CN109432047A - A kind of reverse pulmonary fibrosis nanometer formulation and preparation method thereof - Google Patents
A kind of reverse pulmonary fibrosis nanometer formulation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of reverse pulmonary fibrosis nanometer formulations and preparation method thereof, a kind of nanometer formulation and its carrier of synthesis E5 and polypeptide Z modification, nanometer formulation targets Circulating fibrocyte CXCR4, CCR2, CCR7 receptor by E5, and then pinpoint and reach pulmonary fibrosis damage location, it avoids being removed by internal macrophage and protein encapsulation；It is capable of the alveolar epithelial cells II of selectively targeted high expression integrin receptor α v β 6 by polypeptide Z, realizes efficient targeted delivery nanometer formulation.It include antioxidant and/or fibroblast activation inhibitor in nanometer formulation, respectively from regulation II oxidative stress of alveolar epithelial cells and the activation binary channel regulation of inhibition fibroblast to achieve the purpose that reverse pulmonary fibrosis.
Description
Technical field
The double medicines of load and/or single medicine mediated the present invention relates to a kind of Circulating fibrocyte reverses pulmonary fibrosis nanometer system
Agent, the in particular to preparation of the double medicines of load and/or single medicine nanometer formulation of a kind of pulmonary fibrosis body-internal-circulation fibrocyte targeting
And its application.
Background technique
Pulmonary fibrosis is a kind of progressive, and the high interstitial lung lesion disease of lethality, life cycle is 3-5.In recent years,
Since environmental pollution causes particle in air (PM 2.5) excessively high, lead to alveolar epithelial cells I (AT1), II (AT2) damage.Its
In, AT1 cell structure intracellular is simple, is mainly responsible for the sucking of alveolar oxygen and the exhalation of carbon dioxide；AT2 cell is referred to as lung
The stem cell-like cell of tissue, there is self-renewal capacity.After AT2 is damaged, the proliferative capacity of alveolar will receive serious broken
It is bad, after there is the irreversible destruction of alveolar function, a large amount of inflammatory factors are secreted, activation fibroblast turns to myofibroblast
To change, the myofibroblast of activation is the main source of damage location collagen secretion, it is found in the pathology of pulmonary fibrosis,
There are the adjustings of positive feedback to myofibroblast for the collagen of generation, to cause a large amount of heaps of the collagen at epithelial cell damage position
Product, space between cells forms pulmonary fibrosis by collagen extrusion packing.Currently, having approved the oral of two kinds of pulmonary fibrosis resistants through FDA
Drug, respectively pirfenidone and Nintedanib.But be only capable of reaching and delay disease process, injured pulmonary tissues realization cannot be repaired
Reverse the purpose of pulmonary fibrosis.
AT2 alveolar epithelial cells II plays a crucial role in the development of pulmonary fibrosis.Develop in pulmonary fibrosis
In process, the AT2 being damaged can recruit a large amount of inflammatory cell migration to lung, including macrophage, neutrophil leucocyte, acidophilus
Property cell and basicyte, these cells can secrete a large amount of inflammatory factor under the stimulation of pulmonary fibrosis microenvironment, including
TNF-beta, IL-4, IL-13, IL-1 β etc., inflammatory reaction is further exacerbated by, and the recycled fibre for recruiting a large amount of derived from bone marrow is thin
Born of the same parents and lung fibroblast are converted to myofibroblast, and the myofibroblast of activation is secreted a large amount of collagens and accumulated, in turn
The process of accelerating fibers.Thus, in the treatment of pulmonary fibrosis, the AT2 of repairing damage is can to reverse pulmonary fibrosis disease
The critical therapeutic target spot of disease.
Nanometer formulation obtains more and more extensive concern in disease treatment, but nanometer formulation in pulmonary disease delivering still
Have the shortcomings that targeting is poor, delivery efficiency is low.
Summary of the invention
Purpose: in order to overcome defect present in existing pulmonary fibrosis treatment, the present invention provides a kind of efficient targeted delivery
Reverse pulmonary fibrosis nanometer formulation.
Technical solution: in order to solve the above technical problems, the technical solution adopted by the present invention are as follows:
It is a kind of for loading the nano-preparations carrier of anti-fibrosis drug, it is characterised in that: the nano-preparations carrier be X-
PEG-MAL modifies the targeting peptides with Circulating fibrocyte receptor Y targeting, antibody, chemotactic factor (CF) E5, and/or, modification has
The polypeptide Z that alveolar epithelial cells II targets；Wherein X is hydrophobic section, and X is selected from PLGA, PLA, PGA, PCL；Y is Circulating fibrocyte
High expressed receptor, including CXCR4, CCR2, CCR7；Polypeptide Z includes cRGD, RGDf (c), RGD.
Further, the nano-preparations carrier, it is characterised in that: including being only modified with the carrier PPE of E5, only modifying
There is the carrier PPR of polypeptide Z while being modified with the carrier PPER of E5 and polypeptide Z.
Further, the nano-preparations carrier, it is characterised in that: E5 include the targeting peptides of CXCR4 receptor, antibody,
Chemotactic factor (CF), targeting peptides, antibody or the chemotactic factor (CF) of CCR7 receptor and targeting peptides, antibody or the chemotactic factor (CF) of CCR2 receptor；More
Preferably, using mercapto-modified E5.Polypeptide Z includes cRGD, RGDf (c), RGD.
In the present invention, the anti-fibrosis drug is one or more of antioxidant, inhibitor, and antioxidant is
Alleviate the drug or bioactive molecule of cellular level oxidative stress, inhibitor is drug or the life for inhibiting fibroblast activation
Object bioactive molecule.The anti-fibrosis drug of load can include antioxidant, inhibitor simultaneously, or selected from antioxidant, suppression
One of preparation.The anti-fibrosis drug of load all has certain hydrophobicity, passes through dredging in amphiphilic diblock copolymer
Water section X is realized to be loaded to certain anti-fibrosis drug, is realized the long circulating of polymer micelle in vivo by PEG, is led to
The selectively targeted intracorporal Circulating fibrocyte of E5 of modification is crossed, realizes lung's high-efficiency delivery.It being capable of specific target by polypeptide Z
To the AT2 being damaged, anti-fibrosis drug is realized to being damaged the efficient targeted delivery of AT2.
It is furthermore preferred that the antioxidant is astaxanthin, inhibitor is Trimetinib.The reverse pulmonary fibrosis nanometer system
Agent loads simultaneously Trimetinib and astaxanthin.It is pulmonary fibrosis resistant simultaneously using double medicine coordinated regulation pulmonary fibrosis microenvironments
The high-efficiency delivery of drug and the drug design of reverse pulmonary fibrosis provide a kind of new approach and strategy.
The present invention also provides a kind of reverse pulmonary fibrosis nanometer formulations, it is characterised in that: is above-mentioned nano-preparations carrier
Load has anti-fibrosis drug, including PPER/ drug, PPE/ drug, PPR/ drug.Wherein, anti-fibrosis drug is loaded
It can simultaneously include antioxidant, inhibitor, or be selected from one of antioxidant, inhibitor.Antioxidant is to alleviate cell
Horizontal oxide stress drug or bioactive molecule, inhibitor be inhibit CTGF expression drug or bioactive molecule.
1) antioxidant:
Anti-oxidation medicine: rheum officinale, Radix Notoginseng, ginkgo, dried orange peel, lotus leaf, mulberry leaf, the fleece-flower root, Radix Salviae Miltiorrhizae, Radix Astragali, garlic, Rhizoma Chuanxiong, red scape
It, the Chinese medical extracts such as pilose antler, probucol, indapamide, Verapamil.
Oxidation-resistant active ingredient: vitamin E, carotenoid and its derivative (astaxanthin, canthaxanthin, lutein, β-Hu
Radish element), tuna flavine, angle Huang matter, general ginsenoside, flavonoid glycosides and ginkgolides class, polysaccharides, cyclohexyl biphenyl octene
The plant polyoses such as lignans such as schisanhenol, deoxyschizandrin, schisandrin C, gynostemma pentaphylla, algal polysaccharides, mushroom polysaccharide,
Butylated hydroxy anisole (BHA), dibutyl hydroxy toluene (BHT), propylgallate (PG), tert-butylhydroquinone
(TBHQ)；
2) fibroblast activation inhibitor: Trimetinib, Nintedanib, pirfenidone, nilotinib, silibinin, turmeric
Element, resveratrol, Tanshinone ⅡA, berberine, schizandrin, salviandic acid A, B, luteolin, nutgall catechin, ligustrazine etc..
The anti-fibrosis drug include alleviate cellular level oxidative stress drug or bioactive molecule, inhibit at
The drug or bioactive molecule of fibrocyte activation inhibitor.
Specifically, the preparation method of PPER/ drug:
Step (1) first mixes anti-fibrosis drug with X-PEG-MAL, passes through film dispersion method, direct titrimetric method or anti-
The nanoparticle of load anti-fibrosis drug is prepared to solvent method；
Step (2) reacts the nanoparticle for loading anti-fibrosis drug with mercapto-modified E5 and mercapto-modified polypeptide Z, leads to
The MAL reaction for crossing sulfydryl and the exposure of nanoparticle shell, in outer end the covalent modification E5 and polypeptide Z of nanoparticle；Nanoparticle passes through altogether
The E5 and polypeptide Z of valence modification realize the target that Circulating fibrocyte and alveolar epithelial cells II target.
In reaction, the polymer nanoparticle of addition, mercapto-modified E5 mass ratio are 30:1 ~ 12:1；More preferably 15:1.
In reaction, the polymer nanoparticle of addition, mercapto-modified polypeptide Z mass ratio are 50:1 ~ 35:1；More preferably
40:1。
PPE/ drug the preparation method is as follows:
Step (1) first mixes anti-fibrosis drug with X-PEG-MAL, passes through film dispersion method, direct titrimetric method or anti-
The nanoparticle of load anti-fibrosis drug is prepared to solvent method；
Step (2) reacts the nanoparticle for loading anti-fibrosis drug with mercapto-modified E5, by sulfydryl and nanoparticle outside
The MAL reaction of shell exposure, in the outer end covalent modification E5 of nanoparticle；Nanoparticle realizes recycled fibre by the E5 of covalent modification
The target of cell-targeting.
In reaction, the polymer nanoparticle of addition, mercapto-modified E5 mass ratio are 30:1 ~ 12:1；More preferably 15:1.
PPR/ drug the preparation method is as follows:
Step (1) first mixes anti-fibrosis drug with X-PEG-MAL, passes through film dispersion method, direct titrimetric method or anti-
The nanoparticle of load anti-fibrosis drug is prepared to solvent method；
Step (2) reacts the nanoparticle for loading anti-fibrosis drug with mercapto-modified polypeptide Z, passes through sulfydryl and nanoparticle
The MAL reaction of shell exposure, in the outer end covalent modification polypeptide Z of nanoparticle；Nanoparticle passes through the polypeptide Z of covalent modification, realizes
The target that alveolar epithelial cells II targets.
In reaction, the polymer nanoparticle of addition, mercapto-modified polypeptide Z mass ratio are 50:1 ~ 35:1；More preferably
40:1。
As control, PP/ drug the preparation method is as follows:
Anti-fibrosis drug is dissolved in DMSO, proportion 100:1 ~ 5:1 of X-PEG-MAL and drug first by step (1), more preferably
Scheme 10:1, encapsulation rate 82.4%, drugloading rate 7.2%；
Step (2) is mixed with X-PEG-MAL, loads anti-lung by the preparation of film dispersion method, direct titrimetric method or reversed solvent method
The nanoparticle of fibrosis medicine.
Preferably, the reverse pulmonary fibrosis nanometer formulation, it is characterised in that: in X-PEG-MAL, wherein X
Molecular weight ranges be 1000-50000, the molecular weight ranges of PEG are 200-10000.It the use of molecular weight is more preferably 2000
PEG.
Preferably, the drugloading rate for reversing pulmonary fibrosis nanometer formulation is between 2%-20%, and particle size is in 20 nm-
Between 500 nm.
The present invention claims above-mentioned nano-preparations carrier, pulmonary fibrosis nanometer formulation is reversed to treat pulmonary fibrosis disease in preparation
Application in drug.
The present invention reaches inverse using body-internal-circulation fibrocyte as delivery vector high-efficiency delivery nano double medicine/mono- medicine for one kind
Turn the purpose of pulmonary fibrosis.Feature is that the carrier includes chemicals load composition, and Circulating fibrocyte targets composition and is damaged
Hurt AT2 targeting composition.The chemicals load composition is the amphiphilic polymer that end has maleimide amine-modified, circulation
Fibrocyte targets the polypeptide that composition is sulfhydrylation, and the composition for being damaged AT2 targeting is the PEG for having modified polypeptide Z.
The preparation PP/ drug for being also prepared for no E5 and polypeptide Z modification of the invention, the carrier material of only E5 modification
The carrier material PPR/ drug of PPE/ drug, only polypeptide Z modification, preparation method and the above method phase of these carrier materials
Together.
The utility model has the advantages that the nanometer system provided by the invention for containing double medicine/mono- medicines using Circulating fibrocyte as delivery vector
Agent, compared with prior art, have the advantage that in carrier X-PEG-MAL (X is hydrophobic section, X PLGA, PLA, PGA,
PCL it) can be very good to realize containing for fat-soluble drug, the PEG in carrier can extend the circulation time of carrier in blood,
The E5 of modification in carrier can be very good to realize the selectively targeted of body-internal-circulation fibrocyte, and the polypeptide Z in carrier can
The realization of specificity is damaged the selectively targeted of AT2.The efficient lung delivering of Nano medication can be achieved in the application of this carrier, passes through
Selectively targeted impaired injure repairs AT2, inhibits key protein CTGF, fibroblast activation can be effectively suppressed, to reach
Reverse the purpose of pulmonary fibrosis.The nanometer formulation of E5 of the invention and polypeptide Z modification, it is fine using the selectively targeted body-internal-circulation of E5
Cell is tieed up, selectively targeted can be damaged AT2 using polypeptide Z, realizes the double medicines of efficient pulmonary fibrosis resistant/mono- medicine delivering, from
And reaches and reverse pulmonary fibrosis purpose.The present invention fibrocyte of creative utilization body-internal-circulation for the first time is realized anti-as delivery vector
The efficient lung of pulmonary fibrosis medicine delivers, to be damaged AT2 as therapy target and selectively targeted double medicines/mono- medicine Nano medication
Preparation provides a kind of new approach for pulmonary fibrosis medicine preparation high-efficiency delivery and reversal therapies.In the present invention, innovate for the first time
During pulmonary fibrosis, the Circulating fibrocyte targeting being largely proliferated in vivo is same with E5 and polypeptide Z as delivery system
When load the nano-drug preparation of double medicine/mono- medicines to realize the purpose of reverse pulmonary fibrosis.Currently, total using amphiphilic block
It is common one of method, PLGA(polylactic acid-poly- hydroxyl second that hydrophobic block load hydrophobic drug in polymers, which carries out delivering,
Acid), PLA(polylactic acid), PGA(polyglycolide), PCL(polycaprolactone) be common hydrophobic embedding with good biocompatibility
Section is often used as hydrophobic cores in amphiphilic diblock copolymer, has preferable affinity to most of hydrophobic drug.
In the present invention, we are modified using E5 and polypeptide Z X-PEG (X is hydrophobic section, X PLGA, PLA, PGA,
PCL) nanoparticle is loaded by the hydrophobic section realization in amphiphilic diblock copolymer to certain hydrophobic double medicines/mono- medicine,
Or the nanoparticle of load hydrophilic medicament can be prepared by reversed solvent method, in vivo by PEG realization polymer micelle
Long circulating realizes lung's high-efficiency delivery by the selectively targeted intracorporal Circulating fibrocyte of the E5 of modification.Pass through polypeptide Z energy
Enough selectively targeted AT2 being damaged realize the double medicine/mono- medicines of anti-fibrosis to being damaged the efficient targeted delivery of AT2.
Detailed description of the invention
Fig. 1 is the flow diagram of nanometer formulation preparation of the present invention；
Fig. 2 is each composition optimum charging ratio of nanometer formulation prepared in the present invention；
Fig. 3 is the nanometer formulation particle diameter distribution of optimal formulation of the present invention (PPER/ drug)；
Fig. 4 is the nanometer formulation transmission electron microscope picture of optimal formulation of the present invention (PPER/ drug)；
Fig. 5 is the nanometer formulation transmission electron microscope picture (R=cRGD) of invention formulation (PPER/ drug)；
Fig. 6 is the nanometer formulation transmission electron microscope picture (R=RGD) of invention formulation (PPER/ drug)；
Fig. 7 is that nanometer formulation prepared by the present invention is tested in the intake of cellular level, it was demonstrated that RGDf (c) can be selectively targeted
AT2 increases the intake of nanometer formulation；
Fig. 8, which is that nano-carrier prepared by the present invention is horizontal in vivo, investigates different carriers PPER, PPE, PPR, PP, utilizes and follows
Lung delivery capability and selectively targeted accurate the determining that is damaged AT2 realization nanometer formulation of the circulary fibres cell as delivery system
Position；
Fig. 9 be nano-carrier prepared by the present invention in vivo it is horizontal investigate different time points its using Circulating fibrocyte as
In delivery system, nanometer formulation changes in the accumulation of intrapulmonary；
Figure 10 is that the nanometer formulation of prepared cladding fluorescent dye (DiR) of the present invention is received in the pulmonary fibrosis mice of modeling 3 weeks
The quantitative analysis of the small animal living body imaging picture that metric system agent is accumulated in lung and different organs.
Figure 11, which is that nano-carrier prepared by the present invention is horizontal in vivo, investigates different nanometer formulations in reverse pulmonary fibrosis
Effect analysis.
Specific embodiment
The present invention will be further explained in the following with reference to the drawings and specific embodiments.
The synthesis and preparation of 1 nanometer formulation composition of embodiment, as shown in Figure 1:
One, the preparation of the PLGA-PEG-MAL nanoparticle of double medicine/mono- medicines is contained
Using film dispersion method, direct titrimetric method and reversed solvent method can prepare load anti-fibrosis drug or fluorescent dye
The polymer nanoparticle of (as the model of alternatives to medication, being tracked for preparation).It is currently preferred to use direct titration legal system
The standby PLGA-PEG-MAL nanoparticle for containing the double medicine/mono- medicines (Trimetinib and/or astaxanthin) of anti-fibrosis medicine.Specific preparation
Method is as follows:
It weighs 100 mg PLGA-PEG-MAL and the bis- medicines of 10 mg/mono- medicine is dissolved in respectively in 2 mL DMSO solutions, ultrasonic dissolution.
Under agitation, DMSO solution is added dropwise in 100 mL pure water, after continuing stirring stirring 2h at room temperature, 2500 rpm/min
It is centrifuged the free medicine that 20 min remove unentrapped.It is 500 μ that nanoparticle to volume, which is concentrated, using the super filter tube of molecular weight 10000
L。
Two, the polymer nanoparticle preparation modified with E5 and RGDf (c)
E5 includes the targeting peptides, antibody, chemotactic factor (CF) of CXCR4 receptor, targeting peptides, antibody or the chemotactic factor (CF) of CCR7 receptor and
Targeting peptides, antibody or the chemotactic factor (CF) of CCR2 receptor；It is furthermore preferred that using mercapto-modified E5.Polypeptide Z includes cRGD, RGDf
(c)、RGD。
Anti-fibrosis drug includes:
Anti-oxidation medicine and active constituent:
Anti-oxidation medicine: rheum officinale, Radix Notoginseng, ginkgo, dried orange peel, lotus leaf, mulberry leaf, the fleece-flower root, Radix Salviae Miltiorrhizae, Radix Astragali, garlic, Rhizoma Chuanxiong, red scape
It, the Chinese medical extracts such as pilose antler, probucol, indapamide, Verapamil.
Oxidation-resistant active ingredient: vitamin E, carotenoid and its derivative (astaxanthin, canthaxanthin, lutein, β-Hu
Radish element), tuna flavine, angle Huang matter, general ginsenoside, flavonoid glycosides and ginkgolides class, polysaccharides, cyclohexyl biphenyl octene
The plant polyoses such as lignans such as schisanhenol, deoxyschizandrin, schisandrin C, gynostemma pentaphylla, algal polysaccharides, mushroom polysaccharide,
Butylated hydroxy anisole (BHA), dibutyl hydroxy toluene (BHT), propylgallate (PG), tert-butylhydroquinone
(TBHQ)；
Fibroblast activation inhibitor: Trimetinib, Nintedanib, pirfenidone, nilotinib, silibinin, curcumin,
Resveratrol, Tanshinone ⅡA, berberine, schizandrin, salviandic acid A, B, luteolin, nutgall catechin, ligustrazine etc..
1. the polymer nanoparticle preparation modified with Circulating fibrocyte receptor CXCR 4 targeting peptides and polypeptide Z
The modification of E5: by 6.5 mg of polypeptide of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation, in pure water solution
It is reacted in 4 DEG C of shaking tables overnight, wherein E5 is the target polypeptide of Circulating fibrocyte receptor CXCR 4；
The modification of polypeptide Z: by 2.5 mg of polypeptide RGDf (c) of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation,
It is reacted overnight in 4 DEG C of shaking tables in pure water solution；It is resuspended using 10000 rpm/min centrifugation and collects prepared nanoparticle three times,
Remove the E5 and Z of unreacted sulfhydrylation.
Utilize PP/(Trimetinib and/or astaxanthin prepared by this law), PPE/(Trimetinib and/or astaxanthin),
PPR/(Trimetinib and/or astaxanthin) and PPER/(Trimetinib and/or astaxanthin) drugloading rate between 2%-10%, grain
Diameter size is between 50 nm-500 nm.Optimal formulation (PPER/(Trimetinib and/or astaxanthin) of the present invention) nanometer formulation
Particle diameter distribution, transmission electron microscope picture is as shown in Figure 3, Figure 4, and the nanometer formulation particle diameter distribution is uniform, and form is uniform, and electron microscope shows core
Shell structure is obvious.
2. the polymer nanoparticle preparation modified with Circulating fibrocyte receptor CCR7 targeting antibodies and polypeptide Z
The modification of E5: by 6.5 mg of antibody of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation, in pure water solution
It is reacted in 4 DEG C of shaking tables overnight, wherein E5 is the targeting antibodies of Circulating fibrocyte receptor CCR7；
The modification of polypeptide Z: by 2.5 mg of polypeptide RGDf (c) of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation,
It is reacted overnight in 4 DEG C of shaking tables in pure water solution；It is resuspended using 10000 rpm/min centrifugation and collects prepared nanoparticle three times,
Remove the E5 and Z of unreacted sulfhydrylation.
Utilize PP/(Trimetinib and/or astaxanthin prepared by this law), PPE/(Trimetinib and/or astaxanthin),
PPR/(Trimetinib and/or astaxanthin) and PPER/(Trimetinib and/or astaxanthin) drugloading rate between 2%-10%, grain
Diameter size is between 50 nm-500 nm.Optimal formulation (PPER/(Trimetinib and/or astaxanthin) of the present invention) nanometer formulation
Particle diameter distribution is uniform, and form is uniform.
3. the polymer nanoparticle preparation with Circulating fibrocyte receptor CCR2 targeting chemotactic factor (CF) and polypeptide Z modification
The modification of E5: molten in pure water by chemotactic factor (CF) 6.5 mg of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation
It is reacted in 4 DEG C of shaking tables in liquid overnight, wherein E5 is the targeting antibodies of Circulating fibrocyte receptor CCR7；
The modification of polypeptide Z: molten in pure water by polypeptide Z 2.5 mg of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation
It is reacted overnight in 4 DEG C of shaking tables in liquid；It is resuspended using 10000 rpm/min centrifugation and collects prepared nanoparticle three times, removed not
The E5 and Z of the sulfhydrylation of reaction.
Utilize PP/(Trimetinib and/or astaxanthin prepared by this law), PPE/(Trimetinib and/or astaxanthin),
PPR/(Trimetinib and/or astaxanthin) and PPER/(Trimetinib and/or astaxanthin) drugloading rate between 2%-10%, grain
Diameter size is between 50 nm-500 nm.Optimal formulation (PPER/(Trimetinib and/or astaxanthin) of the present invention) nanometer formulation
Particle diameter distribution is uniform, and form is uniform.
Three, the polymer nanoparticle preparation modified with E5 and cRGD or RGD
The modification of E5: by 6.5 mg of E5 of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation, 4 in pure water solution
Reaction is overnight in DEG C shaking table；
The modification of polypeptide cRGD or RGD: by the polypeptide cRGD or RGD of the PLGA-PEG-MAL nanoparticle of carrying medicament and sulfhydrylation
2.5 mg react overnight in 4 DEG C of shaking tables in pure water solution；It is resuspended three times, prepared by collection using 10000 rpm/min centrifugation
Nanoparticle, remove the E5 and cRGD or RGD of unreacted sulfhydrylation.
Utilize PP/(Trimetinib and/or astaxanthin prepared by this law), PPE/(Trimetinib and/or astaxanthin),
PPR/(Trimetinib and/or astaxanthin) and PPER/(Trimetinib and/or astaxanthin) drugloading rate between 2%-10%, grain
Diameter size is between 50 nm-500 nm.Optimal formulation (PPER/(Trimetinib and/or astaxanthin) of the present invention) nanometer formulation
Particle diameter distribution, transmission electron microscope picture is as shown in Figure 5, Figure 6, and the nanometer formulation particle diameter distribution is uniform, and form is uniform, and electron microscope shows core
Shell structure is obvious.
2 nanometer formulation of embodiment is in the intake analysis of A549 cellular level and flow cytometric analysis
According to preparation PP/ coumarin 6, PPE/ coumarin 6, PPR/ coumarin 6 and PPER/ coumarin 6 nanometer described in embodiment 1
Preparation.By A549 cell respectively with 5 × 105/ mL is inoculated in 24 orifice plates, in 37 DEG C, 5% C02It is adherent in cell incubator
After growing 24 h, culture medium is sucked, after the diluted TGF-β of serum-free (5ng/mL) stimulation for 24 hours is added, is separately added into serum-free training
Support the diluted free coumarin 6 of base, PP/ coumarin 6, PPR/ coumarin 6, PPC/ coumarin 6 and PPCR/ coumarin 6, each hole
Coumarin 6 concentration is 1 μ g/mL, 500 μ L, and three secondary orifices are arranged in every group.Continue to cultivate 4h, three times using PBS cleaning,
(1) laser co-focusing LSM-700 shoots cell to the intake situation of nanoparticle and free coumarin 6；
(2) pancreatin digests, 1500 rpm centrifugation cells, and cell is resuspended with the culture medium without serum, utilizes fluidic cell
Instrument carries out quantitative detection to the coumarin 6 of intake.
Cellular uptake data measured by the present embodiment are as shown in fig. 7, the A549 cell of assessment of levels belongs to gland cancer in vivo
Alveolar substrate epithelial cell is damaged alveolar epithelial cells AT2 to the intake situation of nanoparticle in analog body.In TGF-β
(5ng/mL) for 24 hours after, alveolar epithelial cells is damaged, cell membrane surface height express integrin receptor α v β 6, polypeptide cRGD,
RGDf (c), RGD and α v β 6 can be specifically bound.Focusing results are shown altogether, and the intake of PPR/ coumarin 6 is apparently higher than PP/ perfume
The intake of legumin 6 and coumarin 6, it was demonstrated that cRGD, RGDf (c), being combined with for RGD are conducive to increase A549 cell to nanometer formulation
Specificity intake；In the A549 cell not stimulated by TGF-β, cell membrane surface integrin receptor α v β 6 high will not be expressed, and be tied
Fruit shows its intake to nanoparticle and free coumarin 6 and no significant difference.
The nanometer formulation that embodiment 4 coats fluorescent dye (DiR) is analyzed in lung's specific delivery of pulmonary fibrosis mice
According to preparation PP/DiR, PPE/DiR, PPR/DiR and PPER/DiR nanometer formulation described in embodiment 1.
The modeling test of pulmonary fibrosis model is carried out using the male C57BL/6 mouse of 6-8 week old first, when modeling is applied
Endotracheal intubation is to the direct modeling of mouse lung.It is dense using Bleocin Hydrochloride as mouse pulmonary fibrosis inducer when modeling
Degree is 2USP/Kg, then continues nanoparticle tracer experiment to mouse pulmonary fibrosis molding after three weeks.For judging mouse lung
Fibrosis model at the mould time, lot of documents reports that three weeks beginning mouse pulmonary fibrosis are in very fast period of expansion, body-internal-circulation
Fibrocyte proliferation is the most obvious.Three weeks mouse of modeling are randomly assigned to be 4 groups, every group 4, pass through tail vein injection respectively
Free DiR, PP/DiR, PPE/DiR, PPR/DiR and PPER/DiR, are 1 μ g/g mouse weight as mark using the DiR injected
It is quasi-.1h, 4h, 8h, 12h after tail vein injection, using small animal living body imager living imaging is carried out to mouse for 24 hours.
The nanometer formulation of prepared cladding fluorescent dye (DiR) forms lung after Bleocin Hydrochloride modeling in the present embodiment
The small animal living body imaging picture of fibrosis mouse lung accumulation and its quantitative analysis are as shown in Figure 8；Nanometer formulation is in lungs
Accumulation degree is as follows: PPER/DiR > PPE/DiR > PPR/DiR > PP/DiR, demonstrates E5 and polypeptide Z(cRGD, RGDf
(c), RGD) be modified with to be targeted conducive to nanometer formulation and be delivered to lung and realize high accumulation.
Embodiment 5 coats the nanometer formulation of fluorescent dye (DiI) in pulmonary fibrosis mice, nanoparticle and body-internal-circulation
Attaching situation, lung's depot accumulation time and the delivery mechanism of fibrocyte.
According to preparation PP/DiI, PPE/DiI, PPR/DiI and PPER/DiI nanometer formulation described in embodiment 1.
The modeling test of pulmonary fibrosis model is carried out using the male C57BL/6 mouse of 6-8 week old first, when modeling is applied
Endotracheal intubation is to the direct modeling of mouse lung.It is dense using Bleocin Hydrochloride as mouse pulmonary fibrosis inducer when modeling
Degree is 2USP/Kg, then continues the experiment of nanoparticle delivery mechanism to mouse pulmonary fibrosis molding after three weeks.It is small for judging
Mouse pulmonary fibrosis model at the mould time, lot of documents reports that three weeks beginning mouse pulmonary fibrosis are in very fast period of expansion, in vivo
Circulating fibrocyte proliferation is the most obvious.Three weeks mouse of modeling are randomly assigned to be 4 groups, every group 3, pass through tail vein respectively
Free DiI, PP/DiI, PPE/DiI, PPR/DiI and PPER/DiI are injected, is that 1 μ g/g mouse weight is with the DiI injected
Standard.30min, 1h, 2h, 4h after tail vein injection take mouse lung tissue to carry out the experiment of lung tissue immunostaining.As a result such as
Fig. 9, Figure 10.Wherein DAPI is nucleus blue markings, and α-SMA is Circulating fibrocyte memebrane protein Green Marker, and DiI is nanometer
The included red-label of grain.The results show that nanoparticle carries feux rouges label and the Circulating fibrocyte attaching situation of Green Marker is bright
It is aobvious, and red fluorescence increases with the increase of administration time in lung tissue accumulation therewith.Prove that nanoparticle can pass through circulation
The nanoparticle delivery system that fibrocyte mediates realizes the purpose of targeted delivery by high-efficiency delivery to lung tissue.
6 nanometer formulation PPATER of embodiment reverses the effect analysis of pulmonary fibrosis treating.
Nanometer formulation PP/A, PP/T, PP/AT, PPR/AT, PPE/AT, PPE/ are prepared according to preparation method described in embodiment 1
A, PPE/T and PPER/AT, PPER/A, PPER/T.A represents antioxidant such as astaxanthin, and T represents fibroblast activation and inhibits
Agent such as Trimetinib.
The modeling test of pulmonary fibrosis model is carried out using the male C57BL/6 mouse of 6-8 week old first, when modeling is applied
Endotracheal intubation is to the direct modeling of mouse lung.It is dense using Bleocin Hydrochloride as mouse pulmonary fibrosis inducer when modeling
Degree is 2USP/Kg, then continues nanometer formulation to mouse pulmonary fibrosis molding after three weeks and was treating reverse pulmonary fibrosis
Effect analysis.Three weeks mouse of modeling are randomly assigned to be 8 groups, every group 5, respectively by tail vein injection dissociate PP/A,
PP/T, PP/AT, PPR/AT, PPE/AT, PPE/A, PPE/T and PPER/AT, PPER/A, PPER/T and physiological saline, with institute
The TRA of injection is that 2 μ g/g mouse weights are standard.After treatment 4 weeks, reverse pulmonary fibrosis effect logical different nanometer formulations
It crosses H&E dyeing and carries out analysis result such as Figure 11, it is found that final preparation PPE/AT, PPE/A, PPE/T and PPER/AT,
Compared with BLM group, pulmonary fibrosis degree obviously weakens PPER/A, PPER/T group, wherein PPER/AT group, PPE/AT group effect
Especially good is better than PPR/AT group, PP/AT group, PPE/T group and PP/A group.Importantly, final preparation group PPER/AT and
Single target head PPE/AT group and normal group lung sections are more consistent, it can be seen that clearly alveolar structure shows to recycle by mediating
Efficient lung's targeting and double medicine combination therapies, which may be implemented, in the nanometer formulation delivery system of fibrocyte effectively to reverse
Pulmonary fibrosis.
PLGA(polyglycolic-polylactic acid), PLA(polylactic acid), PGA(polyglycolide), PCL(polycaprolactone) be common
The hydrophobic block with good biocompatibility, hydrophobic cores are often used as in amphiphilic diblock copolymer, to most of
There is preferable affinity with certain hydrophobic drug, or load hydrophilic medicament can be prepared by reversed solvent method
Nanoparticle.In the above-described embodiments, PLA-PEG-MAL, PGA-PEG-MAL, the replacement of PCL-PEG-MAL block copolymer are utilized
PLGA-PEG-MAL block copolymer, can equally load has certain hydrophobic drug, or can be with by reversed solvent method
The nanoparticle of preparation load hydrophilic medicament, forms the purpose of polymer micelle, is clear to those skilled in the art
's.
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of for loading the nano-preparations carrier of anti-fibrosis drug, it is characterised in that: the nano-preparations carrier is
X-PEG-MAL modifies the targeting peptides with Circulating fibrocyte receptor Y targeting, antibody, chemotactic factor (CF) E5, or, modifying tool simultaneously
The polypeptide Z that alveolation epithelial cell II targets；Wherein X is hydrophobic section, and X is selected from PLGA, PLA, PGA, PCL；Y is that recycled fibre is thin
The high expressed receptor of born of the same parents, including CXCR4, CCR2, CCR7；Polypeptide Z includes cRGD, RGDf (c), RGD.
2. nano-preparations carrier according to claim 1, it is characterised in that: the carrier PPE, simultaneously including being only modified with E5
It is modified with the carrier PPER of E5 and polypeptide Z.
3. nano-preparations carrier according to claim 1, it is characterised in that: E5 includes the targeting peptides of CXCR4 receptor, resists
Body, chemotactic factor (CF), targeting peptides, antibody or the chemotactic factor (CF) of CCR7 receptor and targeting peptides, antibody or the chemotactic factor (CF) of CCR2 receptor.
4. nano-preparations carrier according to claim 1, it is characterised in that: the anti-fibrosis drug is anti-oxidant
One or more of agent, inhibitor, antioxidant are the drug or bioactive molecule for alleviating cellular level oxidative stress, suppression
Preparation is the drug or bioactive molecule for inhibiting fibroblast activation.
5. a kind of reverse pulmonary fibrosis nanometer formulation, it is characterised in that: carried for the described in any item nanometer formulations of claim 1-4
Body load has anti-fibrosis drug, including PPER/ drug, PPE/ drug.
6. reverse pulmonary fibrosis nanometer formulation according to claim 5, it is characterised in that: the preparation method of PPER/ drug:
Step (1) first mixes anti-fibrosis drug with X-PEG-MAL, passes through film dispersion method, direct titrimetric method or anti-
The nanoparticle of load anti-fibrosis drug is prepared to solvent method；
Step (2) reacts the nanoparticle for loading anti-fibrosis drug with mercapto-modified E5 and mercapto-modified polypeptide Z, leads to
The MAL reaction for crossing sulfydryl and the exposure of nanoparticle shell, in outer end the covalent modification E5 and polypeptide Z of nanoparticle；Nanoparticle passes through altogether
The E5 and polypeptide Z of valence modification realize the target that Circulating fibrocyte and alveolar epithelial cells II target.
7. reverse pulmonary fibrosis nanometer formulation according to claim 5, it is characterised in that: the preparation method of PPE/ drug is such as
Under:
Step (1) first mixes anti-fibrosis drug with X-PEG-MAL, passes through film dispersion method, direct titrimetric method or anti-
The nanoparticle of load anti-fibrosis drug is prepared to solvent method；
Step (2) reacts the nanoparticle for loading anti-fibrosis drug with mercapto-modified E5, by sulfydryl and nanoparticle outside
The MAL reaction of shell exposure, in the outer end covalent modification E5 of nanoparticle；Nanoparticle realizes recycled fibre by the E5 of covalent modification
The target of cell-targeting.
8. reverse pulmonary fibrosis nanometer formulation according to claim 6 or 7, it is characterised in that: in X-PEG-MAL, wherein X
Molecular weight ranges be 1000-50000, the molecular weight ranges of PEG are 200-10000.
9. reverse pulmonary fibrosis nanometer formulation according to claim 5, it is characterised in that: the reverse pulmonary fibrosis nanometer
The drugloading rate of preparation is between 2-20%, and particle size is between 20 nm-500 nm.
10. reverse pulmonary fibrosis nanometer system described in the described in any item nano-preparations carriers of claim 1-4, claim 5
Application of the agent in preparation treatment pulmonary fibrosis disease drug.
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| CN115429898A (en) * | 2022-09-29 | 2022-12-06 | 中国药科大学 | Stem cell preparation for treating pulmonary fibrosis and preparation method thereof |
| CN115429898B (en) * | 2022-09-29 | 2024-05-28 | 中国药科大学 | Stem cell preparation for treating pulmonary fibrosis and preparation method thereof |
| CN115414492B (en) * | 2022-09-29 | 2024-05-28 | 中国药科大学 | Nanometer preparation for treating pancreatic fibrosis and preparation method thereof |
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