CN109535247A - Polyethyleneglycol modified phycocyanin and preparation method thereof and pharmacy application - Google Patents
Polyethyleneglycol modified phycocyanin and preparation method thereof and pharmacy application Download PDFInfo
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- CN109535247A CN109535247A CN201811581843.XA CN201811581843A CN109535247A CN 109535247 A CN109535247 A CN 109535247A CN 201811581843 A CN201811581843 A CN 201811581843A CN 109535247 A CN109535247 A CN 109535247A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/795—Porphyrin- or corrin-ring-containing peptides
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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
- A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention discloses a kind of polyethyleneglycol modified phycocyanins, also disclose preparation method, use PEG dressing agent for methoxy poly (ethylene glycol) succinimdyl carbonate, after mPEG-SC is reacted with phycocyanin, through anion exchange resin chromatographic isolation to get arrive polyethyleneglycol modified phycocyanin.Polyethyleneglycol modified phycocyanin of the invention can not only obtain active modified outcome, but also the activity of modified outcome is further enhanced than unmodified, and the immunogenicity of modified outcome significantly reduces, and drug half-life is obviously prolonged；Preparation method is simple for polyethyleneglycol modified phycocyanin of the invention.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to a kind of polyethyleneglycol modified phycocyanin and preparation method thereof
With pharmacy application.
Background technique
Phycocyanin is to be present in the water-soluble bluish-green chromoprotein of one of spirulina, according to the difference of absorption spectrum ranges
Phycocyanin can be divided into three kinds: C-Phycocyanin, R-PC and R-PC II, wherein C-Phycocyanin is mainly deposited
It is in cyanobacteria, R-PC is primarily present in red algae, and R-PC II is primarily present in Synechococcus.Phycocyanin
It is made of α subunit and β subunit and an algocyan group, α subunit is connected by cys84 with algocyan, and β subunit passes through
Cys82 and cys153 are connected with algocyan, and conservative alpha-helix rich in, is extracted from different algal species in two subunits
Phycocyanin has the stronger amino acid sequence of similitude and three-D space structure.To the research table of the space structure of phycocyanin
Bright, the mono- aggressiveness of 3 α β constitutes one (α β)3Tripolymer, the tripolymer of phycocyanin are a hollow cylindrical-shaped structure, two
(αβ)3Form one discoid (α β)6Six aggressiveness, (α β)3(α β)6For the functional form of phycocyanin.The purity of phycocyanin
Use A620/A280It indicates, A620/A280It is food grade phycocyanin, A when greater than 0.7620/A280It is blue for order of reaction algae when greater than 3.0
Albumen, A620/A280It is analysis level phycocyanin when greater than 4.0.
Multiple studies have shown that phycocyanin have important application value: phycocyanin is a kind of natural pigment, food,
Cosmetic field is used widely；Phycocyanin has fluorescent characteristic, can be used as fluorescence probe, for immunodiagnostics
Research；Phycocyanin also has important medical value, research shows that there is phycocyanin antitumor, anti-oxidant, anti-inflammatory, liver to protect
The effects of shield effect and removing free radical.
In recent years, with the development of biotechnology, pharmaceutical grade protein is increasingly being applied to the prevention and treatment of disease,
Pharmaceutical grade protein is just increased with the speed of 10%-35% year by year according to estimates.Although pharmaceutical grade protein is curative for effect, action site is special
One, but increasing with the pharmaceutical grade protein of clinical application, people gradually have found some disadvantages of this kind of drug, such as half-life period
The defects of short, there are immunogenicity, easily by proteolytic degradation, renal clearance height and low-solubility, these problems limitation
The further development of pharmaceutical grade protein.In recent years, the method solved these problems is actively all being sought both at home and abroad, is such as changing egg
White matter amino acid sequence reduces the hydrolysis of drug；By pharmaceutical grade protein and Albumin fusion, to extend drug half-life；Make
With suitable drug carrier system etc..Wherein PEG modification is a kind of extremely effective method, the protein medicine after PEG is modified
Physical property matter is stable, toxicity reduces, water-soluble increase, aggregation tendency reduces, immunogenicity reduces, is more stable to proteolytic enzyme.
Polyethylene glycol is a kind of linear, soluble uncharged polymer in aqueous solution, have it is nontoxic, without immunogene
The characteristics such as property and good biocompatibility.PEG can be used as a kind of dressing agent after connecting with active group, can be modified with PEG
Protein drug is modified in agent, improves the property of protein drug, it is made preferably to play drug effect.PEG is mainly from following
Several aspects improve drug effect: (1) protein molecular weight after PEG modification increases, renal clearance reduction, Increased Plasma Half-life；(2)
PEG can cover the antigen recognition site of protein surface, reduce immunogenicity；(3) PEG is water-soluble preferably, improves protein
The solubility of drug in aqueous solution；(4) PEG plays shielding and steric effect in protein surface, reduces the hydrolysis of protease
Effect improves stability.Development recently as PEG modification technique in field of biotechnology, more and more protein medicines
Object improves drug effect using PEG modification technique.But it so far, yet there are no the report that PEG modification is carried out to phycocyanin.
PEG dressing agent to the modification of protein drug mainly on protein or polypeptide amino or-SH into sulfydryl
Row modification.It can be mainly the amino of protein N terminal and the epsilon-amino of lysine by the amino of pointed decoration in protein, usually
The pKa of the amino of protein N terminal is 7.6-8.0, and the pKa of the epsilon-amino of lysine is therefore 10.0-10.2 can pass through control
PH value of solution processed modifies the alpha-amido of protein N terminal.Polyethylene glycol succinimidyl carbonate (mPEG-SC) is mesh
The preceding most common PEG derivative with active group, it is more stable than ester bond with the urethane bond of protein-coupled generation, existing
It is widely used in the coupling reaction with drug.
Summary of the invention
Goal of the invention: being directed to the above-mentioned prior art, and the present invention provides one kind under the premise of keeping phycocyanin active,
Its immunogenicity is reduced, mitigates anaphylactoid polyethyleneglycol modified phycocyanin, and provide preparation method and pharmacy
Using.
Technical solution: the polyethyleneglycol modified phycocyanin of one kind of the present invention, general structure are as follows:
Wherein: m is mono methoxy, and n=0-3, R represent one amino (NH of removal2) phycocyanin molecule.
The preparation method of polyethyleneglycol modified phycocyanin of the present invention, comprising the following steps:
(1) phycocyanin and PEG dressing agent are taken, is dissolved respectively with phosphate buffer；
(2) glycine is added by the dissolved phycocyanin of step (1) and PEG dressing agent hybrid reaction, after reaction to terminate
Reaction；
(3) reaction mixture of step (2) anion exchange resin chromatography is separated, is obtained polyethyleneglycol modified
Phycocyanin.
In step (1), the phycocyanin includes the phycocyanin extracted from all algae.
In step (1), the PEG dressing agent is methoxy poly (ethylene glycol) succinimdyl carbonate (mPEG-SC), point
Son amount is 5-40kD, preferably 20kD.
In step (1), the phosphate buffer pH is 6.0-7.5.
In step (2), the molar ratio of the phycocyanin and PEG dressing agent is 1:1-10, preferably 1:5.
In step (2), reaction temperature is 4 DEG C -25 DEG C, reaction time 1-24h.
In step (3), the mobile phase that anion exchange resin chromatography uses is the phosphate buffer containing NaCl.
In step (3), glycine is added and is terminated to final concentration 1M and reacts.
The medicine of above-mentioned polyethyleneglycol modified phycocyanin disease involved in preparation prevention and/or treatment phycocyanin
Application in object, the disease are cervical carcinoma, liver cancer cells and cancer of pancreas etc..
The utility model has the advantages that being compared to the prior art, the present invention passes through the fixed point ammonia to phycocyanin progress peptide chain aminoterminal
Base modification not only obtains active modified outcome, but also the activity of modified outcome is further enhanced than unmodified, and is repaired
The immunogenicity for adoring product significantly reduces, and drug half-life is obviously prolonged, and has the function of that medication is safer, more efficient.Preparation
The polyethyleneglycol modified phycocyanin of gained can be also used for the drug of preparation treatment tumour.
Detailed description of the invention
Fig. 1 is to detect the electrophoretogram that PEG modifies phycocyanin using SDS-PAGE；Use 15% separation gel, 5% concentration
Glue；Wherein 1 is PC, and 2 be PEG-PC after purification, and 3 be unpurified PEG-PC, and 4 be standard molecular weight albumen；
Fig. 2 is mouse resisting anteserum potency；
Fig. 3 is the immunogenicity determining of PC and PEG-PC；
Fig. 4 is growth inhibition effect of the PEG-PC to Hela cell；
Fig. 5 is growth inhibition effect of the PEG-PC to HepG2 cell；
Fig. 6 is growth inhibition effect of the PEG-PC to MCF-7 cell.
Specific embodiment
The present invention is described in detail below in conjunction with embodiment.
Phycocyanin is according to document (Preventive effect of phycocyanin from Spirulina
platensis on alloxan-injured mice.Environmental Toxicology and Pharmacology,
Method 2012,34:721-726) isolates and purifies to obtain.
Cervical cancer cell Hela, hepatocellular carcinoma H22, pancreatic cancer cell MCF-7 are purchased from Chinese Academy of Sciences's Shanghai cell bank.
mPEG-SC20000Purchased from Beijing Kai Zheng biotech firm.
Embodiment 1
The influence of reaction time and pH value to modified outcome
Accurately weighing four parts of 7.14mg mPEG-SC20000 and being separately added into 1mL pH is respectively 6.0,6.5,7.0,7.5
Phosphate buffer dissolves dressing agent sufficiently.It is 6.0,6.5,7.0,7.5 that the phycocyanin solution prepared is used pH respectively
Phosphate buffer be diluted to concentration be 3mg/mL protein solution.1mL is added into the test tube containing mPEG-SC20000
Concentration is the phycocyanin solution of 3mg/mL, mixes well dressing agent with phycocyanin solution, is reacted in 4 DEG C, respectively anti-
1h, 2h after should starting, it 5h, 9h, 11h, samples for 24 hours, the modification rate of PEG phycocyanin is determined with SDS-PAGE.Experimental result table
Bright, the modification rate of reaction 24 hours is respectively 12%, 23%, 39% and 52% when 6.0,6.5,7.0,7.5 pH；When pH is
7.5 reaction 1h, 2h, 5h, 9h, 11h, modification rate for 24 hours are respectively 0,10%, 23%, 34%, 42% and 52%.With pH and
The extension in reaction time, modification rate improve.When reaction pH is 7.5, the reaction time is modification rate highest when for 24 hours.
Embodiment 2
Influence of the ratio of dressing agent and phycocyanin to modified outcome
By mPEG-SC20000Modification is accurately weighed respectively for 1,3,5,8,10 with the molar ratio of phycocyanin is dissolved in 1mL
The phosphate buffer of pH 7.5.Then the phycocyanin solution that 1mL concentration is 3 mg/mL is added into every pipe, mixes well,
4 DEG C of reactions are for 24 hours.The modification rate of PEG phycocyanin is determined with SDS-PAGE.The experimental results showed that when dressing agent and phycocyanin
Modification rate is respectively 30%, 51% and 55% when molar ratio is 1,3,5, and with the increase of molar ratio, modification rate also increases, when rubbing
When you are than being greater than 5, modification rate is not obviously increased.
Embodiment 3
PEG modifies the preparation of phycocyanin (PEG-PC)
Accurately weigh a certain amount of mPEG-SC20000The phosphate buffer of pH7.5 is added, dissolves dressing agent sufficiently.Accurately
The phosphate buffer that pH7.5 is added in the phycocyanin prepared is weighed, dissolves phycocyanin sufficiently.By above two solution
According to mPEG-SC20000The ratio for being 5 with phycocyanin molar ratio mixes well, for 24 hours in 4 DEG C of reactions.1M glycine is added to terminate
Reaction.2 eluting peaks are obtained through DEAE Sepharose FF or Capto Q column chromatographic purifying, are identified with SDS-PAGE, it is dense
Contracting, freeze-drying obtain PEG modification phycocyanin sterling (Fig. 1 swimming lane 2).
Gained PEG-PC is prepared using embodiment 3 test described in embodiment 4-6.
Embodiment 4
PEG modifies the immunogenicity research of phycocyanin (PEG-PC)
18 mouse are randomly divided into 3 groups (PEG-PC group, PC groups, physiological saline group), every group 6.PEG-PC group: every
Mouse injection 0.1mL PEG-PC solution (1mg/mL, by the calculating of PEG-PC molecular weight) and aluminium glue adjuvant (2mg/mL)；PC group:
Every mouse injection 0.1mL PC solution (1 mg/mL is calculated by PC molecular weight) and aluminium glue adjuvant (2mg/mL)；Physiological saline
Group: every mouse injects 0.2mL physiological saline.Each group is immunized mouse using hypodermic mode, immunologic process are as follows:
Mouse adapts to environment and carries out initial immunity after a week, after two weeks, carries out booster immunization, booster immunization carries out eye to mouse after two weeks
Socket of the eye takes blood, and centrifugation prepares serum.Respectively using PC, PEG-PC as envelope antigen, after being integrated to solid phase carrier, it is small that corresponding each group is added
The serum of mouse, indirect elisa method detect serum titer.
As a result as shown in Fig. 2, PEG-PC group antibody titer is significantly lower than PC group.
Using PC and PEG-PC as envelope antigen, using PC group antiserum as first antibody, indirect elisa method detection is respective to exempt from
Epidemic focus, as a result as shown in figure 3, compared with PC, the immunogenicity of PEG-PC is substantially reduced.
Embodiment 5
PEG-PC is studied in Pharmacokinetics in Rat
SD rat, is randomly divided into 3 groups, every group of 6: one group of tail vein injection saline, one group of tail vein injection PC
(50mg/kg), one group of tail vein injection are equivalent to PC dosage/kg PEG-PC.Respectively at 0.5h, 1h, 2h, 3h, 6h, 12h,
For 24 hours, 48h, 72h, 96h are taken a blood sample by orbital venous plexus, and every is adopted whole blood 0.5ml, anticoagulant heparin, and centrifugal separation plasma is used
ELISA method measures blood concentration.The results show that the half-life period of PEG-PC and PC is respectively 1366 ± 55 and 817 ± 42
(min), plasma clearance is respectively 0.013 ± 0.001 and 0.71 ± 0.09 (L/h/kg), and PEG-PC is compared with PC, half-life period
There is significant extension, plasma clearance is substantially reduced.
Embodiment 6
PEG modifies phycocyanin to the inhibiting effect of tumour cell
The phycocyanin of PEG modification after purification is acted on into cervical cancer cell Hela, hepatocellular carcinoma H22, cancer of pancreas
Cell MCF-7, mtt assay detect growth inhibition effect of the phycocyanin of PEG modification to these tumour cells, concrete operation step
It is as follows: the cell of logarithmic phase is collected, it, will be under the cell piping and druming in bottle wall with fresh culture after being digested with 0.25% pancreatin
Come, adjust the concentration of cell suspension, 100 μ L, 5%CO are added in every hole into 96 orifice plates2, 37 DEG C of cultures, after cell is adherent plus
Enter concentration be respectively 200 μ g/mL, 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, the PEG-PC of 12.5 μ g/mL and concentration be 200 μ g/
The PC of mL, while setting the blank control group of not dosing and the negative control group of cell is not added.After cultivating 48h, 10 μ l are added in every hole
MTT (5mg/mL) continues to cultivate 4h, and after culture, 150 μ l DMSO are added in every hole, sets and is protected from light low speed concussion on shaking table
10min measures each hole in OD with enzyme-linked immunosorbent assay instrument570The light absorption value at place.
Cell inhibitory rate (%)=(1- experimental group OD570/ control group OD570) × 100%
Experimental result is as Figure 4-Figure 6, according to diagram as it can be seen that the work of the inhibition tumour cell for the PC that PEG-PC not only retains
Property, and effect is more preferable under same molar concentration.
Claims (10)
1. a kind of polyethyleneglycol modified phycocyanin, which is characterized in that general structure is as follows:
Wherein: m is mono methoxy, and n=0-3, R represent the phycocyanin molecule of one amino of removal.
2. the preparation method of polyethyleneglycol modified phycocyanin described in claim 1, which comprises the following steps:
(1) phycocyanin and PEG dressing agent are taken, is dissolved respectively with phosphate buffer；
(2) glycine is added by the dissolved phycocyanin of step (1) and PEG dressing agent hybrid reaction, after reaction and terminates reaction；
(3) reaction mixture of step (2) anion exchange resin chromatography is separated, obtains polyethyleneglycol modified algae
Azurin.
3. preparation method according to claim 2, which is characterized in that in step (1), the phycocyanin includes from institute
There is the phycocyanin extracted in algae.
4. preparation method according to claim 2, which is characterized in that in step (1), the PEG dressing agent is methoxy
Base polyethylene glycol succinimdyl carbonate, molecular weight 5-40kD.
5. preparation method according to claim 2, which is characterized in that in step (1), the phosphate buffer pH is
6.0-7.5。
6. preparation method according to claim 2, which is characterized in that in step (2), the phycocyanin and PEG modification
The molar ratio of agent is 1:1-10.
7. preparation method according to claim 2, which is characterized in that in step (2), 4 DEG C -25 DEG C of reaction temperature, reaction
Time 1-24h.
8. preparation method according to claim 2, which is characterized in that in step (3), anion exchange resin chromatography
The mobile phase used is the phosphate buffer containing NaCl.
9. polyethyleneglycol modified phycocyanin described in claim 1 is in preparation prevention and/or treats involved in phycocyanin
Application in the drug of disease.
10. application according to claim 9, which is characterized in that the disease is cervical carcinoma, liver cancer cells or cancer of pancreas.
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Cited By (1)
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| CN110591077A (en) * | 2019-10-17 | 2019-12-20 | 江南大学 | Method for preparing tyrosine oligopeptide and grafted monomethoxy polyethylene glycol through enzyme catalysis |
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Application publication date: 20190329 |