CN106822037A - A kind of preparation method of the nano-particle of the tripeptides modification for targetting colitis tissue - Google Patents
A kind of preparation method of the nano-particle of the tripeptides modification for targetting colitis tissue Download PDFInfo
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- CN106822037A CN106822037A CN201611257241.XA CN201611257241A CN106822037A CN 106822037 A CN106822037 A CN 106822037A CN 201611257241 A CN201611257241 A CN 201611257241A CN 106822037 A CN106822037 A CN 106822037A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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- A61K9/513—Organic macromolecular compounds; Dendrimers
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
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Abstract
The invention discloses a kind of preparation method of the nano-particle of the tripeptides modification for targetting colitis tissue.The targeted molecular of use is a kind of small molecule tripeptides synthesized by lysine, proline and valine（Lys‑Pro‑Val,KPV）, its action principle is that the expression in healthy colon of peptide transporter 1 is extremely low, and the height overexpression in ulcerative colitis tissue, and KPV can specifically bind with peptide transporter 1.Therefore, the present invention, can be specific by treatment of ulcerative colitis related keyword cell after carrying out KPV surface modifications to nano-particle（Colon epithelial cell and macrophage）Efficiently phagocytosis, so as to mediate nano-particle in the enrichment of colitis tissue site.
Description
Technical field
The invention belongs to nano-medicament carrier technical field, and in particular to a kind of tripeptides modification of targeting colitis tissue
The preparation method and application of nano-particle.
Background technology
Ulcerative colitis is a kind of chronic gut inflammation disease, and traditional treatment method therapeutic effect is poor, and can draw
Play stronger toxic and side effect.It is generally, medicine preparation into targeting drug administration preparation, drug targeting to be delivered by the way of now
To diseased region, strengthen the specificity to particular organization, so as to reduce whole body toxic and side effect and heighten the effect of a treatment.
Research shows, peptide transporter（Peptide transporter 1, PepT1）With ulcerative colitis
Excessive height expression in the immunocyte of tissue, this provides a potential target site for its targeted therapy.Small molecule three
Peptide（Lys-Pro-Val, KPV）Can efficiently be combined with PepT1 and be transported to by it is intracellular, therefore, we can use KPV conducts
Ligand molecular carries out surface modification to nano-particle, so that mediate the targeting of nano-particle to swallow, and in diseased region enrichment.
The content of the invention
It is an object of the invention to provide a kind of preparation method of the nano-particle of the tripeptides modification for targetting colitis tissue
And application.
The preparation method of the nano-particle of the tripeptides modification of this targeting colitis tissue, comprises the following steps：
1）By Poly(D,L-lactide-co-glycolide（Polylactic-co-glycolic acid, PLGA）And coumarin 6
（Coumarin-6, CM-6）It is dissolved in jointly in 2 mL methylene chloride-methanol mixed solvents, is made oil phase；
2）By step 1）Oil phase be added dropwise in the mixing aqueous phase solution of polyvinyl alcohol and shitosan；
3）It is subsequently ultrasonicated for 6 times, 10 s are forming oil-in-water emulsion every time；
4）By step 3）The emulsion for obtaining is poured into rapidly in polyvinyl alcohol aqueous phase solution, forms emulsion；
5）By step 4）Emulsion in organic solvent volatilized under the conditions of low vacuum；
6）By step 5）Emulsion after volatilization is centrifuged, and collection obtains nano-particle, and is washed with deionized three times；
7）By step 6）Obtain nano-particle vortex and be dispersed in the disubstituted polyethyleneglycol derivative of different functional group：N- hydroxysuccinimidyl acyl
Imines-polyethylene glycol-maleic anhydride（N- Hydroxysuccinimide-polyethylene glycol-maleimide,
NHS-PEG-MAL）In buffer solution, 2 h are reacted；
8）Centrifugation step 7）The solution for obtaining, collection obtains nano-particle, and is washed with deionized twice；
9）By step 8）The nano-particle for obtaining is dispersed in the small molecule tripeptides synthesized by lysine, proline and valine
（Lys-Pro-Val, KPV）The aqueous solution in, react 2 h；
10）Centrifugation step 9）The solution for obtaining, collection obtains nano-particle, and is washed with deionized twice；
11）By step 10）The nano-particle for obtaining is dispersed in the aqueous solution of 1 mL containing 5% trehalose again；
12）By step 11）The solution for obtaining carries out frozen dried, obtains can be used for the tripeptides modification for targetting colitis tissue
Nano-particle, is stored in standby in -20 degrees Celsius of refrigerator.
Preferential, the step 1）In, the mass ratio of PLGA and CM-6 is 100 mg:4 mg ~ 100 mg:12 mg,
The ratio of dichloro methane-methanol is 5:5~8:2；The step 2）The totality of middle polyvinyl alcohol and shitosan mixed aqueous solution
Product is 2 ~ 6 mL, and both concentration ranges are respectively 2 ~ 5% and 0.2 ~ 0.5%, and chitosan molecule amount is 1 ~ 10 × 104；The step
Rapid 3）In, the parameter of ultrasound is ultrasonic amplitude 30 ~ 80%.
Preferential, the step 4）In, the cumulative volume of polyvinyl alcohol water solution is 20 ~ 200 mL, and concentration is 0 ~ 1%；Institute
State step 6）, step 8）With step 10）In, centrifugation rate is 8000 ~ 20000 revs/min, and centrifugation time is 8 ~ 40 min；Institute
State step 7）In, the content of NHS-PEG-MAL is 5 ~ 20 mg in solution；The step 9）In, in KPV solution KPV contents be 1 ~
8 mg；The step 11）In, trehalose concentration is 5 ~ 10% in aqueous trehalose solution；The step 12）In, the step of freeze-drying
Rapid is first, in -60 ~ -80 degrees Celsius of freeze overnights, to be then placed in and 12~36 h are freezed in freeze dryer.
Relative to existing technology, the advantage of the invention is that：
1）The present invention with will synthesize small molecule tripeptides KPV introduce drug targeting delivery system, KPV have excellent water solubility,
Biocompatibility, non-immunogenic, in vivo can by enzyme effect Natural Degradation.
2）KPV of the present invention carries sulfhydryl reactive group, is easy to chemical modification.
3）KPV of the present invention is to height overexpression on colitis tissue site colon epithelial cell and macrophage
PepT1 adhesivenesses are very high, and high specificity, phagocytic rate is high.
4）The present invention has synthesized the nano-particle for carrying CM-6, and has carried out surface modification with KPV, is to existing curative
One of thing breaks through and important innovations.
5）Present invention firstly provides, prepare and carry out KPV modification nanoparticle formulation, this will be helpful to us and more preferably takes off
Show that nano-particle is delivered to the mechanism and rule of diseased region, while to design the load with more excellent effect on a molecular scale
Medicine nano-particle provides theoretical foundation.
Brief description of the drawings
In order that the object, technical solutions and advantages of the present invention are clearer, below in conjunction with accompanying drawing the present invention is made into
The detailed description of one step, wherein：
Fig. 1：The transmission electron microscope figure of the load CM-6 nano-particles of KPV surface modifications（a）And particle diameter distribution（b）.
Fig. 2：Flow cytometer determines phagocytosis situation of the macrophage to KPV Property of Capped Inorganic Nanoparticles.
Fig. 3：Express PepT1 and do not express the phagocytosis feelings of the colon epithelial cell to KPV Property of Capped Inorganic Nanoparticles of PepT1
Condition.
Fig. 4：KPV surface modifications can promote the fluorogram that colitis tissue swallows to nano-particle.
Specific embodiment
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.
Embodiment
Embodiment is a kind of preparation method of the nano-particle of the tripeptides modification of the targeting colitis tissue for providing, i.e. KPV
Surface modification carries the preparation method of CM-6 nano-particles, comprises the following steps：
1) 100 mg PLGA and 8 mg CM-6 are weighed and is codissolved in 2 mL methylene chloride-methanols（8:2）In mixed solvent, oil is made
Phase；
2) oil phase is dropwise added into polyvinyl alcohol（5%）And shitosan（0.5%）Mixing aqueous phase solution（4 mL）In；
3) ultrasonically treated 6 times, 10 s every time, ultrasonic power is 40%, to form oil-in-water emulsion；
4) emulsion is poured into rapidly 40 mL polyvinyl alcohol（0.5%）In mixing aqueous phase solution；
5) organic solvent is volatilized under the conditions of low vacuum；
6) it is centrifuged（12000 revs/min, 15 min）Above-mentioned nano-particle is collected, and is washed with deionized three times；
7) nano-particle is vortexed and is dispersed in the aqueous solution containing 10 mg NHS-PEG-MAL, react 2 h；
8) it is centrifuged（12000 revs/min, 15 min）Nano-particle is collected, and is washed with deionized twice；
9) nano-particle is vortexed and is dispersed in the aqueous solution containing 2 mg KPV, react 2 h；
10) it is collected by centrifugation（12000 revs/min, 15 min）Nano-particle, and be washed with deionized twice；
11) above-mentioned nano-particle is dispersed in the aqueous solution of 1 mL containing 5% trehalose again；
12) above-mentioned nano-particle is freezed（- 60 degrees Celsius, 24 h）, it is stored in -20 degrees Celsius of refrigerators.
Comparative example
Comparative example is the polyester nano particle preparation method of polyethyleneglycol modified load coumarin 6, is comprised the following steps：
1) 100 mg PLGA and 8 mg CM-6 are weighed and is codissolved in 2 mL methylene chloride-methanols（8:2）In mixed solvent, oil is made
Phase；
2) oil phase is dropwise added into polyvinyl alcohol（5%）And shitosan（0.5%）Mixing aqueous phase solution（4 mL）In；
3) ultrasonically treated 6 times, 10 s every time, ultrasonic power is 40%, to form oil-in-water emulsion；
4) emulsion is poured into rapidly 40 mL polyvinyl alcohol（0.5%）In mixing aqueous phase solution；
5) organic solvent is volatilized under the conditions of low vacuum；
6) it is centrifuged（12000 revs/min, 15 min）Above-mentioned nano-particle is collected, and is washed with deionized three times；
7) nano-particle is vortexed and is dispersed in the aqueous solution containing 10 mg NHS-PEG-MAL, react 2 h；
8) it is centrifuged（12000 revs/min, 15 min）Nano-particle is collected, and is washed with deionized twice；
9) nano-particle is vortexed and is dispersed in the aqueous solution containing Cys2 mg, react 2 h；
10) it is collected by centrifugation（12000 revs/min, 15 min）Nano-particle, and be washed with deionized twice；
11) above-mentioned nano-particle is dispersed in the aqueous solution of 1 mL containing 5% trehalose again；
12) above-mentioned nano-particle is freezed（- 60 degrees Celsius, 24 h）, it is stored in -20 degrees Celsius of refrigerators.
Fig. 1 is the transmission electron microscope figure of KPV Property of Capped Inorganic Nanoparticles（a）And grain size distribution（b）.Fig. 1 a can be with
Find out, KPV Property of Capped Inorganic Nanoparticles is spherical, and particle diameter distribution is more uniform；As shown in Figure 1 b, nano-particle hydration particle diameter
Between 260 nm ~ 275 nm, particle diameter distribution is smaller, illustrates that the Particle dispersity of nano-particle is good.
Fig. 2 is phagocytosis of the flow cytometric analysis macrophage to KPV Property of Capped Inorganic Nanoparticles.Such as Fig. 3
Shown, for polyethyleneglycol modified nano-particle, KPV surface modifications can significantly improve nano-particle by macrophage
Phagocytosis efficiency；And in the presence of having free KPV, cell is decreased obviously to the phagocytic rate of KPV Property of Capped Inorganic Nanoparticles, show trip
From KPV competition cells surface PepT1 transport sites, so as to the binding capacity for causing nano-particle is reduced.This explanation, nano-particle quilt
During phagocytosis, KPV serves mediation really, so as to improve phagocytosis efficiency of the cell to nano-particle.
Fig. 3 is expression PepT1 and does not express phagocytosis figure of the PepT1 cells to nano-particle.As illustrated, we divide
Two kinds of colon epithelial cell systems, a kind of cell to express PepT1 have not been used（Caco2-BBE）, it is another not express PepT1's
Cell（HT-29）.As can be seen that after the cell line of expression PepT1 is modified with KPV, the phagocytosis efficiency to nano-particle is significantly carried
It is high；Cell line without expressing PepT1, after nano-particle is through KPV surface modifications, to the phagocytosis efficiency increase of nano-particle not
Substantially.It can thus be seen that KPV is strictly to be combined and mediated cell phagocytosis by with PepT1, so that KPV surface modifications are received
Rice corpuscles is enriched with colitis tissue site.
Fig. 4 can improve the fluorogram that colitis histocyte swallows to nano-particle for KPV surface modifications.We use copolymerization
Phagocytosis of the burnt fluorescence microscope tissue to nano-particle.Nano-particle of the control group without KPV surface modifications is compared to,
The nano-particle of KPV surface modifications has more enrichments in colitis tissue, shows that KPV modifications can effectively facilitate colitis tissue pair
Nano-particle swallows.
Claims (3)
1. it is a kind of target colitis tissue tripeptides modification nano-particle preparation method, it is characterised in that：Including following step
Suddenly：
1）By Poly(D,L-lactide-co-glycolide（Polylactic-co-glycolic acid, PLGA）And coumarin 6
（Coumarin-6, CM-6）It is dissolved in jointly in 2 mL methylene chloride-methanol mixed solvents, is made oil phase；
2）By step 1）Oil phase be added dropwise in the mixing aqueous phase solution of polyvinyl alcohol and shitosan；
3）It is subsequently ultrasonicated for 6 times, 10 s are forming oil-in-water emulsion every time；
4）By step 3）The emulsion for obtaining is poured into rapidly in polyvinyl alcohol aqueous phase solution, forms emulsion；
5）By step 4）Emulsion in organic solvent volatilized under the conditions of low vacuum；
6）By step 5）Emulsion after volatilization is centrifuged, and collection obtains nano-particle, and is washed with deionized three times；
7）By step 6）Obtain nano-particle vortex and be dispersed in the disubstituted polyethyleneglycol derivative of different functional group：N- hydroxysuccinimidyl acyl
Imines-polyethylene glycol-maleic anhydride（N- Hydroxysuccinimide-polyethylene glycol-maleimide,
NHS-PEG-MAL）In buffer solution, 2 h are reacted；
8）Centrifugation step 7）The solution for obtaining, collection obtains nano-particle, and is washed with deionized twice；
9）By step 8）The nano-particle for obtaining is dispersed in the small molecule tripeptides synthesized by lysine, proline and valine
（Lys-Pro-Val, KPV）The aqueous solution in, react 2 h；
10）Centrifugation step 9）The solution for obtaining, collection obtains nano-particle, and is washed with deionized twice；
11）By step 10）The nano-particle for obtaining is dispersed in the aqueous solution of 1 mL containing 5% trehalose again；
12）By step 11）The solution for obtaining carries out frozen dried, obtains can be used for the tripeptides modification for targetting colitis tissue
Nano-particle, is stored in standby in -20 degrees Celsius of refrigerator.
2. it is according to claim 1 it is a kind of target colitis tissue tripeptides modification nano-particle preparation method, its
It is characterised by：The step 1）In, the mass ratio of PLGA and CM-6 is 100 mg:4 mg ~ 100 mg:12 mg, dichloromethane
The ratio of alkane-methanol solution is 5:5~8:2；The step 2）The cumulative volume of middle polyvinyl alcohol and shitosan mixed aqueous solution be 2 ~
6 mL, both concentration ranges are respectively 2 ~ 5% and 0.2 ~ 0.5%, and chitosan molecule amount is 1 ~ 10 × 104；The step 3）In,
The parameter of ultrasound is ultrasonic amplitude 30 ~ 80%.
3. it is according to claim 1 it is a kind of target colitis tissue tripeptides modification nano-particle preparation method, its
It is characterised by：The step 4）In, the cumulative volume of polyvinyl alcohol water solution is 20 ~ 200 mL, and concentration is 0 ~ 1%；The step
6）, step 8）With step 10）In, centrifugation rate is 8000 ~ 20000 revs/min, and centrifugation time is 8 ~ 40 min；The step
7）In, the content of NHS-PEG-MAL is 5 ~ 20 mg in solution；The step 9）In, KPV contents are 1 ~ 8 mg in KPV solution；
The step 11）In, trehalose concentration is 5 ~ 10% in aqueous trehalose solution；The step 12）In, it is the step of freeze-drying
First in -60 ~ -80 degrees Celsius of freeze overnights, then it is placed in and 12~36 h is freezed in freeze dryer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107308461A (en) * | 2017-07-12 | 2017-11-03 | 西南大学 | A kind of nano-particle of colon tumor cell active targeting and preparation method thereof |
| CN107335064A (en) * | 2017-07-12 | 2017-11-10 | 西南大学 | A kind of nano-particle for macrophage targeted delivery of drugs and preparation method thereof |
-
2016
- 2016-12-30 CN CN201611257241.XA patent/CN106822037A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107308461A (en) * | 2017-07-12 | 2017-11-03 | 西南大学 | A kind of nano-particle of colon tumor cell active targeting and preparation method thereof |
| CN107335064A (en) * | 2017-07-12 | 2017-11-10 | 西南大学 | A kind of nano-particle for macrophage targeted delivery of drugs and preparation method thereof |
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