CN110038132A - Natural polymer-albumen composition and its preparation method and application - Google Patents
Natural polymer-albumen composition and its preparation method and application Download PDFInfo
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- CN110038132A CN110038132A CN201910337984.5A CN201910337984A CN110038132A CN 110038132 A CN110038132 A CN 110038132A CN 201910337984 A CN201910337984 A CN 201910337984A CN 110038132 A CN110038132 A CN 110038132A
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- natural polymer
- albumen
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- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61P35/00—Antineoplastic agents
Abstract
The present invention provides a kind of natural polymer-albumen compositions and its preparation method and application, compound provided by the invention is obtained with active function albumen by the chemistry key connection of acid response by being coupled small numerator modified natural polymer, active function albumen is set to form the nanostructure relationship surrounded by natural polymer, so that compound is with water-soluble and biocompatibility；In the weakly acidic microenvironment of tumour, active function albumen dissociates from compound and restores its bioactivity, realizes the function of adjusting the effect of tumor locus microenvironment or raising immunotherapy of tumors, can be applied in the combination therapy of tumour.
Description
Technical field
The present invention relates to drug field more particularly to a kind of natural polymer-albumen composition and preparation method thereof and answer
With.
Background technique
Cancer is to endanger one of principal disease of human health, with the development of science and technology, the oxygen content of tumor locus
Influence of the relatively low weary oxygen region to tumor proliferation gradually attracts attention.Since the exception of tumour cell increases
It grows, the demand of the energy matters such as oxygen is caused to increase extremely, so that blood supply in tissue then relative deficiency is accordingly resulted in,
Further cause the weary oxygen of tumor tissues.Improve the weary oxygen of tumor locus mainly include but is not limited to lower hypoxia-inducible factor (HIF),
Oxygen etc. is generated in situ to tumor locus conveying oxygen, in tumor locus.Improving the weary oxygen of tumor locus also can be by reducing tumour
The content of outer cellular matrix, so that diastole intratumoral vasculature is realized with increasing the blood supply of tumor locus.
Photodynamic therapy (photodynamic therapy, PDT) is a kind of emerging tumor therapeuticing method, because it is special
The strong advantage of property, compared with traditional treatment method, photodynamic therapy safety is higher, complication is less, to biological bulk damage
It is lower.The basic principle of optical dynamic therapy is to excite the photosensitive molecular being enriched in tumor locus by the light of specific wavelength, is generated
Have cytotoxic active oxygen, causes tumour impaired and death by damaging tumor cell gene structure, reach therapeutic purposes.
The study found that demand of the photodynamic therapy to oxygen is larger, thus the presence of the weary oxygen situation of tumor locus will be unfavorable for light power
Treatment.Albumen/enzyme that the weary oxygen situation of tumor locus can thus be improved to tumor locus conveying by nano particle, will greatly
Enhance the curative effect of optical dynamic therapy.
In recent years, the application of immunotherapy in cancer treatment gradually attracts wide attention.Tumour cell has certain
The ability for fleeing from immune system identification and remove, to existence and be proliferated in the microenvironment of load.By restarting simultaneously
Restore the normal anti-tumor capacity of immune system, and then inhibit tumour growth and further removing tumor tissues and tumour cell and
The new antitumoral therapy for reaching therapeutic purposes is referred to as tumour immunotherapy, can be pressed down by monoclonal antibodies immunologic test point
Preparation (immune checkpoint inhibitor), micromolecular inhibitor and therapeutic antibodies etc. are realized.Monoclonal antibody
The use of para-immunity checkpoint inhibitor is to study most commonly used a kind of immunotherapy at present.Wherein common monoclonal antibody
Death protein 1 (programmed death 1, PD-1), -1 (programmed of programmed death molecule ligand
Death ligand 1, PD-L1) and programmed death molecule ligand -2 (programmed death ligand 2, PD-L2),
The corresponding antibody such as cytotoxic T lymphocyte epitope (cytotoxic T-lymphocyte antigen 4, CTLA-4) belongs to
Protide antibody.But active function albumen can be inactivated by intracorporal proteolytic enzymes hydrolize or the active function egg of external source
The white immune response that can cause in body, causes active function albumen that can not effectively reach target position.
Summary of the invention
In view of this, technical problem to be solved by the present invention lies in provide a kind of natural polymer-albumen composition and
Preparation method and application effectively increase active function albumen in the enrichment effect of tumor locus, the activity of security function albumen
And utilization rate.
The present invention provides a kind of natural polymer-albumen composition, the compound passes through idol by active function albumen
Connection small molecule is connect with natural polymer, is formed in around the active function albumen compound receiving that there is natural polymer to surround
Rice structure；The natural polymer and the coupling small molecule pass through chemistry key connection；The active function albumen and the idol
Join small molecule by having the chemistry of acid response to be keyed.
The active function albumen and the natural polymer form nanostructure relationship, and natural polymer is protected as one layer
Sheath effectively prevents active function albumen in compound from causing to inactivate with directly contacting for the proteolytic enzyme in organism, or
It is immunological rejection of the organism to foreign protein；On the other hand, the natural polymer-albumen composition is in tumor locus
Under weakly acidic microenvironment, there is the chemical bond linkage group of acid response can hydrolyze, active function protein active function
Albumen is dissociated from compound, acts on tumor tissues, achievees the effect that enhancing treatment.
Optionally, the coupling small molecule has before connecting with the natural polymer and the active function albumen
At least one dibasic acid anhydride structure, and the coupling small molecule has at least one halo groups.
Optionally, carbon atom adjacent with carbonyl in the acid anhydride structure of the coupling small molecule is connected with carbon-carbon double bond.
Optionally, the coupling small molecule isWherein, R1, R2The alkyl for being 1~10 for carbon chain lengths
Chain；X is halogenated atom.Optionally, with the R of different carbon chain lengths1Coupling small molecule can be used in combination, the length of carbochain
The arrangement density of the natural polymer around the active function albumen can be improved in difference.
Optionally, the coupling small molecule is a bromo-derivative and its derivative for 3,4,5,6- tetrahydrophthalic anhydride.
Optionally, the coupling small molecule is a bromo-derivative of 2,3- dimethyl maleic anhydride3,4,5,
One bromo-derivative of 6- tetrahydrophthalic anhydrideOr combinations thereof object.
Optionally, the natural polymer surface has at least one hydroxyl group, the optional natural polymer attached bag
Include glucan, starch, cellulose, hyaluronic acid and combinations thereof.
Optionally, the active function albumen includes the matrix such as hyaluronidase, Collagenase, matrix metalloproteinase
Hydrolysising protease and combinations thereof.
Optionally, the active function albumen includes the hydroperoxides such as catalase, superoxide dismutase or surpasses
Oxide catalyst enzyme and combinations thereof.
Optionally, the active function albumen is antibody；
Optionally, the antibody include immunoglobulin G, recombinant antibodies, PD-1 antibody, PD-L1 antibody, PD-L2 antibody,
CTLA-4 antibody, and combinations thereof.
Optionally, the molar ratio of the natural polymer and the coupling small molecule is 1:(1~150).
Optionally, the molar ratio of the albumen and the natural polymer is 1:(2~50).
Optionally, the molecular weight of the natural polymer is the 000Da of 20 000Da~100.
Optionally, the partial size of the natural polymer-albumen composition is in 100nm~200nm.
The present invention also provides a kind of preparation methods of natural polymer-albumen composition, include the following steps:
S1: natural polymer is connect to the derivative to form natural polymer with coupling small molecule by substitution reaction；
S2: the derivative for the natural polymer that S1 step is obtained and the active function albumen are anti-by being acylated
It should obtain natural polymer-albumen composition.
Sequence precedence relationship in the preparation method in S1 and S2 step, can effective guarantee active function albumen biology
Activity.
Optionally, the reaction condition of substitution reaction described in the S1 step are as follows: under the conditions of 20-30 DEG C, sodium hydroxide
(NaOH) concentration is that 10-15 hour is reacted in dimethyl sulfoxide (DMSO) solution of 30-50mg/mL.
Optionally, the reaction condition of acylation reaction described in the S2 step are as follows: solvent is that pH value is 8.0~9.0
4- hydroxyethyl piperazineethanesulfonic acid (HEPES) buffer, and the mass ratio of active function albumen used and the buffer HEPES is
1:(5000~50 are 000).
The present invention also provides a kind of natural polymer-albumen compositions to be used to prepare in tumor therapeutic agent or preparation
Purposes.
Optionally, in the application in preparation tumor therapeutic agent or preparation, the active function albumen includes base simultaneously
At least two classes in matter hydrolysising protease, hydroperoxide or superoxides catalyzing enzyme and antibody.It is living described at least two classes
Natural polymer-albumen composition made of sexual function albumen has one compared to single class active function albumen in oncotherapy
Fixed combined effect.
The present invention also provides a kind of natural polymer-albumen compositions of the present invention to improve tumor locus in preparation
Application in the drug of weary oxygen situation and enhancing optical dynamic therapy.
Compared with prior art, a kind of natural polymer-albumen composition provided by the invention, it is of the present invention compound
Object by active function albumen by be coupled it is small numerator modified after natural polymer be keyed by the chemistry of acid response
It obtains, effectively prevents organism to the immunological rejection of foreign protein and the hydrolysis of protein hydrolysate, protect to a certain extent
Bioactivity of active function albumen during body circulation is protected；Good dispersibility is all had under water and physiological condition；
Obtained nano particle has higher enrichment in tumor locus, after the composite nanoparticles enter tumor locus, tumour
Interior hydrogen ion can enter the inside of the composite nanoparticles by the gap of the compound, promote the active function
The dissociation of albumen gradually discharges active function protein molecular, achievees the purpose that adjuvant therapy is treated, it is weary to be effectively improved tumor locus
Oxygen situation has certain application in the optical dynamic therapy of subsequent enhancing tumour；The experimental results showed that day provided by the invention
Right macromolecule-albumen composition, it is right by cooperating subsequent laser irradiation to carry out optical dynamic therapy to mouse tail vein injection
Tumor tissues, which increase, has apparent rejection ability, carries out frozen section dyeing to tumor tissues by immunofluorescence dyeing technology
Observation, the compound can be effectively improved the weary oxygen situation of tumor tissues；The present invention provides natural polymer-albumen composition can be with
As the nano material for improving the weary oxygen of tumor locus, the curative effect of subsequent optical dynamic therapy is further enhanced.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of glucan derivative described in embodiment 1；
Fig. 2 is the fourier transform infrared spectroscopy figure of glucan derivative described in embodiment 1；
Fig. 3 is the ultraviolet visible absorption spectra figure of DEX-HAase described in embodiment 1；
Fig. 4 is DEX-HAase dynamic laser grain size distribution described in embodiment 1；
Fig. 5 is the transmission electron microscope photo figure of DEX-HAase nano particle；
Fig. 6 is the change of size figure of DEX-HAase under different ph values；
Fig. 7 is relative activity histogram of the DEX-HAase of various concentration before and after dissociation in 0.5 hour；
Fig. 8 is the specific value that DEX-HAase is distributed in major organs；
Fig. 9 is the blood circulation data of DEX-HAase；
Figure 10 is to evaluate DEX-HAase by immunofluorescence staining to improve the weary oxygen performance of tumor locus；
Figure 11 is the variation diagram of gross tumor volume；
Figure 12 is glucan-recombinant antibodies DEX- (anti-PD-L1) dynamic laser grain size distribution described in embodiment 8；
Figure 13 is the blood circulation data of DEX- (anti-PD-L1)；
Figure 14 is the variation diagram of gross tumor volume.
Specific embodiment
The present invention provides a kind of natural polymer-albumen composition, the compound passes through idol by active function albumen
Connection small molecule is connect with natural polymer, is formed in around the active function albumen compound receiving that there is natural polymer to surround
Rice structure；The natural polymer and the coupling small molecule pass through chemistry key connection；The active function albumen and the idol
Join small molecule by having the chemistry of acid response to be keyed.
According to the present invention, in the natural polymer-albumen composition, the formula (I)The compound of structure
It is 1:(1~150 with the molar ratio of natural polymer), more preferably 1:(130~140)；The albumen and natural polymer
Molar ratio is 1:(2~50), more preferably 1:(2~20)；The molecular weight of the natural polymer is 20 000Da~100
000Da, more preferably 20 000Da；The type of the natural polymer includes glucan, starch, cellulose, hyaluronic acid；Institute
The type for stating active function albumen includes extracellular matrix degrading enzymes, such as hyaluronidase, Collagenase；With catalytic effect
Enzyme, such as catalase, superoxide dismutase；Albumen with therapeutic effect, such as immunoglobulin G, recombinant antibodies,
Such as hyaluronidase and antibody anti-PDL1.
It is clearly and completely described below in conjunction with the technical solution of the embodiment of the present invention.
Embodiment 1
Glucan-hyaluronic acid multienzyme complex (DEX-HAase) is prepared, specifically includes the following steps:
S1: natural polymer is connect to the derivative to form natural polymer: tool with coupling small molecule by substitution reaction
Body, the sodium hydroxide (NaOH) of glucan (DEX), 160mg that 142mg molecular weight is 20000Da is dissolved in the diformazan of 5mL
In sulfoxide (DMSO), the formula (I) of 20.5mg is added after reacting 12 hours under the conditions of 25 DEG C into systemChemical combination
Object, after reacting 12 hours under the conditions of 25 DEG C, the HEPES buffer solution for being 8.5 by reaction system pH value is saturating under the conditions of 25 DEG C
Analysis 4 hours, during which changed a dialyzate every 20 minutes.After the liquid freezing drying in bag filter, it is fluffy to obtain light brown
The glucan derivative (DEX-MMfu) of powder.
S2: the derivative for the natural polymer that S1 step is obtained and the active function albumen are anti-by being acylated
Should obtain natural polymer-albumen composition: specifically, then by resulting 1.2mg glucan derivative (DEX-MMfu),
1.3mg hyaluronidase (HAase) is dissolved in the HEPES buffer solution that the pH value of 5mL is 8.5, and it is small that 2 are reacted under the conditions of 25 DEG C
Reaction system is passed through Sephacryl S-300HR Sephacryl column, resulting glucan-hyaluronidase by Shi Hou
Cryo-conservation after compound (DEX-HAase) solution ultrafiltration.
It (includes: that nuclear-magnetism is total that the glucan obtained to embodiment 1-hyaluronic acid multienzyme complex (DEX-HAase), which is characterized,
Vibration hydrogen spectrum, uv-visible absorption spectra, dynamic light scattering, transmission electron microscope).
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of glucan derivative described in embodiment 1, the chemical potential of each Hydrogen Proton in figure
It moves, can be shown that the successful preparation of glucan derivative.Fig. 2 is that the Fourier transform of glucan derivative belonging to embodiment 1 is infrared
Spectrogram, the characteristic peak in figure further demonstrate that the successful preparation of glucan derivative.Fig. 3 is glucan-described in embodiment 1
The uv-visible absorption spectra of hyaluronic acid multienzyme complex (DEX-HAase), the characteristic absorption peak of hyaluronidase show egg
The successful preparation of white compound.
Fig. 4 is the dynamic laser grain size distribution of the DEX-HAase, it can be seen from the figure that DEX-HAase is formed
Nano-particle diameter between 100nm-200nm, wherein peak value is about 120nm, and monodisperse is presented；Fig. 5 is described
The transmission electron microscope photo figure of DEX-HAase, particle size are relatively uniform.
Embodiment 2:
Hydrolysis test of the DEX-HAase in weakly acidic solution, including following test condition:
By DEX-HAase be dissolved in pH value be respectively 6.0 and 7.4 buffer solution in, test the grain of different time points
Diameter variation.
Fig. 6 is diameter change of the DEX-HAase nano particle in the buffer of different pH value, it can be seen from the figure that
The DEX-HAase be able to maintain in the buffer of pH neutrality it is relatively stable, it is described and in the weakly acidic buffer of pH
Change dramatically has occurred in the partial size of DEX-HAase, and partial size drops to 50nm or so in 2 hours, and partial size drops in 4 hours
30nm or so, partial size drops to 15nm or so in 8 hours, close to the partial size of hyaluronidase, shows hyaluronidase
It will be completely dissociated.
Embodiment 3:
After a series of chemical modification techniques, DEX-HAase keeps the aptitude tests of relative activity, including following survey
Strip part:
The standard solution and DEX-HAase solution for configuring a series of hyaluronidase concentration of concentration, to 96 orifice plates
The hyaluronic acid solution that the mass fraction of 20 μ L is 0.5%, 37 DEG C of conditions are followed by added in the enzyme solutions that 20 μ L are added in every hole
It is lower to cultivate 30 minutes, the cow's serum of 160 μ L is added after taking-up to every hole, after room temperature stands 30 minutes after shaking 1 minute, test is every
Absorbance of the hole solution at 640nm, using enzyme concentration as abscissa, corresponding absorbance draws standard curve as ordinate,
The standard curve with level-one linear relationship and fitting are obtained, the relative activity of sample is calculated with this.Fig. 7 is by weak acid solution
Opposite enzyme activity from the DEX-HAase of front and back, Cong Tuzhong after dissociation, are released it can be found that compared with not dissociated sample
The hyaluronidase of releasing enzymatic activity with higher.
Embodiment 4:
Real-time tracking imaging of the DEX-HAase of fluorochrome label in rat kidney tissue and point in each organ
Cloth experiment.
It, can be with the cyanine dyes amber of n-hydroxysuccinimide (NHS) activation due to containing albumen in DEX-HAase structure
Imide ester (Cy5.5-NHS) reaction obtains the nano particle (Cy5.5-DEX-HAase) of fluorescent marker.Fig. 8 is to utilize fluorescence
The DEX-HAase nano particle of label carries out the figure of distribution tracking in vivo by tail vein injection, using living body fluorescent imaging technique,
The enriching quantity for observing each organ and tumor locus nano particle, the fluorescence that each organ is tested after each organ of mouse is taken out are strong
Degree meets Treatment need it can be seen from the figure that nano particle is preferable in the intracorporal distribution of mouse.
Embodiment 5:
The DEX-HAase of fluorochrome label is tested in the blood circulation of rat kidney tissue.
By Cy5.5-DEX-HAase nano particle by tail vein injection to Mice Body, at scheduled time point from old
Rathole ball takes out the blood of 15 μ L or so, examines DEX-HAase nano particle to exist by fluorescence signal intensity in test blood
The intracorporal blood circulation situation of mouse.As a result see that Fig. 9, Fig. 9 are the blood circulation data of DEX-HAase, it can be seen from the figure that
DEX-HAase nano particle has relatively long circulation time, has good application value.
Embodiment 6:
DEX-HAase nano particle improves the weary oxygen situation experiment of tumor locus:
By DEX-HAase nano particle by the way that in tail vein injection to Mice Body, after 24 hours, experiment mice sacrifice is taken
Tumor tissues carry out frozen section out, are dyed using immunofluorescence staining to tumor biopsy blood vessel and weary oxygen region, lead to
Cross the ability that confocal microscopy nano particle improves the weary oxygen situation of tumor locus.It can be seen from fig. 10 that with compareing
The tumor biopsy of group is compared, and the greyish white intensity of colour that weary oxygen degree is represented in the tumor region of DEX-HAase nano particle has been injected
It is obvious weaker, show that DEX-HAase nano particle can be effectively improved the weary oxygen situation of tumor locus, this is beneficial to subsequent optical
Dynamic therapy.
Embodiment 7:
DEX-HAase nano particle combines photodynamic therapy and inhibits tumor proliferation experiment:
Choose 5 backs with 4T1 tumour mouse as experimental group, it is small by 8 from tail vein injection DEX-HAase
Then Shi Hou will swell after 24 hours from the nano particle (Ce6 liposome) of tail vein injection liposome photosensitive molecular
Tumor position, which is exposed under 660 nanometers of LED light, irradiates 45min.Mouse (every group 5) of the other four groups of backs with tumour is as right
It is the healthy mice of (1) not Jing Guo any processing respectively according to a group test；(2) DEX-HAase group is only injected；(3) injection is same
DEX-HAase the and Ce6@liposome of dosage is without additional light source irradiation group；(4) same dose of Ce6@liposome is only injected
Additional laser irradiation.After having handled every group of mouse, the gross tumor volume of back of mice is primary every measurement in two days.
Figure 11 is the variation diagram of gross tumor volume, and as shown in figure 11, the tumour of experimental mice is handled by DEX-HAase
Later carry out optical dynamic therapy again, growth is significantly suppressed, and other control group tumours are constantly being grown, show through
The processed treatment of DEX-HAase is crossed compared with single therapy, the ability with more excellent inhibition tumour growth.
Embodiment 8:
Glucan-recombinant antibodies compound [DEX- (anti-PD-L1)] is prepared, specifically includes the following steps:
The pH value that 1.2mg glucan derivative (DEX-MMfu), recombinant antibodies (anti-PD-L1) are dissolved in 1mL is 8.5
HEPES buffer solution in, after being reacted 2 hours under the conditions of 4 DEG C, by reaction system pass through Sephacryl S-300HR propylene Portugal
Polysaccharide gel column, resulting glucan-recombinant antibodies compound [DEX- (anti-PD-L1)] cryo-conservation.
Figure 12 is the dynamic laser grain size distribution of the DEX- (anti-PD-L1), it can be seen from the figure that DEX-
(anti-PD-L1) nano-particle diameter is formed by between 100nm-200nm, and peak value is about 140nm, and monodisperse is presented.Table
The successful preparation of face nano particle.
It, can be with the cyanines of n-hydroxysuccinimide (NHS) activation due to containing albumen in DEX- (anti-PD-L1) structure
Dyestuff succinimide ester (Cy5.5-NHS) reaction obtains the nano particle [Cy5.5-DEX- (anti-PD- of fluorescent marker
L1)]。
Figure 13 is by Cy5.5-DEX- (anti-PD-L1) nano particle by making a reservation in tail vein injection to Mice Body
Time point the blood of 15 μ L or so is taken out from mouse eyeball, DEX- is examined by fluorescence signal intensity in test blood
(anti-PD-L1) nano particle is in the intracorporal blood circulation situation of mouse.It can be seen from the figure that DEX- (anti-PD-L1)
Nano particle has relatively long circulation time, has good application value.
Black rat of 5 backs with 4T1 tumour is chosen as experimental group, from tail vein injection DEX- (anti-PD-
L1), in addition mouse (every group 5) of two groups of backs with tumour is tested as control group, is (1) respectively not by any place
The healthy mice of reason；(2) same dose of anti-PD-L1 group is only injected.The gross tumor volume of back of mice measured one every two days
It is secondary.
Figure 14 is the variation diagram of gross tumor volume, as shown, compared with the control group, the tumour growth of experimental mice obtains
Certain inhibition.Show the recombinant antibodies crossed by glucan derivative composite joint after the dissociation still with good anti-swollen
Tumor effect and natural polymer-albumen composition structure have certain universality.
One kind natural polymer-albumen composition provided by the invention, the compound pass through idol by active function albumen
Connection small molecule is connect with natural polymer, is formed in around the active function albumen compound receiving that there is natural polymer to surround
Rice structure.The compound effectively prevents organism to the immunological rejection of foreign protein, and protects egg to a certain extent
White bioactivity during body circulation；Good dispersibility is all had under water and physiological condition；Obtained nano particle
There is higher enrichment in tumor locus, be effectively improved the weary oxygen situation of tumor locus, in the optical dynamic therapy of subsequent enhancing tumour
With certain application；The experimental results showed that cooperating subsequent laser irradiation to carry out light power by mouse tail vein injection
Treatment has apparent joint rejection ability to tumor cell proliferation, is carried out by immunofluorescence dyeing technology to tumor tissues
Frozen section dyeing observation, the compound can be effectively improved the weary oxygen situation of tumor tissues, and it is weary to can be used as improvement tumor locus
The nano material of oxygen further enhances the curative effect of optical dynamic therapy.
Embodiment described above is only illustrative embodiment of the invention, it is noted that for the art
For those of ordinary skill, being equal for being made without departing from the principle of the present invention is sexually revised, also in guarantor of the invention
It protects in range.
Claims (12)
1. a kind of natural polymer-albumen composition, which is characterized in that the compound is small by being coupled by active function albumen
Molecule is connect with natural polymer, is formed in the composite Nano knot surrounded around the active function albumen with natural polymer
Structure；
The natural polymer and the coupling small molecule pass through chemistry key connection；
The active function albumen and the coupling small molecule are by having the chemistry of acid response to be keyed.
2. natural polymer-albumen composition according to claim 1, which is characterized in that the coupling small molecule with
Before the natural polymer and active function albumen connection, there is at least one dibasic acid anhydride structure, the dibasic acid anhydride
The carbon atom adjacent with carbonyl is connected with carbon-carbon double bond in structure, and the coupling small molecule has at least one halo groups.
3. natural polymer-albumen composition according to claim 2, which is characterized in that the coupling small molecule structure
Formula isWherein, R1, R2 are the alkyl chain that carbon chain lengths are 1~10；X is halogenated atom.
4. natural polymer-albumen composition according to claim 2, which is characterized in that the coupling small molecule is 2,
One bromo-derivative of 3- dimethyl maleic anhydrideAn or bromo-derivative of 3,4,5,6- tetrahydrophthalic anhydrideAnd
Its composition.
5. natural polymer-albumen composition according to claim 1, which is characterized in that the active function albumen packet
Include hyaluronidase, Collagenase, matrix metalloproteinase and combinations thereof.
6. natural polymer-albumen composition according to claim 1, which is characterized in that the active function albumen packet
Include catalase, superoxide dismutase and combinations thereof.
7. natural polymer-albumen composition according to claim 1, which is characterized in that the active function albumen packet
Include immunoglobulin G, recombinant antibodies, PD-1, PD-L1, PD-L2, CTLA-4 and combinations thereof.
8. natural polymer-albumen composition preparation method described in claim 1-7 any one, which is characterized in that packet
Include following steps:
S1: natural polymer is connect with coupling small molecule by substitution reaction, the derivative of natural polymer is formed；
S2: the derivative for the natural polymer that S1 step is obtained and the active function albumen are connected by acylation reaction
It connects, obtains natural polymer-albumen composition.
9. natural polymer-albumen composition preparation method according to claim 8, which is characterized in that the S1 step
Described in substitution reaction reaction condition are as follows: under the conditions of 20-30 DEG C, sodium hydroxide (NaOH) concentration be 30-50mg/mL two
10-15 hour is reacted in first sulfoxide (DMSO) solution.
10. preparation method according to claim 8, which is characterized in that acylation reaction described in the S2 step it is anti-
Answer condition are as follows: solvent is 4- hydroxyethyl piperazineethanesulfonic acid (HEPES) buffer that pH value is 8.0~9.0, and the active function
The mass ratio of albumen and the buffer HEPES be 1:(5000~50 000).
11. natural polymer-albumen composition described in claim 1~8 any one be used to prepare tumor therapeutic agent or
Purposes in preparation.
12. natural polymer-albumen composition described in claim 11 is used to prepare the use in tumor therapeutic agent or preparation
On the way, which is characterized in that the active function albumen includes Matrix lysis protease, hydroperoxide or superoxides catalysis simultaneously
At least two classes in enzyme and antibody.
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| WO2020155688A1 (en) * | 2019-01-29 | 2020-08-06 | 苏州杰纳生物科技有限公司 | Natural polymer-protein complex and preparation method therefor and application thereof |
| CN113855788A (en) * | 2021-07-13 | 2021-12-31 | 南昌大学第一附属医院 | Antibody nano-particle and preparation method and application thereof |
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| US20050181985A1 (en) * | 2002-03-06 | 2005-08-18 | Jurgen Hemberger | Coupling proteins to a modified polysaccharide |
| CN102652836A (en) * | 2011-03-03 | 2012-09-05 | 华中科技大学同济医学院附属协和医院 | Targeting drug release anticancer protein or polypeptide polymer prodrug and preparation method thereof |
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| US20050181985A1 (en) * | 2002-03-06 | 2005-08-18 | Jurgen Hemberger | Coupling proteins to a modified polysaccharide |
| CN102652836A (en) * | 2011-03-03 | 2012-09-05 | 华中科技大学同济医学院附属协和医院 | Targeting drug release anticancer protein or polypeptide polymer prodrug and preparation method thereof |
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| CN113855788A (en) * | 2021-07-13 | 2021-12-31 | 南昌大学第一附属医院 | Antibody nano-particle and preparation method and application thereof |
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Application publication date: 20190723 |