CN106474486A - A kind of polymer micelle and its application - Google Patents
A kind of polymer micelle and its application Download PDFInfo
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- CN106474486A CN106474486A CN201610901264.3A CN201610901264A CN106474486A CN 106474486 A CN106474486 A CN 106474486A CN 201610901264 A CN201610901264 A CN 201610901264A CN 106474486 A CN106474486 A CN 106474486A
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Abstract
The invention discloses a kind of polymer micelle and its application, it is related to pharmaceutical technology field, described polymer micelle is nucleocapsid structure, is self-assembly of in water by amphipathic block copolymer;The present invention with hyaluronic acid as main chain, by hydrophobic polymer R is connected on main chain1With hydrophilic polypeptide R2Prepare and there is the polymer micelle carrying medicine function, medicine can be promoted to enter dermal layer of the skin, and under the acidic pH environment of skin, there is good stability and biocompatibility, the local target administration of skin can be carried out in conjunction with genomic medicine.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly, to a kind of polymer micelle and its application.
Background technology
Transdermal drug delivery system (transdermal therapeutic system, TTS) refers to be administered in skin surface, medicine
Thing penetrates horny layer, epidermal area, skin corium successively with constant speed, eventually enters into body circulation, produces whole body or local treatment is made
Emerging preparation.Transdermal administration has following 4 advantages:
(1) transdermal drug delivery system can avoid the first pass effect of liver and medicine to inactivate in gastrointestinal, and the absorption of medicine is not
Affected by gastrointestinal factors. reduce the individual variation of medication.
(2) constant effective blood drug concentration or physiological effect are maintained, it is to avoid the blood drug level peak valley phenomenon that oral administration causes,
Reduce toxicity.
(3) reduce administration number of times, improve therapeutic efficacy, extend action time, it is to avoid multiple dose administration, make most patient
It is easy to accept.
(4) easy to use, patient can independently medication it is also possible at any time cancel medication.
Skin is the natural cover for defense of human body, medicine can be hindered to enter internal;Most drug, even dosage low, treat
Imitate some high medicines, percutaneous rate is also difficult to meet treatment needs, and this becomes the biggest obstacle of research and development TTS.How to protect
The drugs through skin of card q.s enters and reaches therapeutic dose in vivo, is the emphasis of TTS research, new and high technology and method should
With being the important channel of solve problem.
It is presently used for promoting the technology of Cutaneous permeation can be divided into chemical method and Physical.
Chemical method includes the chemical reagent such as laurocapram, organic acid and its ester type compound, ketopyrrolidine analog derivative,
Its mechanism of action is dissolving skin lipid or makes skin protein degeneration, increases the randomness of lipoids skeleton, thus promoting medicine
In horny layer diffusion, increase medicine dissolubility in skin, so that Drug Percutaneous Absorption is increased.
Physical method includes iontophoresiss and promotees saturating method, the ultrasound wave saturating method of rush, electroporation saturating method of rush etc., mainly logical
Cross the physical means such as electromagnetic field, ultrasound wave, laser to promote the Transdermal absorption of medicine, physics promotees saturating technology and is most appropriate to albumen
The Transdermal absorption of matter, peptides and some macromolecular drugs.
But, above two method has their limitation, and chemical method destroys the surface texture of skin due to meeting, so
The irritative response of some skins can be led to;And Physical relies primarily on the effect in the external world, generally require some special equipment,
So limiting the application of this kind of method.
In recent years, nano-medicament carrier increases sharply in the research in percutaneous dosing field.Some nano-drug preparations enter
Enter clinical investigation phase, certain formulations product such as heparin liposome, diclofenac liposome, povidone iodine liposome, estradiol
Nano-emulsion, indomethacin nano-emulsion etc. list application.Nano-medicament carrier can effectively facilitate the Transdermal absorption of small-molecule drug,
And also present good prospect in terms of macromolecular drug percutaneous dosing research.
As a kind of structure of Nano grade, the modifiability on its surface, biocompatibility becomes micellar material
A kind of pharmaceutical carrier receiving much attention, is widely used in medicine delivery, the aspect such as antitumor and targeted therapy, but is at present
Only, the design of micelle is substantially based on tumor microenvironment, and micelle is used in transdermal aspect and have not been reported.
Content of the invention
For above-mentioned deficiency, the invention provides a kind of polymer micelle and its application, this polymer micelle can carry
Medicine, promotes medicine to enter dermal layer of the skin, and the acidic pH environment in skin has good stability and biocompatibility,
The local target administration of skin can be carried out with bound drug.
In order to achieve the above object, the technical solution adopted in the present invention is as follows:A kind of polymer micelle, is core-shell structure copolymer knot
Structure, is self-assembly of in water by amphipathic block copolymer, shown in the general structure such as formula (I) of described block copolymer,
Wherein, R1For Poly(D,L-lactide-co-glycolide, polylactic acid, polystyrene, poly- amino ester, polyoxy acrylic acid
Alkyl ester or their derivant;R2For transdermal peptide, its aminoacid sequence is ACTGSTQHQCG, RRRRRRR, ACSSSPSKHCG,
ACKTGSHNQCG or HIITDPNMAEYL;M, n, z are the integer more than 2.
In above-mentioned polymer micelle, R1Part is hydrophobic section;Hyaluronic acid and R2Part is hydrophilic section;M refers to polymer latex
It is connected with R in bundle1Hyaluronic acid construction unit unit number;N refers to the hyaluronic acid structure being connected with polymer micelle
The unit number of unit;Z refers to be not connected with R1And R2Hyaluronic acid construction unit unit number.
R1The height of percent grafting and R1Molecular size range the targeting of medicine is all had an impact, preferably, described R1
Percent grafting in the monomer of place is 1~20%.
Preferably, in polymer micelle, described R1Total molecular weight be 1000~50000.
R2The height of percent grafting has an impact to the transdermal effect of whole polymer micelle, preferably, described R2Single being located
Percent grafting in body is 1~20%.
Preferably, described R1For poly- amino ester, R2Aminoacid sequence be ACTGSTQHQCG, m:N=1:1, the program
Not only target-oriented drug is good, and transdermal effect is also optimal, can preferably play the effect of medicine.
Present invention also offers described polymer micelle is as the application in dermal drug carrier.
Present invention also offers a kind of polymer micelle complex of carrying medicaments, including medicine and carrier, described carrier
For described polymer micelle.
Specifically, described medicine is DNA, siRNA, miRNA or hydrophobic class chemicalses.
Compared with prior art, the invention has the advantages that:
(1) present invention is with hyaluronic acid as main chain, by connecting hydrophobic polymer R on main chain1With hydrophilic polypeptide R2
Prepare and there is the polymer micelle carrying medicine function, medicine can be promoted to enter dermal layer of the skin, and the acid pH in skin
Under environment, there is good stability and biocompatibility, the local target administration of skin can be carried out in conjunction with genomic medicine.
(2) Inventive polymers micelle can efficient carrying gene medicine, and act on skin, realize the local target of skin
To administration.
Brief description
Fig. 1 is hyaluronic acid in polymer micelle/FITC-DNA complex1(solvent is D to H-NMR collection of illustrative plates2O);
Fig. 2 is transdermal peptide (ACTGSTQHQCG) in polymer micelle/FITC-DNA complex1H-NMR collection of illustrative plates (solvent
For D2O);
Fig. 3 is polymer R in polymer micelle/FITC-DNA complex1's1(solvent is CDCL to H-NMR collection of illustrative plates3);
Fig. 4 is hyaluronic acid-polypeptide in polymer micelle/FITC-DNA complex1(solvent is D to H-NMR collection of illustrative plates2O);
Fig. 5 is polymer micelle/FITC-DNA complex1(solvent is D to H-NMR collection of illustrative plates2O);
Fig. 6 is the TEM electron microscope of polymer micelle/FITC-DNA complex;
Fig. 7 is the DLS particle diameter measurements schematic diagram of polymer micelle/FITC-DNA complex;
Fig. 8 is the TEM electron microscope after polymer micelle/FITC-DNA complex carrying gene;
Fig. 9 is that the born of the same parents that enter after polymer micelle/FITC-DNA complex carrying gene FITC-DNA scheme;In figure A be micelle/
FITC-DNA group;B is naked FITC-DNA group;
Figure 10 is the transdermal under laser co-focusing after polymer micelle/FITC-DNA complex carrying gene FITC-DNA
Design sketch;In figure A is micelle/FITC-DNA;B is naked FITC-DNA group;
Specific embodiment
In the embodiment of the present invention, hyaluronic acid derives from Shandong Fu Ruida Pharmaceutical Group, and the polypeptide after synthesis is purified, its
Purity is 95%, takes 5mg hyaluronic acid or polypeptide sample, is dissolved in D2O, using nuclear magnetic resonance analyser (Brooker,Switzerland company)
It is analyzed, both 13H NMR spectra are as shown in Figure 1 and Figure 2.
Embodiment 1
Polymer micelle and the preparation of polymer micelle/FITC-DNA complex:
1st, high molecular polymer R1The synthesis of (poly- amino ester)
Take 3.73g triamido propanol and 10g diacrylate-Isosorbide-5-Nitrae-fourth diester, be placed at 90 DEG C and stir and be heated to reflux, enter
Row homopolymerization 3 hours;After completion of the reaction, product is dissolved in 20ml chloroform, add 10 times of volumes through pre-cooling
Diethyl ether solution, make product precipitate;Repeat to filter the product three times of precipitation, the product vacuum after filtering is dried 24 hours, obtains
To the higher polymer poly amino ester of purity, nuclear magnetic resonance result is as shown in Figure 3.
2nd, the synthesis of hyaluronic acid-polypeptide
Take 100mg hyaluronic acid (MW=17000), be placed in stirring and dissolving in 20ml ultra-pure water, be added thereto to 15mg
NHS and 20mg EDC, activation hyaluronic acid, after 1 hour, adds 1mg transdermal peptide (ACTGSTQHQCG), continues stirring 0.5 hour
Carry out completely to reaction within~5 hours;Reacted reactant liquor loading molecular weight is in 3500 bag filter, dialyses 24 hours,
Remove the impurity on unreacted and polypeptide, add freeze drying protectant and carry out lyophilizing 24 hours, obtain the hyaluronic acid-many of drying
Peptide solid, nuclear magnetic resonance result is as shown in Figure 4.
3rd, the synthetic method of polymer micelle
50mg hyaluronic acid-polypeptide is dissolved in 20ml water, after stirring and dissolving, adds 5mg NHS and 10mg EDC, stirring
1h makes remaining part activated carboxylic on hyaluronic acid.
Take 0.1g polymer R1, it is dissolved in 10ml chloroform, add 100 μ l propane diamine, after stirring 12h, pour pre-cooling into
In the diethyl ether solution crossed, take out precipitation and be placed in the vacuum drying oven under room temperature, obtain through amido modified polymer
R1.
By 0.1g through the polymer R modifying1It is dissolved in the water of pH=3, be subsequently added the hyaluronic acid-polypeptide after activation
Solution, continues stirring 6 hours, and end-product is dialysed 24 hours, removes impurity and unreacted raw material;Add frozen-dried protective
Agent, and lyophilizing 24 hours, obtain the final product polymer micelle of drying, and nuclear magnetic resonance result is as shown in Figure 5.
4th, the method for polymer micelle loaded gene
Take 10mg polymer micelle, be dissolved in 1ml water, adjust pH to 3, so that polymer micelle is dissolved completely in water.
Take 2 μ g FITC-DNA, be added thereto to the polymer micelle solution of 10 μ l, be subsequently diluted to 30 μ l, at 37 DEG C, be incubated 15 points
Clock is obtained polymer micelle/FITC-DNA complex.
Embodiment 2
Polymer micelle and the preparation of polymer micelle/FITC-DNA complex:
1st, high molecular polymer R1The synthesis of (poly- amino ester)
Take 3.73g triamido propanol and 10g diacrylate-Isosorbide-5-Nitrae-fourth diester, be placed at 90 DEG C and stir and be heated to reflux, enter
Row homopolymerization 3 hours;After completion of the reaction, product is dissolved in 20ml chloroform, add 10 times of volumes through pre-cooling
Diethyl ether solution, make product precipitate;Repeat to filter the product three times of precipitation, the product vacuum after filtering is dried 24 hours, obtains
To the higher polymer poly amino ester of purity, nuclear magnetic resonance result is as shown in Figure 3.
2nd, the synthesis of hyaluronic acid-polypeptide
Take 100mg hyaluronic acid (MW=17000), be placed in stirring and dissolving in 20ml ultra-pure water, be added thereto to 15mg
NHS and 20mg EDC, activation hyaluronic acid, after 1 hour, adds 50mg transdermal peptide (ACTGSTQHQCG), continues stirring 0.5 hour
Carry out completely to reaction within~5 hours;Reacted reactant liquor loading molecular weight is in 3500 bag filter, dialyses 24 hours,
Remove the impurity on unreacted and polypeptide, add freeze drying protectant and carry out lyophilizing 24 hours, obtain the hyaluronic acid-many of drying
Peptide solid, nuclear magnetic resonance result is as shown in Figure 4.
3rd, the synthetic method of polymer micelle
50mg hyaluronic acid-polypeptide is dissolved in 20ml water, after stirring and dissolving, adds 5mg NHS and 10mg EDC, stirring
1h makes remaining part activated carboxylic on hyaluronic acid.
Take 1g polymer R1, it is dissolved in 10ml chloroform, add 100 μ l propane diamine, after stirring 12h, pour into precooled
Diethyl ether solution in, take out in the vacuum drying oven that precipitation is placed under room temperature, obtain through amido modified polymer R1.
By 1g through the polymer R modifying1It is dissolved in the water of pH=3, be subsequently added the hyaluronic acid-polypeptide after activation molten
Liquid, continues stirring 6 hours, and end-product is dialysed 24 hours, removes impurity and unreacted raw material;Add freeze drying protectant,
And lyophilizing 24 hours, obtain the final product polymer micelle of drying, nuclear magnetic resonance result is as shown in Figure 5.
4th, the method for polymer micelle loaded gene
Take 10mg polymer micelle, be dissolved in 1ml water, adjust pH to 3, so that polymer micelle is dissolved completely in water.
Take 2 μ g FITC-DNA, be added thereto to the polymer micelle solution of 10 μ l, be subsequently diluted to 30 μ l, at 37 DEG C, be incubated 15 points
Clock is obtained polymer micelle/FITC-DNA complex.
Embodiment 3
Take 100mg hyaluronic acid (MW=17000), be placed in stirring and dissolving in 20ml ultra-pure water, be added thereto to 15mg
NHS and 20mg EDC, activation hyaluronic acid, after 1 hour, adds 10mg transdermal peptide (ACTGSTQHQCG), continues stirring 4 hours extremely
Reaction is carried out completely;Reacted reactant liquor loading molecular weight is in 3500 bag filter, dialyses 24 hours, remove unreacted
On impurity and polypeptide, add freeze drying protectant and carry out lyophilizing 24 hours, obtain drying hyaluronic acid-polypeptide solid.
50mg hyaluronic acid-polypeptide is dissolved in 20ml water, after stirring and dissolving, adds 5mg NHS and 10mg EDC, stirring
1h makes remaining part activated carboxylic on hyaluronic acid.
Take 0.5g polymer R1, it is dissolved in 10ml chloroform, add 100 μ l propane diamine, after stirring 12h, pour pre-cooling into
In the diethyl ether solution crossed, take out precipitation and be placed in the vacuum drying oven under room temperature, obtain through amido modified polymer
R1.
By 0.5g through the polymer R modifying1It is dissolved in the water of pH=3, be subsequently added the hyaluronic acid-polypeptide after activation
Solution, continues stirring 6 hours, and end-product is dialysed 24 hours, removes impurity and unreacted raw material;Add frozen-dried protective
Agent, and lyophilizing 24 hours, obtain the final product polymer micelle of drying, and this product is the glue of gained under optimum experiment condition
Bundle.
The checking of polymer micelle/FITC-DNA complex:
(1) to unloaded polymer micelle with carry the polymer micelle after DNA/FITC-DNA complex and carry out Appearance View
Examine
Polymer micelle/FITC-DNA complex after taking the polymer micelle of zero load and carrying DNA, is added in special respectively
Under transmission electron microscope, on copper mesh, directly observe size and the form of particle, result is as shown in Figure 6 and Figure 8.
(2) picked-up experiment in melanoma cell for the polymer micelle/FITC-DNA complex
By B16F10 cell (1 × 105/ hole) it is inoculated in 12 orifice plates, incubated overnight, it is separately added into polymer micelle/FITC-
DNA complex and blank FITC-DNA solution, after culture 3h in incubator, wash cell three times using PBS (PH=7.4), eventually
Only cell, to the picked-up adding complex or solution, collects cell, and cell is placed in the sun detecting cell in flow cytometer
Property rate, result is as shown in Figure 9.
Result shows, can significantly improve complex after micelle carries FITC-DNA enters born of the same parents' efficiency, after only 3 hours
Just can by micelle/FITC-DNA complex enter proximal to 80% intracellular, and individually naked FITC-DNA almost cannot enter
Enter cell.
(3) polymer micelle/FITC-DNA complex
Take big Corium Mus, absorbent cotton carefully removes subcutaneous tissue and the fat of skin, uses normal saline clearing skin, by skin
It is fixed between supply chamber and the receiving chamber of Franz Transdermal diffusion cell, upward, receiving chamber fills PBS solution (PH=to horny layer
7.4), supply chamber adds the mixed solution containing polymer micelle and FITC-DNA that 1ml prepares, and with sealed membrane sealing, keeps away
Exempt from supply chamber liquid evaporation.Diffusion cell be placed on continuously stirred in 32 DEG C of waters bath with thermostatic control, rotating speed be 300rmp, stopped after 24 hours
Only test, remove diffusion cell, gently that skin wiping is clean with cotton swab, it is placed on microscope slide, be placed in copolymerization at once burnt aobvious
Micro- Microscopic observation polymer micelle/distribution in skin for the FITC-DNA complex.
With vertical skin horny layer as z-axis, with keratodermatitis as sweep starting point, carry out successively sweeping of skin along z-axis
Retouch, at interval of 10 μm of run-downs.With 488 for FITC excitation wavelength, with blank FITC-DNA solution as matched group, observe skin
Fluorescence in skin, result is as shown in Figure 10.
Claims (8)
1. a kind of polymer micelle, is nucleocapsid structure, is self-assembly of in water by amphipathic block copolymer, its feature
It is, shown in the general structure such as formula (I) of described block copolymer,
Wherein, R1For Poly(D,L-lactide-co-glycolide, polylactic acid, polystyrene, poly- amino ester, polyoxy alkyl acrylate or
Their derivant;R2For transdermal peptide, its aminoacid sequence is ACTGSTQHQCG, RRRRRRR, ACSSSPSKHCG,
ACKTGSHNQCG or HIITDPNMAEYL.M, n, z are the integer more than 2.
2. polymer micelle as claimed in claim 1 is it is characterised in that described R1Percent grafting in the monomer of place be 1~
20%.
3. polymer micelle as claimed in claim 1 is it is characterised in that in polymer micelle, described R1Total molecular weight be
1000~50000.
4. polymer micelle as claimed in claim 1 is it is characterised in that described R2Percent grafting in the monomer of place be 1~
20%.
5. polymer micelle as claimed in claim 1 is it is characterised in that described R1For poly- amino ester, R2Aminoacid sequence be
ACTGSTQHQCG, m:N=1:1.
6. described polymer micelle as arbitrary in Claims 1 to 5 is as the application in dermal drug carrier.
7. the polymer micelle complex of a kind of carrying medicaments, including medicine and carrier it is characterised in that described carrier is right
Require 1~5 arbitrary described polymer micelle.
8. carrying medicaments as claimed in claim 7 polymer micelle complex it is characterised in that described medicine be DNA, siRNA,
MiRNA or hydrophobic class chemicalses.
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