CN101953804A - Shell layer dropping type nanometer medicine carrier preparation based on amphiphilic block copolymer and preparation method thereof - Google Patents
Shell layer dropping type nanometer medicine carrier preparation based on amphiphilic block copolymer and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a shell layer dropping type nanometer medicine carrier preparation based on an amphiphilic block copolymer and a preparation method thereof. The preparation is prepared from the following components in parts by weight: 1 to 20 parts by weight of active ingredient medicines, 10 to 200 parts by weight of amphiphilic block copolymers and 20 to 500 parts by weight of organic solvents. The nanometer medicine micelle carrier preparation is in a core-shell structure, the core of which is a hydrophobic chain segment used for wrapping active ingredients and the shell of which is an amphiphilic block copolymer hydrophilic chain segment, and a hydrophilic segment and a hydrophobic segment in the amphiphilic block copolymer are connected through a disulphide bond S-S. The medicine carrier preparation can be preserved easily and has the advantages of high stability, high medicine cladding ratio, large medicine loading capacity, low toxicity and high medicine bioavailability.
Description
Technical field
The invention belongs to macromolecular material and engineering in medicine field, be specifically related to a kind of tear-away formula nano-medicament carrier preparation of shell based on amphipathic nature block polymer and technology of preparing thereof.
Background technology
Cancer is the commonly encountered diseases of harm humans life and health, and along with the change of The development in society and economy and human lives's custom, the M ﹠ M of cancer is tangible ascendant trend.Chemotherapy is the basic skills of treatment of cancer, and chemotherapy is significant for the transfer of treatment for cancer and control cancer cell, but chemotherapy also is faced with many an open questions still.There are shortcoming separately in widely used low molecule and macromolecular drug at present: (1) low-molecule drug is by oral or drug administration by injection, and vivo medicine concentration far surpasses the actual demand amount in the short time, and lacks the selectivity that enters human body; Metabolism is fast, and the half-life is short, the very fast reduction of bulk concentration and affecting the treatment, thus the heavy dose of administration of needs, and too high drug level can strengthen side effects of pharmaceutical drugs.(2) the easy in vivo enzymolysis inactivation of biopharmaceutical macromolecular drug, biological half-life is short, needs repeat administration; Also be subjected to as immune system, tissue, the restriction of cell membrane etc., most being difficult for by these biological barriers, thereby the bioavailability of macromolecular drug is lower.
At these shortcomings of direct administration, pharmaceutical carrier begins to be widely studied.Yet when traditional pharmaceutical carrier entered blood, the protein in the blood can be adsorbed in the surface of these pharmaceutical carriers very soon.This adsorption can destroy pharmaceutical carrier, causes medicine to dash forward and releases.And adsorbed the physiological function that proteinic pharmaceutical carrier can disturb body intravascular coagulation system and fibrinolytic system, even cause the disorder of interior environment regulatory function.In addition, opsonin in the blood plasma with can produce opsonic action after pharmaceutical carrier combines, its conditioning product can not only be made the dose that enters lesions position reduce by reticuloendothelial system (RES) picked-up, and make medicine be gathered in the RES organ, the RES organ is produced toxic and side effects.
Based on the deficiency of conventional medicament carrier, people begin to explore some new drug delivery systems and improve these deficiencies, thereby reduce side effect, improve utilization ratio of drug.Wherein, a class medicine transmission media that enjoys people to pay close attention to is the micelle that amphipathic nature block polymer forms in aqueous solution.Form in the micellar process in self assembly, the hydrophobic segment of amphipathic nature polyalcohol can form micellar kernel, and hydrophilic segment can form micellar shell.The hydrophobic kernel of micelle can be used for the hydrophobic medicine of load, reduces the toxic and side effects of medicine in transmittance process.Micellar hydrophilic of amphipathic nature polyalcohol and mobile well shell, can effectively improve the water solublity of medicine, and can stop the hydrophobic combination between tumor tissues vascular endothelial cell and hydrophobic drug, thereby make medicine can utilize the high-permeability of tumor tissues blood vessel wall successfully to enter tumor tissues, improve bioavailability of medicament.Therefore this micelle with nucleocapsid structure is expected to the pharmaceutical carrier as a new generation.
Yet polymer nano micelle also is faced with some shortcomings as pharmaceutical carrier.Chemotherapeutics could produce curative effect after generally need entering in the tumor cell, and the not obviously difference of the difference of drug release behavior inside and outside cell of traditional nano-carrier, medicine is more just to be discharged in the extracellular, causes bioavailability of medicament lower, and side effect is bigger.At present common stimuli responsive type nano-micelle can not be distinguished in the cell and extracellular environment, and therefore the intelligent polymer nano micelle that research can localization discharges in tumor cell is significant as pharmaceutical carrier.
Summary of the invention
The object of the invention is to provide the tear-away formula nano-medicament carrier of a kind of shell based on amphipathic nature block polymer preparation, has solved in the prior art polymer nano micelle as all deficiencies of pharmaceutical carrier.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
The tear-away formula nano-medicament carrier of a kind of shell based on amphipathic nature block polymer preparation is characterized in that described preparation comprises in the parts by weight of its component:
Active ingredient medicine 1～20 weight portion;
Amphipathic nature block polymer 10～200 weight portions;
Organic solvent 20～500 weight portions;
Described Nano medication micelle carrier formulation is hydrophobic chain segment coating active composition medicine for nuclear, and shell is the nucleocapsid structure of amphipathic nature block polymer hydrophilic segment; And be connected by disulfide bond S-S between hydrophilic section and the hydrophobic section in the described amphipathic nature block polymer.
Preferably, described amphipathic nature block polymer is selected from two block structure copolymers or many block structures copolymer.
Preferably, the hydrophilic segment in the described amphipathic nature block polymer is selected from any homopolymer or the copolymer of one or more formation in Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethylacrylic acid amino ester, polyacrylic acid and the polymethylacrylic acid.
Preferably, the hydrophobic chain segment in the described amphipathic nature block polymer is selected from any homopolymer or the copolymer of one or more formation in polylactic acid, polycaprolactone, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polyamino acid and the polyphosphazene.
Preferably, described organic solvent is selected from acetone, methanol, ethanol, oxolane, dioxane, N, dinethylformamide, N, any mixing of one or more organic solvents in N-diethylformamide, N,N-dimethylacetamide, the dimethyl sulfoxide.
Preferably, described medicine is selected from one or more any mixing in amycin, paclitaxel, fluorouracil, methotrexate, camptothecine, zitazonium, griseofulvin, Progesterone, Alprostadil, chloromycetin, tolbutamide, rifampicin, epirubicin, diprivan see propofol, the Halofantrine.
Preferably, described preparation is the freeze-dried powder dosage form, and the particle size range of described preparation is the 10-300 nanometer.
The present invention also provides the method for a kind of preparation based on the tear-away formula nano-medicament carrier of the shell of amphipathic nature block polymer preparation, it is characterized in that said method comprising the steps of:
(1) with medicine 1-20 weight portion, amphipathy macromolecule 10-200 weight portion is dissolved in 20-500 weight portion organic solvent in proportion fully, forms transparent oil phase;
(2) oil phase that step (1) is made places bag filter, dialyses 12-72 hour in the water of 10-500 times of oil phase amount then, changes dialysis solution once in every 2-6 hour, after dialysis finishes, collects the carrier micelle aqueous solution in the bag filter; The carrier micelle aqueous solution is prepared into required pharmaceutical dosage form.
Technical solution of the present invention is by the structure of design polymer and micelle carrier, can satisfy after pharmaceutical carrier enters tumor cell, can be in cell under the influence of reproducibility environment, micellar hydrophilic shell optionally comes off, the kernel of packaging medicine is exposed out, thereby realize that intracellular drug releasing rate is far longer than extracellular rate of release, therefore can greatly improve bioavailability of medicament, improve the effect of chemotherapy of tumors.
The amphipathic nature block polymer that is adopted in the technical solution of the present invention, it is (as shown in Figure 1) that the disulfide bond (S-S) by reduction-sensitive gets up hydrophilic segment and hydrophobic segment bridge joint, by the self assembly in aqueous solution, can prepare the pharmaceutical carrier of reduction responsive type.Because glutathione concentrations is than normal cell height in the tumor cell, reducing environment is provided, when the carrier micelle that contains the S-S key enters tumor cell, S-S key to the reducing environment sensitivity can rupture, the hydrophilic section of copolymer and hydrophobic section are separately, the hydrophilic shell comes off, and micellar structure is destroyed, and medicine is discharged into tumor cell inside (as shown in Figure 2).
The employed copolymer of preparation shell of the present invention tear-away formula nano-micelle carrier is an amphipathic block, adopt disulfide bond (S-S) bridge joint (as shown in Figure 1) between hydrophilic section and the hydrophobic section, can be two block structures or many block structures, adopt this weak chemical bond of disulfide bond (S-S) to be connected between its hydrophilic section and the hydrophobic section.Hydrophilic segment can be the homopolymer or the copolymer of one or more formation in the hydrophilic polymeies such as Polyethylene Glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyacrylamide, polymethylacrylic acid amino ester, polyacrylic acid and polymethylacrylic acid.Hydrophobic chain segment can be the homopolymer or the copolymer of one or more formation in polylactic acid, polycaprolactone, the hydrophobicity degradable polymers such as poly-Acetic acid, hydroxy-, bimol. cyclic ester, polyamino acid and polyphosphazene.
When the present invention is prepared based on the tear-away formula nano-medicament carrier of the shell of above-mentioned amphipathic nature block polymer preparation, can adopt following concrete steps:
Take by weighing medicine (as the antitumor drug paclitaxel) 1-20 part, amphipathy macromolecule 10-200 part, organic solvent 20-500 part is dissolved in medicine and macromolecule in the organic solvent in proportion fully, forms transparent oil phase; The solution that makes is placed bag filter, in the water that 10-500 doubly measures, dialysed 12-72 hour then, changed dialysis solution once in every 2-6 hour.Dialysis is lyophilized into powdery solid with the carrier micelle aqueous solution that forms in the bag filter after finishing, and its particle size range is the 10-300 nanometer.
In sum, the present invention obtains a kind of cancer therapy drug tear-away formula nano-medicament carrier of shell preparation that localization discharges in cell and preparation method thereof that is used to realize, the nano-particle carrier that application the present invention obtains can be carried the medicine (as the antitumor drug paclitaxel) that is insoluble in water in vivo, and after the medicine carrying granule enters cell, utilize the interior special reproducibility environment of tumor cell to impel the particulate hydrophilic shell of medicine carrying optionally to come off, thereby realize that the localization of medicine in tumor cell discharges.Use the nano-medicament carrier preparation that the present invention obtains and to pass through the whole body medication, as: vein, oral cavity, subcutaneous, mucosa, suction etc.; Also can be by inside tumor insertion administration method treatment cancer.Nano drug-carrying granule lyophilized preparation provided by the invention can directly be dissolved in 5% the glucose or normal saline, is used for the insertion administration in whole body administration or the tumor.Pharmaceutical carrier preparation with method preparation provided by the invention is easy to preservation, stability height, medicine clad ratio height, drug loading is big, toxicity is little, drug bioavailability is high.
With respect to scheme of the prior art, advantage of the present invention is:
The present invention proposes the technology of preparing of the tear-away formula nano-micelle of a kind of shell carrier, can be used for medicine being wrapped up or being dispersed in carrier, thereby reach medicine localization in tumor cell is discharged.Utilize the nano-medicament carrier preparation of the technology of the present invention preparation to have the following advantages: a) to improve the dissolubility of insoluble drug in water; B) blood circulation time of prolong drug; C) dosage is few, improves the safety of medication; D) improve bioavailability of medicament; E) realize that the localization of medicine in tumor cell discharges.
Description of drawings
Below in conjunction with drawings and Examples the present invention is further described:
Fig. 1 is the amphipathic di-block copolymer structural representation of reduction responsive type by the disulfide bond bridge joint;
Fig. 2 is a drug release principle schematic in the polymer drug-carried micellar cell of amphipathic disulfide bond bridge joint.
The specific embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are used to the present invention is described and are not limited to limit the scope of the invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
Embodiment 1 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing the triblock copolymer and the 10mg paclitaxel of 50mg Polyethylene Glycol and polycaprolactone, with the dissolving of 60mL oxolane, ultrasonic 10min under the room temperature fully disperses polymer and medicine and dissolves, and forms transparent organic facies; The organic phase solution that makes is placed bag filter, in the water of 1L, dialysed 24 hours then, changed dialysis solution once in per 3 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 20 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.041.The TEM photo shows that the mean diameter of nano-particle is 92nm, and particle is spherical in shape, disperses more even.
Embodiment 2 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing 30mg Polyethylene Glycol and poly-leucic di-block copolymer and 8mg amycin, use 20mL N, the mixed solvent dissolving of dinethylformamide and 20mL oxolane, ultrasonic 10min under the room temperature, polymer and medicine are fully disperseed and dissolve, form transparent organic facies; The organic phase solution that makes is placed bag filter, in the water of 500mL, dialysed 30 hours then, changed dialysis solution once in per 4 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 24 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.107.The TEM photo shows that the mean diameter of nano-particle is 115nm, and particle is spherical in shape, disperses more even.
Embodiment 3 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing the di-block copolymer and the 20mg camptothecine of 80mg poly-N-isopropyl acrylamide and polycaprolactone, use 100mL N, dinethylformamide dissolving, ultrasonic 15min under the room temperature fully disperses polymer and medicine and dissolves, and forms transparent organic facies; The organic phase solution that makes is placed bag filter, in 1.5L water, dialysed 48 hours then, changed dialysis solution once in per 2.5 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 18 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.063.The TEM photo shows that the mean diameter of nano-particle is 84nm, and particle is spherical in shape, disperses more even.
Embodiment 4 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing the triblock copolymer and the 10mg methotrexate of 40mg Polyethylene Glycol and polylactic acid, with the dissolving of 50mL oxolane, ultrasonic 10min under the room temperature fully disperses polymer and medicine and dissolves, and forms transparent organic facies; The organic phase solution that makes is placed bag filter, in 800mL water, dialysed 30 hours then, changed dialysis solution once in per 4 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 28 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.127.The TEM photo shows that the mean diameter of nano-particle is 145nm, and particle is spherical in shape, disperses more even.
Embodiment 5 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing the triblock copolymer and the 3mg rifampicin of 10mg polymethylacrylic acid dimethylaminoethyl and polycaprolactone, use the 12mL acetone solution, ultrasonic 9min under the room temperature fully disperses polymer and medicine and dissolves, and forms transparent organic facies; The organic phase solution that makes is placed bag filter, in 450mL water, dialysed 20 hours then, changed dialysis solution once in per 3 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 30 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.097.The TEM photo shows that the mean diameter of nano-particle is 95nm, and particle is spherical in shape, disperses more even.
Embodiment 6 is based on the preparation of the nano-medicament carrier preparation of amphipathic copolymer
Take by weighing the di-block copolymer and the 4mg zitazonium of 15mg polyvinylpyrrolidone and polylactic acid, mixed solvent dissolving with 10mL acetone and 10mL oxolane, ultrasonic 13min under the room temperature fully disperses polymer and medicine and dissolves, and forms transparent organic facies; The organic phase solution that makes is placed bag filter, in 400mL water, dialysed 36 hours then, changed dialysis solution once in per 4 hours.After dialysis finishes, collect the carrier micelle aqueous solution that forms in the bag filter, lyophilization is 26 hours then, obtains the pulverulent solids preparation.With the particle size distribution of dynamic laser light scattering apparatus mensuration particle, polydispersity is 0.135.The TEM photo shows that the mean diameter of nano-particle is 118nm, and particle is spherical in shape, disperses more even.
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (8)
1. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer preparation is characterized in that described preparation comprises in the parts by weight of its component:
Active ingredient medicine 1～20 weight portion;
Amphipathic nature block polymer 10～200 weight portions;
Organic solvent 20～500 weight portions;
Described Nano medication micelle carrier formulation is hydrophobic chain segment coating active composition medicine for nuclear, and shell is the nucleocapsid structure of amphipathic nature block polymer hydrophilic segment; And be connected by disulfide bond S-S between hydrophilic section and the hydrophobic section in the described amphipathic nature block polymer.
2. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation is characterized in that described amphipathic nature block polymer is selected from two block structure copolymers or many block structures copolymer.
3. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation is characterized in that the hydrophilic segment in the described amphipathic nature block polymer is selected from any homopolymer or the copolymer of one or more formation in Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethylacrylic acid amino ester, polyacrylic acid and the polymethylacrylic acid.
4. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation is characterized in that the hydrophobic chain segment in the described amphipathic nature block polymer is selected from any homopolymer or the copolymer of one or more formation in polylactic acid, polycaprolactone, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polyamino acid and the polyphosphazene.
5. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation, it is characterized in that described organic solvent is selected from acetone, methanol, ethanol, oxolane, dioxane, N, dinethylformamide, N, any mixing of one or more in N-diethylformamide, N,N-dimethylacetamide, the dimethyl sulfoxide.
6. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation is characterized in that described medicine is selected from one or more any mixing in amycin, paclitaxel, fluorouracil, methotrexate, camptothecine, zitazonium, griseofulvin, Progesterone, Alprostadil, chloromycetin, tolbutamide, rifampicin, epirubicin, diprivan see propofol, the Halofantrine.
7. the tear-away formula nano-medicament carrier of the shell based on amphipathic nature block polymer according to claim 1 preparation is characterized in that described preparation is the freeze-dried powder dosage form, and the particle size range of described preparation is the 10-300 nanometer.
8. method for preparing based on the tear-away formula nano-medicament carrier of the shell of amphipathic nature block polymer preparation is characterized in that said method comprising the steps of:
(1) with medicine 1-20 weight portion, amphipathy macromolecule 10-200 weight portion is dissolved in 20-500 weight portion organic solvent in proportion fully, forms transparent oil phase;
(2) oil phase that step (1) is made places bag filter, dialyses 12-72 hour in the water of 10-500 times of oil phase amount then, changes dialysis solution once in every 2-6 hour, after dialysis finishes, collects the carrier micelle aqueous solution in the bag filter; The carrier micelle aqueous solution is prepared into required pharmaceutical dosage form.
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| CN102408560B (en) * | 2011-10-20 | 2013-05-01 | 同济大学 | Preparation method of environment response type radial copolymer |
| CN102408560A (en) * | 2011-10-20 | 2012-04-11 | 同济大学 | Preparation method of environment response type radial copolymer |
| CN103520110A (en) * | 2013-09-24 | 2014-01-22 | 中国科学技术大学 | Method for preparing nano particles of camptothecin polymeric prodrug amphipathic molecules as well as product and application of nano particles |
| CN103755953B (en) * | 2013-12-12 | 2015-11-18 | 深圳先进技术研究院 | A kind of intelligent polycation nano-carrier, its preparation method and application thereof |
| CN103705931A (en) * | 2013-12-12 | 2014-04-09 | 深圳先进技术研究院 | Shell-droppable polymer nano carrier as well as preparation method and application thereof |
| CN103755953A (en) * | 2013-12-12 | 2014-04-30 | 深圳先进技术研究院 | Intelligent polycation nano-carrier, and preparation method and application thereof |
| CN103705931B (en) * | 2013-12-12 | 2015-11-11 | 深圳先进技术研究院 | A kind of shell-droppable polymer nano carrier, its preparation method and application thereof |
| CN103865069A (en) * | 2014-02-24 | 2014-06-18 | 西南交通大学 | Active targeting star polymer carrier with physiological environment response function and preparation method thereof |
| CN103865069B (en) * | 2014-02-24 | 2016-05-18 | 西南交通大学 | There is active target star polymer carrier of physiological environment response function and preparation method thereof |
| CN103865049B (en) * | 2014-03-25 | 2015-12-30 | 国家纳米科学中心 | A kind of Amphiphilic Block Polymers, preparation method and its usage |
| CN103865049A (en) * | 2014-03-25 | 2014-06-18 | 国家纳米科学中心 | Amphiphilic block polymer as well as preparation method and application of amphiphilic block polymer |
| CN103965420A (en) * | 2014-04-11 | 2014-08-06 | 西北师范大学 | Reduced response type degradable drug carrier based on disulfide bond as well as preparation and application thereof |
| CN103965420B (en) * | 2014-04-11 | 2016-05-25 | 西北师范大学 | A kind of based on disulfide bond reduction response type degradable medicaments carrier and preparation and application |
| CN105646907A (en) * | 2016-03-09 | 2016-06-08 | 山东理工大学 | Preparation method of polyvinyl alcohol-polypeptide grafted copolymer micelle |
| CN105542198A (en) * | 2016-03-09 | 2016-05-04 | 山东理工大学 | Preparation method of polyvinyl alcohol-poly(trimethylene carbonate)-poly(lactic acid-glycolic acid) dual-grafted copolymer micelle |
| CN105542196A (en) * | 2016-03-09 | 2016-05-04 | 山东理工大学 | Preparation method of polyvinyl alcohol-poly(trimethylene carbonate)- polypeptide dual-grafted copolymer micelle |
| CN105542197A (en) * | 2016-03-09 | 2016-05-04 | 山东理工大学 | Preparation method of polyvinyl alcohol-poly(lactic acid-glycolic acid)-polypeptide dual-grafted copolymer micelle |
| CN105622963A (en) * | 2016-03-09 | 2016-06-01 | 山东理工大学 | Preparation method for polyvinyl alcohol-poly (p-dioxanone)-poly lactic acid-glycolic acid double-grafted copolymer micellae |
| CN105670006A (en) * | 2016-03-09 | 2016-06-15 | 山东理工大学 | Preparation method of polyvinyl alcohol-poly(lactide-glycolide) graft copolymer micelle |
| CN105646908A (en) * | 2016-03-09 | 2016-06-08 | 山东理工大学 | Preparation method of polyvinyl alcohol-poly trimethylene carbonate-poly (p-dioxanone) double-grafted copolymer micelle |
| CN105622964A (en) * | 2016-03-14 | 2016-06-01 | 山东理工大学 | Method for preparing polyving akohol-poly(lactic acid-glycolic acid)-poly(p-dioxanone) dual grafted copolymer micelle |
| CN105646909A (en) * | 2016-03-14 | 2016-06-08 | 山东理工大学 | Method for preparing polyvinyl alcohol-poly(trimethylene carbonate)-poly(p-dioxanone) double-grafted copolymer glairin |
| CN105646910A (en) * | 2016-03-14 | 2016-06-08 | 山东理工大学 | Method for preparing polyvinyl alcohol-poly(lactic acid-glycolic acid)-polypeptide double-grafted copolymer glairin |
| CN105622965A (en) * | 2016-03-14 | 2016-06-01 | 山东理工大学 | Method for preparing polyving akohol-poly(p-dioxanone)-polypeptide dual grafted copolymer micelle |
| CN105670007A (en) * | 2016-03-14 | 2016-06-15 | 山东理工大学 | Method for preparing polyvinyl alcohol-poly trimethylene carbonate-poly lactic acid-glycolic acid double-grafted copolymer micelle |
| CN105694067A (en) * | 2016-03-14 | 2016-06-22 | 山东理工大学 | Method for preparing polyvinyl alcohol-poly (lactic acid-glycolic acid)-polycaprolactone bi-grafted copolymer micelle |
| CN105968370B (en) * | 2016-06-22 | 2019-05-24 | 国家纳米科学中心 | The polyethylene glycol polycaprolactone triblock polymer and its preparation method and application of triple disulfide bond connections |
| CN105968370A (en) * | 2016-06-22 | 2016-09-28 | 国家纳米科学中心 | Triple disulfide-bond linked polyethylene glycol-polycaprolactone triblock copolymer as well as preparation method and application thereof |
| CN106729737A (en) * | 2016-12-30 | 2017-05-31 | 中国药科大学 | A kind of " shelling " formula intelligent nano medicinal composition and preparation method thereof |
| WO2019111121A1 (en) * | 2017-12-05 | 2019-06-13 | International Business Machines Corporation | Block copolymers and self-assembling nanoparticles formed therefrom |
| GB2583602A (en) * | 2017-12-05 | 2020-11-04 | Ibm | Block copolymers and self-assembling nanoparticles formed therefrom |
| CN112004848A (en) * | 2017-12-05 | 2020-11-27 | 国际商业机器公司 | Block copolymers and self-assembled nanoparticles formed therefrom |
| DE112018005698B4 (en) * | 2017-12-05 | 2020-12-03 | Institute Of Bioengineering And Nanotechnology | BLOCK CO-POLYMERS AND SELF-ORGANIZING NANOPARTICLES FORMED FROM THEM |
| GB2583602B (en) * | 2017-12-05 | 2022-06-08 | Ibm | Block copolymers and self-assembling nanoparticles formed therefrom |
| CN108379225A (en) * | 2018-04-16 | 2018-08-10 | 湘潭大学 | Amphipathic oral medicament-carried nano micelle of one kind and preparation method thereof |
| CN110755607A (en) * | 2019-11-19 | 2020-02-07 | 中国科学院过程工程研究所 | Zinc oxide and antigen co-drug-loaded nano vaccine, and preparation method and application thereof |
| CN110755607B (en) * | 2019-11-19 | 2021-12-28 | 中国科学院过程工程研究所 | Zinc oxide and antigen co-drug-loaded nano vaccine, and preparation method and application thereof |
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