of hyaluronic acid oligosaccharide and acetate buffer is (2 ~ 8) g
:1mL.
2. preparation method according to claim 1, is characterized in that, in step 1, phospholipid and paclitaxel is dissolved in solvent, and then solvent evaporates makes the cellular thin film of phospholipid-paclitaxel.
3. preparation method according to claim 1; it is characterized in that; in step 1, described phospholipid is selected from least one in dioxane acyl phospholipids phatidylcholine, dioleyl phosphatidyl choline, dioxane acyl phospholipids acyl hydramine, dioleoyl phosphatidyl hydramine, dioxane acyl phospholipids acyl glycerol and dioxane acyl phospholipids amic acid.
4. preparation method according to claim 1, it is characterized in that, described phospholipid is the mixture of two lauroyl PHOSPHATIDYL ETHANOLAMINE and PE, and wherein, the mass ratio of two lauroyl PHOSPHATIDYL ETHANOLAMINE and PE is (9 ~ 1)
:1.
5. preparation method according to claim 1, is characterized in that, in step 3, the pH value of described acetate buffer is 4.5.
6. preparation method according to claim 1, is characterized in that, preincubate at least 1 ~ 3h in step 3 is hatched in step 4 as at least 4 ~ 12h.
7. preparation method according to claim 1, is characterized in that, in step 3, preincubate temperature is 37 DEG C, and in step 4, incubation temperature is 37 DEG C.
8. preparation method according to claim 1, is characterized in that, in step 5, and the mixture dialysis that step 4 is obtained, homogenizing, dry, make the Paclitaxel liposome that oligosaccharide wraps up.
9. the Paclitaxel liposome of the hyaluronic acid oligosaccharide parcel that according to claim 1 prepared by preparation method.
10. the Paclitaxel liposome of hyaluronic acid oligosaccharide according to claim 9 parcel, is characterized in that, shown in the Paclitaxel liposome of hyaluronic acid oligosaccharide parcel the content of paclitaxel be 2 ~ 5wt%, hyaluronic acid oligosaccharide content is 0.8 ~ 1.2 wt%.
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| CN111773185A (en) * | 2020-08-14 | 2020-10-16 | 上海市普陀区中心医院 | Hyaluronic acid modified bufalin-loaded nano liposome as well as preparation method and application thereof |
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| CN1174557A (en) * | 1994-12-01 | 1998-02-25 | 生化学工业株式会社 | Keratan sulfate oligosaccharide fraction and drug containing the same |
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| US6593308B2 (en) * | 1999-12-03 | 2003-07-15 | The Regents Of The University Of California | Targeted drug delivery with a hyaluronan ligand |
| CA2445985A1 (en) * | 2001-05-04 | 2002-11-14 | University Of Utah Research Foundation | Hyaluronic acid containing bioconjugates: targeted delivery of anti-cancer drugs to cancer cells |
| WO2010118200A2 (en) * | 2009-04-08 | 2010-10-14 | Brian Salvatore | Liposomal formulations of tocopheryl amides |
| US20120082717A1 (en) * | 2009-06-05 | 2012-04-05 | Snu R&Db Foundation | Complex, multilayer using the same, and device coated with the multilayer |
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Non-Patent Citations (4)
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| Characterization of CD44-Mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes;Hussaini syed sha qhattal et al.;《molecular pharmaceutics》;20110622;第8卷;第1233-1246页，尤其是第1234页右栏第3段，右栏第4段，左栏最后1段，第1237页表A，第1244页右栏第2段 * |
| Gal Journo-Gershfeld et al..Hyaluronan Oligomers-HPMA Copolymer Conjugates for Targeting Paclitaxel to CD44-Overexpressing Ovarian Carcinoma.《Pharm Res》.2010,第1121-1133页. |
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