CN102429870A - Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug - Google Patents
Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug Download PDFInfo
- Publication number
- CN102429870A CN102429870A CN2011104318700A CN201110431870A CN102429870A CN 102429870 A CN102429870 A CN 102429870A CN 2011104318700 A CN2011104318700 A CN 2011104318700A CN 201110431870 A CN201110431870 A CN 201110431870A CN 102429870 A CN102429870 A CN 102429870A
- Authority
- CN
- China
- Prior art keywords
- pamam
- drug
- carrier
- camptothecine
- camptothecin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to preparation of a novel target nano carrier and application of the novel target nano carrier in a camptothecin drug targeting delivery system. The system can be represented as PAMAM-HA/drug, wherein PAMAM is polyamide amine-amine arboraceous macromolecules of different generations, HA is hyaluronic acid of different molecular weights, and the drug is one or more of camptothecin anticancer drugs such as camptothecin, 10- hydroxycamptothecine, topotecan and the like. The carrier is used for wrapping the camptothecin drugs, and has the actions of prolonging the drug blood circulation time, improving the drug bioavailability, reducing the non-tumor part concentration of the drug, reducing the drug cytotoxicity, and simultaneously protecting the lactonic rings of the camptothecin drugs from damage, thereby improving the tumor treatment efficiency from multiple aspects. The nano carrier provided by the invention has important significance in promoting the safe delivery of the camptothecin drugs and the effective treatment of tumor.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to the preparation and the application in the camptothecine targeted delivery thereof of the tree-shaped polymer nanocomposite carrier of a kind of novel tumor targeting.With camptothecine with hyaluronic acid decorated tree-shaped polymer enclose after; Help camptothecine compounds with the closed activity form administration of lactonic ring; Compare with existing commercial preparation; Have and improve bioavailability, intensifier target tropism, reduce toxic and side effects, prolong drug half-life, but and advantage such as storage-stable.
Background technology
(Camptothecin CPT) is a kind of pyrroles [3,4-b] quinoline alkaloid to camptothecine, from China's distinctive plant Nyssaceae Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) trunk, is separated first by people such as Wall and gets in 1966.Find that after deliberation camptothecine all has certain curative effect to multiple malignant tumor such as tumor of head and neck, bladder cancer and leukemia.(Hydroxycamptothecin OPT) has more obvious suppression effect to multiple animal tumor to its derivant 10-hydroxycamptothecine, and toxicity is less, but the part patient still has toxic and side effects such as hematuria, urgent micturition, frequent micturition.Until 1985; People such as Hsiang find that camptothecine and derivant thereof are through the synthetic mechanism of bringing into play antitumaous effect of the DNA of targeting property inhibition topology isomerase (Topo I); So far; More camptothecin derivant is arisen at the historic moment, and becomes the new focus of anticancer area research, and causes people's attention again.
The integrity of the hexa-atomic hydroxy-lactone ring of camptothecine is to guarantee that it is the essential structure of topoisomerase enzyme inhibitor; Yet lactone type is a poorly water soluble drugs; Adopt the method for alkalization open loop that it is processed sodium salt liquid drugs injection and powder pin at present clinically; Though increased its water solublity, active 1/10 of the lactone form that is merely, curative effect reduce and the half-life weak point.Simultaneously, lactone type fat-soluble also very low, preparations such as preparation liposome or microemulsion also are difficult to reach clinical required drug loading.For the insoluble chemical compound of profit partition coefficient between-0.3 to 4.5, its liposome drug loading and envelop rate are all very low.The chemical constituent of biologically active all belonged to above-mentioned category during camptothecine compounds was numerous, so the liposome drug loading and the medicine fat of preparation are lower than all, was difficult to reach clinical consumption requirement, and medicine is prone to dash forward to release let out crystalline substance, poor stability.
Polyamide-amide dendrimer (Polyamide-amine dendrimer; PAMAM) as a kind of novel high branch, the macromole of 3-d tree-like structure; Compare with linear macromolecule, have regular structure, clear and definite molecular weight and molecular dimension, and can accurately control molecular shape and functional group etc. through the regulation and control building-up process; Can solve the various problems of biological barrier in the cancer therapy drug transmission: (1) inner a large amount of cavitys can wrap up micromolecular compound; And under certain condition it is disengaged, make loaded drugs have slow, controlled release properties, help medicine in the longer time of tumor locus effect.Simultaneously inner drug molecule is produced the significant protection effect is arranged; Can prevent the degraded of internal milieu, can avoid the pharmaceutically active forfeiture, help the storage and the transportation of medicine drug molecule; And can prevent the gathering of drug molecule, increase medicine and contact etc. with biomembranous.(2) highly branched structure and unique single dispersing characteristic make molecular surface have high functional group densities, its functional end-group can with many Organic substances, inorganic matter generation chemical reaction.Introduce hydrophobic group or targeting part, antibody etc. through modifying, can improve biocompatibility, bioavailability and active targeting property.(3) nano-scale that utilizes PAMAM also can bigger tumor locus reaches passive infiltration and accumulating effect (EPR) so that medicine is in the space; And can get into cell through modes such as endocytosis, pinocytosis; Therefore possibly increase medicine to biomembranous permeability, when drug resistance especially occurring or special barrier being arranged.Existing research proof, the PAMAM drug-loading system can overcome the drug resistance problem of tumour medicine to a certain extent.(4) compare with traditional nano-carriers such as liposome, polymer micelles, also have stability height, non-immunogenicity, hypotoxicity, can be one type of promising non-virus carrier through characteristics such as urine and feces excrete.
But the locating effect that only utilizes nano effect to carry out passive target is not very desirable.And whole a large amount of amino groups are arranged for PAMAM dendrimer surface, under the physiological pH condition, be prone to protonated and therefore positively charged unavoidably has certain cytotoxicity.It is to reduce its toxicity, improve one of effective ways of its biocompatibility that the micromolecule part that utilizes nontoxic, good water solubility is modified PAMAM.And utilize the interaction of part and tumor inner recipient, and can reach specific effect more efficiently, to remedy the deficiency of simple passive target, strengthen the specificity of drug-supplying system to tumor cell to particular organization or specific cells targeting ability.
Hyaluronic acid (Hyaluronic acid; HA) extensively exist in vivo; Be a kind of electronegative linear glycosaminoglycans, in lubricated joint, connect in the connective tissue and play a significant role, and in the structure of keeping extracellular matrix and regulate in the cell aspect such as activity and also play an important role.The CD44 molecule is a kind of glycoprotein that is distributed widely in cell surface; All can detect its expression at lymphocyte, fibroblast, a matter and hemopoietic source sexual cell and multiple malignant tumor cell surface; Cell stick with transfer process in play an important role, be one of important receptor of HA on the cell surface.Nearest research shows that the interaction between HA and its specific receptor CD44 can be used as the research basis of HA targeted therapy malignant tumor.Successfully use HA that medicine is carried out chemical modification or HA is equipped on liposome, the well targeting low toxicity transmission efficiently of nanoparticle outer surface realization medicine both at home and abroad.
The present invention grafts on tree-shaped polymer surfaces with hyaluronic acid; Utilize the neutralization of hyaluronic negative electricity and with the interaction of tumor cell surface CD44 receptor, both can reduce the toxicity of polymer, improve its biocompatibility; Can reduce the nonspecific action of PAMAM and cell surface again; Reduce the delay of medicine at non-tumor locus, thus the partial drug level of many-sided increase focus, the untoward reaction that alleviates camptothecine.Simultaneously, also can increase medicine water solublity and stability in vivo, improve the slow release effect and the bioavailability of medicine.
Summary of the invention
One of the object of the invention is to provide a kind of good biocompatibility, tumor cell is had targeting property, can reduce poisonous side effect of medicine, increases the tree-shaped polymer nanocomposite carrier of anticancer therapeutic.
Two of the object of the invention is to carry camptothecine with freshly prepd targeting vector bag, to reduce the open loop of camptothecine lactonic ring, increases curative effect and utilizes the dual cancer target that size is passive, the receptor active role reaches medicine simultaneously.
The objective of the invention is to realize like this:
A kind of tree-shaped polymer target carrier; Characteristics are that this carrier is a nanoparticle; Have following structure: that be positioned at centronucleus is tree-shaped polymer polyamide-amide PAMAM, and outermost end is a hyaluronic acid targeting group, and combines bag to carry suitable medicine through physics parcel or static.
General formula is PAMAM-HA/drug, wherein PAMAM be 2.0-5.0 for the tree-shaped polymer of polyamide-amide, HA is the hyaluronic acid of different molecular weight, drug be camptothecines such as camptothecine, 10-hydroxycamptothecine, TPT one or more.
The method for preparing of above-mentioned nano-carrier is: get an amount of PAMAM-HA, be dissolved in an amount of absolute methanol, 50 ℃ of insulations down.Other gets camptothecine and is dissolved in right amount in the hydrochloric acid solution, drug solution is added drop-wise in the PAMAM-HA solution through constant pressure funnel, and the dropping time is controlled at 30-45min, lucifuge incubated at room 24h under the nitrogen protection condition.With the redistilled water 24h that dialyses, lyophilizing gets white powder PAMAM-HA/drug, and low-temperature dark is preserved.The mol ratio of its Chinese medicine and tree-shaped polymer support PAMAM-HA is 10: 1-5: 1, and the concentration of drug solution is 1-2mol/L, the concentration of tree-shaped polymer support PAMAM-HA solution is 0.5-1mg/mL.
The preparation of said tree-shaped polymer support PAMAM-HA may further comprise the steps:
A) prepare the integer PAMAM molecule in generation through the Michael addition of acrylic acid methyl ester. and the ammonolysis reaction of ethylenediamine;
B) daiamid and hyaluronic acid are that condensing agent reacts 48h with functional group's molar ratio reaction of 1: 4 in dimethyl sulfoxide solvent with 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl);
C) reaction mixture is used excessive pH7.4 phosphate-buffered salt and distill water dialysis 24h successively, after the lyophilization white powder, i.e. PAMAM-HA, low-temperature dark is preserved.
Above-mentioned carrier can be used for the targeted delivery of camptothecine.
Targeting vector of the present invention has following characteristics:
1. has high bio-compatibility, low immunogenicity and cytotoxicity;
2. the core texture size is meticulous adjustable, and surface amino groups and hyaluronic acid number are controlled;
3. thereby passive target combines that with the active targeting tumor cell is had the height Targeting Performance, further improves targeting efficient, realizes the high-efficiency low-toxicity treatment of cancer;
4. the hydrophilic high mol finishing can prolong the blood circulation time of nano-complex particle, strengthens the water solublity of medicine and strengthens it in stability in blood;
5. tree-shaped polymer support produces the significant protection effect to the camptothecine molecule that is wrapped in internal cavities; Can prevent the degraded of internal milieu to drug molecule; The loss of activity that can avoid the medicine lactonic ring to break and cause helps the stability of medicine in storage and transportation;
6. compare with nanoparticle such as liposome, the nanoparticle that tree-shaped polymer part forms can not discharge medicine because of dissociating and cause the seepage of medicine to release with prominent in the blood circulation process.
Description of drawings
The tree-shaped polymer supported nano target carrier system sketch map of Fig. 1 PAMAM G4.0-HA of the present invention (6900)
D=medicine wherein.
Hyaluronic absworption peak appears in the H-NMR collection of illustrative plates of Fig. 2 HA (6900), PAMAM G4.0, PAMAM G4.0-HA (6900) between 3.5-5.0, proved the access of targeting group.
The UV scanning collection of illustrative plates of Fig. 3 PAMAM G4.0, PAMAM G4.0-HA (6900), HA (6900) can be seen the skew at PAMAM grafting hyaluronic acid post-absorption peak, has proved hyaluronic access.
Fig. 4 PAMAM G4.0 infared spectrum.
Fig. 5 PAMAM G4.0-HA (6900) infared spectrum, the significant change at 1000-500cm-1 place has proved the change of structure.
Fig. 6 PAMAM G4.0-HA (6900) weak solution (0.05mol/L) dynamic scattering collection of illustrative plates can find out that monodispersity is good.
Release in vitro curve behind Fig. 7 PAMAM G4.0-HA (6900) enclose TPT in the different ionic strength release medium; The ionic strength of from 1 to 3 solution progressively strengthens, be respectively pure water, normal saline and with the pH7.4 phosphate-buffered salt of normal saline with concentration.The combination that has proved medicine and carrier with dissociate relevant with charge interaction.
The specific embodiment
Below in conjunction with specific embodiment the present invention is further detailed:
1.PAMAM synthetic
A) purification of raw material
Methanol is with the dry 24h of iodine grain (adding post-heating to 66 degree maintains droplet and dropwise drips backflow 24h) back air-distillation, and collecting fraction is 64-66 ℃;
Acrylic acid methyl ester. is with anhydrous sodium sulfate drying 24h (adding post-heating to 78 degree maintains droplet and dropwise drips backflow 24h) back air-distillation, and collecting fraction is 77-79 ℃;
Ethylenediamine with the dry 24h of potassium hydroxide after distilling under reduced pressure (pressure is collected 45-47 ℃ of fraction 1000 ± 50Pa).
B) PAMAM G0.5's is synthetic
Take by weighing 2.0068g ethylenediamine (about 0.033mol) in the there-necked flask of 250mL, under ice-water bath, electromagnetic agitation, nitrogen protection condition, add 22.0103g methanol, behind the mix homogeneously; With constant pressure funnel 22.9714g (about 0.267mol) acrylic acid methyl ester. is added drop-wise in the there-necked flask; Rate of addition is 1/s, continues to stir 15min, deoxidation; There-necked flask is put into 35 ℃ water bath with thermostatic control, reaction 24h.
Behind the reaction 24h, product is carried out distilling under reduced pressure, remove excessive acrylic acid methyl ester. and methanol, promptly obtain the polyamide-amide dendrimer of 0.5G.Weigh productive rate.
C) PAMAM G1.0's is synthetic
The PAMAM that takes by weighing 4.9933g (about 0.012mol) 0.5G is in there-necked flask; 16.0020g methanol splashed in the there-necked flask 0.5GPAMAM is fully dissolved; Electromagnetic agitation 20min deoxidation under ice-water bath, nitrogen protection condition; Then 14.8447g (about 0.247mol) ethylenediamine is splashed in the there-necked flask with constant pressure funnel, rate of addition is 1/s, continues to stir 15min.There-necked flask put in 25 ℃ of waters bath with thermostatic control react 24h.
Behind the reaction 24h, product is carried out distilling under reduced pressure, remove unnecessary ethylenediamine and methanol, promptly obtain 1.0G polyamide-amide dendrimer.The calculating productive rate of weighing.
Repeat B), C) step, up to obtaining purified PAMAM G4.0.
2. the activation of hyaluronic acid (molecular weight=6900)
2mmol hyaluronic acid (molecular weight=6900) joins in the 10mL dimethyl sulfoxide (DMSO); 50 ℃ of heating in water bath magnetic agitation make its dissolving; Be cooled to room temperature; Add 14 times of excessive 1-ethyl-3-(3-dimethylamine propyl) carbodiimides (EDC) hydrochlorate respectively, stir and make its abundant haptoreaction 1h under 30 ℃ of following lucifuges, nitrogen protection.
3.PAMAM G4.0-HA's (6900) is synthetic
Take by weighing 1.38mmol 4.0 generation polyamide-amide and be dissolved among the DMSO, mild heat stirs, and waits to dissolve postcooling to room temperature, and the HA drips of solution after the activation is added to wherein.Mixed liquor is stirring reaction 48h in the nitrogen environment at room temperature, and it is in 8000 the bag filter that product is transferred to molecular cut off, uses 200mL pH 7.4 phosphate-buffered salts and distill water dialysis 24h successively.Get white powder, cryopreservation after the lyophilization.
4. medicine is written into
Get synthetic PAMAM G4.0-HA (6900) 89.6mg in the step 3, be dissolved among 50 ℃ the absolute methanol 10mL, 50 ℃ of insulations down.Other gets in the hydrochloric acid solution that camptothecine 10mg is dissolved in 16mL 0.1mol/L, drug solution is added drop-wise in PAMAM G4.0-HA (6900) solution lucifuge stirring reaction 24h under the nitrogen protection condition through constant pressure funnel.
With the redistilled water 24h that dialyses, lyophilizing gets white powder, cryopreservation.
1.PAMAM synthetic
A) purification of raw material
Methanol is with the dry 24h of iodine grain (add post-heating to 66 ℃ maintain droplet dropwise drip backflow 24h) back air-distillation, and collecting fraction is 64-66 ℃;
Acrylic acid methyl ester. is with anhydrous sodium sulfate drying 24h (add post-heating to 78 ℃ maintain droplet dropwise drip backflow 24h) back air-distillation, and collecting fraction is 77-79 ℃;
Ethylenediamine with the dry 24h of potassium hydroxide after distilling under reduced pressure (pressure is collected 45-47 ℃ of fraction 1000 ± 50Pa).
B) PAMAM G0.5's is synthetic
Take by weighing 2.0068g ethylenediamine (about 0.033mol) in the there-necked flask of 250mL, under ice-water bath, electromagnetic agitation, nitrogen protection condition, add 22.0103g methanol, behind the mix homogeneously; With constant pressure funnel 22.9714g (about 0.267mol) acrylic acid methyl ester. is added drop-wise in the there-necked flask; Rate of addition is 1/s, continues to stir 15min, deoxidation; There-necked flask is put into 35 ℃ water bath with thermostatic control, reaction 24h.
Behind the reaction 24h, product is carried out distilling under reduced pressure, remove excessive acrylic acid methyl ester. and methanol, promptly obtain the polyamide-amide dendrimer of 0.5G.Weigh productive rate.
C) PAMAM G1.0's is synthetic
The PAMAM that takes by weighing 4.9933g (about 0.012mol) 0.5G is in there-necked flask; 16.0020g methanol splashed in the there-necked flask PAMAM G0.5 is fully dissolved; Electromagnetic agitation 20min deoxidation under ice-water bath, nitrogen protection condition; Then 14.8447g (about 0.247mol) ethylenediamine is splashed in the there-necked flask with constant pressure funnel, rate of addition is 1/s, continues to stir 15min.There-necked flask put in 25 ℃ of waters bath with thermostatic control react 24h.
Behind the reaction 24h, product is carried out distilling under reduced pressure, remove unnecessary ethylenediamine and methanol, promptly obtain 1.0G polyamide-amide dendrimer.The calculating productive rate of weighing.
Repeat B), C) step, up to obtaining purified PAMAM G4.0.
2. the activation of hyaluronic acid (molecular weight=9900)
2mmol hyaluronic acid (molecular weight=9900) joins in the 10mL dimethyl sulfoxide (DMSO); 50 ℃ of heating in water bath magnetic agitation make its dissolving; Be cooled to room temperature; Add 14 times of excessive 1-ethyl-3-(3-dimethylamine propyl) carbodiimides (EDC) hydrochlorate respectively, stir and make its abundant haptoreaction 1h under 30 ℃ of following lucifuges, nitrogen protection.
3.PAMAM G4.0-HA's (9900) is synthetic
Take by weighing the 1.49mmol tree and be dissolved among the 20mL DMSO, mild heat stirs, and waits to dissolve postcooling to room temperature, and the HA solution after the activation slowly is added drop-wise to wherein.Mixed liquor is stirring reaction 48h in the room temperature nitrogen environment., it is in 10000 the bag filter that product is transferred to molecular cut off, uses 200mL pH7.4 phosphate-buffered salt and distill water dialysis 24h successively.Get white powder, cryopreservation after the lyophilization.
4. medicine is written into
Get synthetic PAMAM G4.0-HA (9900) 95.7mg in the step 3, be dissolved in the absolute methanol of 10mL, 50 ℃ of insulations down.Other gets camptothecine 10mg, is dissolved in the hydrochloric acid solution of 16mL 0.1mol/L, drug solution is added drop-wise in PAMAM G4.0-HA (9900) solution lucifuge stirring reaction 24h under the nitrogen protection condition through constant pressure funnel.
With the redistilled water 24h that dialyses, lyophilizing gets white powder, cryopreservation.
Embodiment 3-4
With PAMAM G3.0, the PAMAM G5.0 replacement PAMAM G4.0, other is with embodiment 1 except that respectively.
Embodiment 5-6
With PAMAM G3.0, the PAMAM G5.0 replacement PAMAM G4.0, other is with embodiment 2 except that respectively.
Embodiment 7-8
With the 10-hydroxycamptothecine replacement camptothecine, other is with embodiment 1,2 except that respectively.
Embodiment 9-10
With the TPT replacement camptothecine, other is with embodiment 1,2 except that respectively.
In the above-described embodiments, made particle diameter between 50-300nm, based on the cancer target carrier of tree-shaped polymer.The foregoing description only is used to the present invention is described but is not limited thereto that should be appreciated that in not departing from the scope of the present invention to have multiple accommodation or alternative.
Claims (10)
1. one kind is used to wrap the targeted nano carrier that carries camptothecine compounds; It is characterized in that this carrier is is parent nucleus with polyamide-amide (PAMAM) dendrimer; Realize obtaining after the chemical coupling with targeting sexual function factor hyaluronic acid, can realize medicine carrying through Electrostatic Absorption or physics parcel with camptothecine.
2. nano-carrier as claimed in claim 1 is characterized in that described polyamide-amide dendrimer, and its algebraically is 3-5 generation.
3. nano-carrier as claimed in claim 1 is characterized in that the described targeting sexual function factor can be the micromolecule hyaluronic acid of different polymerization degree (n=60-120).
4. camptothecine as claimed in claim 1, can be camptothecin derivants such as camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 7-ethyl-10-hydroxycamptothecine, TPT or irinotecan one or more.
5. targeted nano carrier as claimed in claim 1, the particle diameter that it is characterized in that said ball shaped nano grain is 50-300nm, the polyamide-amide that its particle diameter can be through adopting different algebraically and the hyaluronic acid of different molecular weight are regulated and control.
6. the method for preparing of tree-shaped polymer nanocomposite carrier as claimed in claim 1 may further comprise the steps:
The first step: as core, aminoterminal again and ethylenediamine (EDA) aminolysis, obtains integer with the amino ending for the PAMAM molecule with the method for dispersing repeatedly and acrylic acid methyl ester. (MA) Michael addition with ethylenediamine;
Second step: the polyamide-amide that the first step obtains and hyaluronic acid react under 1-ethyl-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl) catalysis, and lyophilizing gets white powder behind the purification, i.e. PAMAM-HA, low-temperature dark preservation.
7. the method for preparing of tree-shaped polymer support as claimed in claim 6; It is characterized in that: the purification of first step integer tree-shaped polymer of generation; Can in vacuum distillation process, in explosion-proof ball, add a small amount of concentrated sulphuric acid, by quickening separating out of ethylenediamine with the salt-forming reaction of ethylenediamine; And increase along with algebraically; The excessive multiple of acrylic acid methyl ester., ethylenediamine is how much multiples from initial 2 times, 6 times respectively to be increased; The response time in half generation, whole generation prolonged from initial 24 hours, 18 hours respectively gradually, and the maximum that is beneficial to subsequent reactions is carried out and the maximum purification of product; PAMAM and hyaluronic rate of charge are converted by functional group's mol ratio at 1: 4 in second step, and EDC needs excessive 14 times.
8. camptothecine loading method as claimed in claim 1 is: the weighting profit requires the PAMAM-HA that obtains in 6, be dissolved in an amount of methanol, and insulation at a certain temperature; Other gets appropriate amount of drug and is dissolved in hydrochloric acid solution, slowly drips through constant pressure funnel, and incubated at room is 24 hours under the nitrogen protection; The dialysis purification, lyophilizing gets white powder PAMAM-HA/drug, and low-temperature dark is preserved.
9. the bag support method of camptothecine as claimed in claim 7 is characterized in that: the ratio of medicine and nano-carrier will be confirmed through the mensuration of microtrabeculae centrifuging envelop rate, make to reach maximum enclose.
10. carrying mode that the tree-shaped polymer nanocomposite carrier of camptothecine can lyophilized powder like the bag of the said preparation of claim 5 stores or uses; Perhaps dilute also filtration sterilization and perhaps further be processed into granule, pill, capsule or tablet to mix other adjuvant after the suitable adsorbents adsorb to be used for intravenous injection through water for injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104318700A CN102429870A (en) | 2011-12-21 | 2011-12-21 | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104318700A CN102429870A (en) | 2011-12-21 | 2011-12-21 | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102429870A true CN102429870A (en) | 2012-05-02 |
Family
ID=45978460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104318700A Pending CN102429870A (en) | 2011-12-21 | 2011-12-21 | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102429870A (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797163A (en) * | 2015-05-20 | 2016-07-27 | 于军 | Medicine for treating retinal disease and preparation method thereof |
| CN107049955A (en) * | 2016-11-21 | 2017-08-18 | 中国药科大学 | A kind of multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) and preparation method thereof |
| CN107115320A (en) * | 2017-04-13 | 2017-09-01 | 徐州医科大学附属医院 | A kind of targeted nano granule for loading Temozolomide and preparation method thereof |
| CN107126561A (en) * | 2017-04-18 | 2017-09-05 | 徐州医科大学附属医院 | A kind of achievable chemotherapy and the antitumor cooperative compositions of PTT/PDT therapeutic alliances and its application |
| CN107281164A (en) * | 2017-07-10 | 2017-10-24 | 福州大学 | It is a kind of that the self-assembled nanometer grain of cancer therapy drug is loaded and its in the application of anti-tumor aspect based on low generation PAMAM dendrimers |
| CN107308457A (en) * | 2017-05-19 | 2017-11-03 | 四川大学 | A kind of deep layer degraded with tumor microenvironment response penetrates nanoscale medicine delivery system |
| CN107412787A (en) * | 2017-04-18 | 2017-12-01 | 徐州医科大学附属医院 | A kind of sensitising agent targeted nano granule for optical therapeutic and its preparation method and application |
| CN107510849A (en) * | 2017-08-16 | 2017-12-26 | 暨南大学 | A kind of glutathione response type dual drug carrier and its preparation method and application |
| CN107794008A (en) * | 2017-10-25 | 2018-03-13 | 西南石油大学 | One kind synthesis hydridization polyamines drilling fluid inhibitor and preparation method thereof |
| CN109456490A (en) * | 2018-10-23 | 2019-03-12 | 青岛大学 | A kind of preparation method and product of dendritic macromole hydrogel |
| CN110652518A (en) * | 2019-05-05 | 2020-01-07 | 海南亚洲制药股份有限公司 | Targeting type nano drug-loading system and preparation method thereof |
| CN112472805A (en) * | 2019-07-26 | 2021-03-12 | 浙江大学 | Boron-containing preparation with cell nucleus targeting property and preparation method and application thereof |
| CN114606190A (en) * | 2022-03-08 | 2022-06-10 | 东南大学 | Nano reagent for killing and foaming cells, cell micro-vesicle and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181225A (en) * | 2007-11-30 | 2008-05-21 | 南开大学 | System for transferring nanometer polyalcohol micelle medicament and preparing method as well as application thereof |
| WO2009115579A1 (en) * | 2008-03-20 | 2009-09-24 | National University Of Ireland, Galway | Biodegradable nanoshells for delivery of therapeutic and/or imaging molecules |
-
2011
- 2011-12-21 CN CN2011104318700A patent/CN102429870A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181225A (en) * | 2007-11-30 | 2008-05-21 | 南开大学 | System for transferring nanometer polyalcohol micelle medicament and preparing method as well as application thereof |
| WO2009115579A1 (en) * | 2008-03-20 | 2009-09-24 | National University Of Ireland, Galway | Biodegradable nanoshells for delivery of therapeutic and/or imaging molecules |
Non-Patent Citations (1)
| Title |
|---|
| SHUHONG DUAN等: "PAMAM dendrimer composite membrane for CO2 separation:additon of hyaluronic acid in gutter layer and application of novel hydroxyl PAMAM dendrimer", 《DESALINATION》 * |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797163B (en) * | 2015-05-20 | 2018-07-13 | 于军 | It is a kind of to be used to treat drug of retinal disease and preparation method thereof |
| CN105797163A (en) * | 2015-05-20 | 2016-07-27 | 于军 | Medicine for treating retinal disease and preparation method thereof |
| CN107049955A (en) * | 2016-11-21 | 2017-08-18 | 中国药科大学 | A kind of multistage targeting hyaluronan nanoparticle for carrying methotrexate (MTX) and preparation method thereof |
| CN107115320A (en) * | 2017-04-13 | 2017-09-01 | 徐州医科大学附属医院 | A kind of targeted nano granule for loading Temozolomide and preparation method thereof |
| CN107115320B (en) * | 2017-04-13 | 2019-11-26 | 徐州医科大学附属医院 | A kind of targeted nano granule and preparation method thereof loading Temozolomide |
| CN107126561A (en) * | 2017-04-18 | 2017-09-05 | 徐州医科大学附属医院 | A kind of achievable chemotherapy and the antitumor cooperative compositions of PTT/PDT therapeutic alliances and its application |
| CN107412787B (en) * | 2017-04-18 | 2020-04-17 | 徐州医科大学附属医院 | Photosensitizer targeted nanoparticle for optical treatment and preparation method and application thereof |
| CN107412787A (en) * | 2017-04-18 | 2017-12-01 | 徐州医科大学附属医院 | A kind of sensitising agent targeted nano granule for optical therapeutic and its preparation method and application |
| CN107126561B (en) * | 2017-04-18 | 2020-03-10 | 徐州医科大学附属医院 | Anti-tumor synergistic composition capable of realizing combined treatment of chemotherapy and PTT/PDT and application thereof |
| CN107308457A (en) * | 2017-05-19 | 2017-11-03 | 四川大学 | A kind of deep layer degraded with tumor microenvironment response penetrates nanoscale medicine delivery system |
| CN107281164A (en) * | 2017-07-10 | 2017-10-24 | 福州大学 | It is a kind of that the self-assembled nanometer grain of cancer therapy drug is loaded and its in the application of anti-tumor aspect based on low generation PAMAM dendrimers |
| CN107281164B (en) * | 2017-07-10 | 2020-05-08 | 福州大学 | Self-assembled nanoparticles based on low-generation PAMAM (polyamidoamine) dendrimer loaded anticancer drug and application of self-assembled nanoparticles in antitumor aspect |
| CN107510849B (en) * | 2017-08-16 | 2020-02-07 | 暨南大学 | Glutathione response type dual drug carrier and preparation method and application thereof |
| CN107510849A (en) * | 2017-08-16 | 2017-12-26 | 暨南大学 | A kind of glutathione response type dual drug carrier and its preparation method and application |
| CN107794008A (en) * | 2017-10-25 | 2018-03-13 | 西南石油大学 | One kind synthesis hydridization polyamines drilling fluid inhibitor and preparation method thereof |
| CN109456490A (en) * | 2018-10-23 | 2019-03-12 | 青岛大学 | A kind of preparation method and product of dendritic macromole hydrogel |
| CN110652518A (en) * | 2019-05-05 | 2020-01-07 | 海南亚洲制药股份有限公司 | Targeting type nano drug-loading system and preparation method thereof |
| CN112472805A (en) * | 2019-07-26 | 2021-03-12 | 浙江大学 | Boron-containing preparation with cell nucleus targeting property and preparation method and application thereof |
| CN112472805B (en) * | 2019-07-26 | 2021-11-09 | 浙江大学 | Boron-containing preparation with cell nucleus targeting property and preparation method and application thereof |
| CN114606190A (en) * | 2022-03-08 | 2022-06-10 | 东南大学 | Nano reagent for killing and foaming cells, cell micro-vesicle and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102429870A (en) | Novel tumor-targeting arboraceous polymer nano carrier of camptothecin drug | |
| US8466127B2 (en) | Pegylated and fatty acid grafted chitosan oligosaccharide, synthesis method and application for drug delivery system | |
| CN110522910B (en) | Nano drug delivery system based on metal organic framework and preparation method and application thereof | |
| CN104434806B (en) | Lipid-mixed poly (lactic-co-glycolic acid) (PLGA) nanoparticle having high drug loading amount and active targeting effect | |
| CN103611165B (en) | Hyaluronic acid-cyclodextrin-diamantane (obsolete) polyethylene glycol carrier and its preparation method and application | |
| CN104530256B (en) | Hyaluronic acid-vitamin E succinate polymer as well as preparation and application thereof | |
| US9980919B2 (en) | Preparation of pH-responsive nanoparticles and promoted delivery of anticancer drugs into deep tumor tissues and application thereof | |
| CN111632153B (en) | Chemical gene drug co-loaded targeting nano drug delivery system and preparation method thereof | |
| CN104983716A (en) | Tumor cell membrane/nuclear membrane double-targeting tumor nano-drug slow-release system and preparation and application thereof | |
| CN100428960C (en) | Method for preparing nano liver-target biodegradating medicine carrier material | |
| CN113663079B (en) | Carrier-free self-assembly nano particle and preparation method and application thereof | |
| WO2022052413A1 (en) | Drug-loaded polymer vesicle having asymmetric membrane structure, preparation method therefor, and application thereof in preparation of drugs for treating acute myeloid leukemia | |
| CN109846857B (en) | Preparation method and application of active natural supramolecular photosensitizer | |
| CN109464676B (en) | Preparation method and product of chitosan oligosaccharide photosensitive targeting nanoparticles | |
| US20220280516A1 (en) | Pegylated heparin nanomicelle loaded with carboxylic acid anti-tumor drug and preparation method thereof | |
| CN111743861B (en) | Targeted triple-negative breast cancer hypoxia response chiral drug micelle and preparation method thereof | |
| CN105037739B (en) | Reduction sensitive polymer with arginine membrane penetration effect and preparation method and application | |
| CN114652699B (en) | Size-transition type nano drug delivery carrier and preparation method and application thereof | |
| CN100434120C (en) | Amphipathic fluorescence target nano micelle and its preparation method | |
| CN110575544A (en) | preparation method of adriamycin nanoparticles with folic acid modified chitosan as carrier | |
| CN102178652B (en) | Taxol-loaded nano lipid carrier and preparation method thereof | |
| CN112546236B (en) | PH-sensitive double-drug-skeleton polymer prodrug, and preparation method and application thereof | |
| WO2022088679A1 (en) | Method for removing tumor stem cells, anti-cancer drug, drug delivery system, and use thereof | |
| CN104001184A (en) | Macromolecule doxorubicin bonding medicine and preparing method thereof | |
| CN111643679B (en) | Preparation method and application of chitosan oligosaccharide modified betulinic acid drug delivery system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120502 |
|
| WD01 | Invention patent application deemed withdrawn after publication |