CN104940949B - A kind of antineoplastic polypeptide Nano medication and its preparation method and application - Google Patents
A kind of antineoplastic polypeptide Nano medication and its preparation method and application Download PDFInfo
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Abstract
The invention provides a kind of antineoplastic polypeptide Nano medication and its preparation method and application, the antineoplastic polypeptide Nano medication includes amphipathic antineoplastic polypeptide and the sour response functional molecular with the coupling of amphipathic antineoplastic polypeptide.For the present invention using amino acid as raw material, synthesizing amphipathic antineoplastic polypeptide molecule then introduces sour response functional molecular on amphipathic antineoplastic polypeptide molecule, then carries out being self-assembly of the antineoplastic polypeptide Nano medication.The antineoplastic polypeptide Nano medication good biocompatibility of the present invention, toxic side effect is low, has sour response, bioavilability is high, has high biological safety.The preparation method of the present invention is simple, covalence key is not generated in self assembling process, without back reaction, the antineoplastic polypeptide Nano medication being prepared has broad application prospects.
Description
Technical field
The present invention relates to Nano medication field, is related to a kind of antineoplastic polypeptide Nano medication and its preparation method and application.
Background technology
The research and development of antineoplastic polypeptide class medicine receive much concern in recent years.Compared with antibody and small-molecule drug, polypeptide drugs
The shortcomings that immunogenicity is low, acceptor Percentage bound is high, it is low to prepare cost and is easy to transformation and use in conjunction, but it is maximum is internal half
Phase of declining is short, is easily easily degraded by proteases and the internal organs metabolism such as liver kidney.Therefore, the pharmacokinetics of polypeptide is improved without reducing its curative effect
It is the important directions of polypeptide drugs research and development.
Nano medication is emerging pharmaceutical dosage form, by designing and regulating and controlling the nano-meter characteristic of organic or inorganic material, is prepared
Stability Analysis of Structures, nano-carrier vdiverse in function and good biocompatibility, it can significantly extend drug half-life, improve targeting, drop
Low dosage simultaneously realizes drug combination.Pass through the molecular structure and change external environment of Reasonable Regulation And Control polypeptide, some polypeptides point
Using non-covalent weak interaction force between a certain fragment and another fragment between son or in peptide molecule, such as hydrogen bond, Fan De
Hua Li, electrostatic force, hydrophobic effect and pi-pi accumulation effect etc., it is self-assembled into point with particular sorted order to spontaneous or triggering
Sub- aggregation.Polypeptide itself has good biocompatibility and controllable degradation property, but its stability in vivo is not
Enough, molecular structure is readily broken.If by antineoplastic polypeptide by transformation can direct-assembling formation of nanostructured, can develop
Go out good dispersion, purity height, the anti-tumor nano medicine that toxic side effect is low and stability is high.
In addition, research shows that the pH environment of malignant tumor tissue is subacidity, and tumour cell position pH value is in 6.7-7.2
Between.Therefore, in order to reduce toxic side effect of the medicine for normal tissue cell, it is desirable to access and a kind of transported in vivo
It can be stabilized in journey, and can discharge medicine when reaching tumor locus and be received with reaching the pH responses for the treatment of tumour purpose
Rice medicine.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of antineoplastic polypeptide Nano medication and its preparation
Methods and applications.Antineoplastic polypeptide Nano medication of the present invention overcomes the short bottleneck of antineoplastic polypeptide drug half-life,
There is provided a kind of has that tumor locus weakly acidic condition response, good biocompatibility, stability is strong, safe and bioavilability
High antineoplastic polypeptide Nano medication.
To reach this goal of the invention, the present invention uses following technical scheme:
On the one hand, the present invention provides a kind of antineoplastic polypeptide Nano medication, and the antineoplastic polypeptide Nano medication includes two
Parent's property antineoplastic polypeptide and the sour response functional molecular with the coupling of amphipathic antineoplastic polypeptide.
Most of peptide molecule with antitumor activity that presently, there are is hydrophilic, but its Half-life in vivo is short,
Easily it is easily degraded by proteases and is metabolized with internal organs such as liver kidneys, and some a small number of Amphiphilic peptide molecules is due to hydrophobic and hydrophilic segment
Between ratio it is uncoordinated cause to be hardly formed nano particle, therefore, the present invention hydrophilic anti-tumor polypeptide is transformed, will
Hydrophilic anti-tumor polypeptide fragment and hydrophobic peptides fragment are combined, and are transformed into amphipathic antineoplastic polypeptide, are then rung with acid
The antineoplastic polypeptide Nano medication that sexual function molecule coupling labeled obtains is answered, compatibility is good, stable so that its half-life period in vivo prolongs
It is long, the bioavilability of the targeting and antineoplastic polypeptide molecule to tumor locus is also improved, further, since in the medicine
Cause the Nano medication that there is sour response containing sour response functional molecular, using tumor extracellular matrix pH value as acidity
In the environment of, reach preferable therapeutic effect.
The antineoplastic polypeptide medicine preparation is the tumour because nanoparticle system is stable into nano particle by the present invention
Enrichment is strong, has targeting, in addition, being prepared the acceptor that nano particle is also possible that on hydrophilic anti-tumor polypeptide
Binding site improves the stability of hydrophilic anti-tumor peptide molecule in vivo outside being not exposed to.
Because peptide molecule side chain can be with different electric charges, by designing and modification makes peptide molecule have subacidity pH responses
Property, wherein most easy method is exactly to be built by Amphiphilic peptide self assembly mode.Amphiphilic peptide is inclined in aqueous
In its hydrophilic segment is formed into interface exposed to outer layer and hydrone, and hydrophobic part is then gathered in.It is more in neutral environment
Peptide molecule mainly by the Physical interaction power of hydrophobic effect and hydrogen bond, is self-assembly of nano particle;In slightly acidic environment
In, peptide molecule hydrophobic side is protonated, and the positive charge repulsive force between hydrophobic side makes self-assembly depolymerization, discharges polypeptide point
Son.This method can make antineoplastic polypeptide medicine form nanostructured in physiological environment, extend its half-life period in vivo,
Nanostructured special response depolymerization in subacidity tumor microenvironment, peptide molecule is discharged, play antitumor action.
In antineoplastic polypeptide Nano medication of the present invention, the amphipathic antineoplastic polypeptide includes to be coupled by amido link
Hydrophilic anti-tumor polypeptide and hydrophobic peptides together.
Preferably, the sour response functional molecular carries the functional group with amino reaction;
Preferably, the sour response functional molecular is isocyanates organic molecule, more preferably 3- (diethyl
Amino) propyl dithiocarbamate isocyanates;
It is preferably, described that to state sour response functional molecular to carry out the pH value of sour response be 6.7-7.2, for example, 6.7,6.8,
6.9th, 7.0,7.1 or 7.2.
The faintly acid pH value of acid response of the present invention is the people for the pH value in human body in normal structure
The pH value of body normal structure is 7.4, and the pH value of tumor locus is 6.7-7.2, therefore for human normal tissue, is swollen
The pH environment at tumor tissue position is faintly acid.
Sour response functional molecular can be protonated when pH value is 6.7-7.2, cause to produce between polypeptide hydrophobic side
Positive charge repulsive force, it is destroyed self-assembling nanoparticles form.
Because the pH value of tumor locus is that weak acid environment is (6.7-7.2), the medicine is 6.7-7.2 in pH value, can be made
Obtain medicament nano particle to be destroyed, the binding site on antineoplastic polypeptide, which exposes, to be come, and reaches the purpose for the treatment of.
Preferably, the sour response functional molecular is coupled on hydrophobic peptides by hydrophobic peptides terminal amino group.
Preferably, the antineoplastic polypeptide Nano medication is also comprising the lysine being connected with hydrophobic peptides.
Preferably, the sour response functional molecular is connected on hydrophobic peptides by lysine.
Heretofore described sour response functional molecular, which refers to have under the stimulation under certain sour environment, occurs certain
The molecule of the ability of reaction, for example, 3- (diethylamino) propyl dithiocarbamate isocyanate molecules can be by matter under sour environment
Sonization.
In antineoplastic polypeptide Nano medication of the present invention, the lysine being connected with hydrophobic peptides is 1 bad ammonia
Acid or the peptide chain of 2-5 lysine formation, such as hydrophobic peptides can connect 1 lysine, or hydrophobic peptides can be with
It is connected with the peptide chain that 2,3,4 or 5 lysines are formed.Lysine is introduced on hydrophobic peptides, is then drawn again by lysine
Enter sour response functional molecular, multiple sour response functional moleculars can be so introduced on antineoplastic polypeptide, for example, when hydrophobic
Property polypeptide when being not connected to lysine, a sour response functional molecular is connected by hydrophobic amino acid terminal amino group, and when dredging
When water-based polypeptide connects a lysine, 2 sour responses can be connected altogether by the terminal amino group and side-chain amino group of lysine
Functional molecular, if hydrophobic peptides connection is peptide chain that 4 lysines are formed, the end of lysine peptide chain can be passed through
Amino and side-chain amino group connect 5 sour response functional moleculars altogether.Amphiphilic can be ensured by connecting multiple sour response functional moleculars
Property polypeptide hydrophobic side hydrophobicity, and cause medicine tumor locus occur acid response power it is stronger.
Preferably, the terminal amino group of the lysine and side-chain amino group are connected with the sour response functional molecular.
In antineoplastic polypeptide Nano medication of the present invention, the hydrophilic anti-tumor polypeptide is thin with tumour is suppressed
Born of the same parents, tumor vessel, lymphangiogenesis or mesenchyma stroma of tumors cell function peptide molecule in any one or at least two group
Close.
Preferably, the hydrophilic anti-tumor polypeptide is the soluble polypeptide containing 5-30 amino acid, such as can be
Soluble polypeptide containing 5,6,7,8,9,10,13,15,18,20,24,26,28 or 30 amino acid.
In antineoplastic polypeptide Nano medication of the present invention, the hydrophobic peptides are to contain 5-40 hydrophobic amino acid
Polypeptide, such as in specific embodiments, hydrophobic peptides can contain 5,6,7,8,9,10,13,15,18,20,24,
26th, 28,30,32,34,36,38 or 40 hydrophobic amino acids.
Preferably, the hydrophobic amino acid be leucine, alanine, glycine, isoleucine, leucine, methionine,
In valine or tyrosine any one or at least two combination.
The particle diameter of antineoplastic polypeptide Nano medication of the present invention is 10-200nm.Nanoparticles stable in the range of this,
With tumour enrichment, the targeting of medicine and the bioavilability of medicine can be improved.
On the other hand, the invention provides the preparation side of antineoplastic polypeptide Nano medication as described in the first aspect of the invention
Method, methods described are:Using amino acid as raw material, synthesizing amphipathic antineoplastic polypeptide molecule, then in amphipathic antineoplastic polypeptide
Sour response functional molecular is introduced on molecule, then carries out being self-assembly of the antineoplastic polypeptide Nano medication.
Preferably, the amphipathic antineoplastic polypeptide includes the hydrophilic anti-tumor polypeptide being coupled together by amido link
And hydrophobic peptides.
Preferably, hydrophilic anti-tumor polypeptide is between suppression tumour cell, tumor vessel, lymphangiogenesis or tumour
In the peptide molecule of cell plastid function any one or at least two combination.
Preferably, the hydrophilic anti-tumor polypeptide is the soluble polypeptide containing 5-30 amino acid.
Preferably, the hydrophobic peptides are the polypeptide containing 5-40 hydrophobic amino acid.
Preferably, the hydrophobic amino acid is leucine, alanine, glycine, isoleucine, methionine, valine
In tyrosine any one or at least two combination.
Preferably, the hydrophobic peptides end of the amphipathic antineoplastic polypeptide molecule is connected with lysine.
Preferably, the synthesis of the amphipathic antineoplastic polypeptide molecule is realized by solid-phase synthesis.
Preferably, the sour response functional molecular carries the functional group with amino reaction.
Preferably, the sour response functional molecular is isocyanates organic molecule, more preferably 3- (diethyl
Amino) propyl dithiocarbamate isocyanates.
Preferably, the hydrophobic peptides end of the sour response functional molecular and amphipathic antineoplastic polypeptide molecule is bad
Propylhomoserin is coupled.
As the preferred technical solution of the present invention, the preparation method of antineoplastic polypeptide Nano medication of the invention is including following
Step:
(1) using amino acid as raw material, the amphiphilic of lysine is connected with using solid-phase synthesis synthesizing hydrophobic peptide termini
Property antineoplastic polypeptide molecule;
(2) lysine and acid for making the hydrophobic peptides end of the amphipathic antineoplastic polypeptide molecule of step (1) synthesis ring
Answer sexual function molecule coupling labeled;
(3) by the product of step (2), self assembly obtains the antineoplastic polypeptide Nano medication in neutral water environment.
In the preparation method of antineoplastic polypeptide Nano medication of the present invention, step (1) using between amino acid to send out
Raw condensation reaction obtains amphipathic antineoplastic polypeptide molecule, can be even on the hydrophobic peptides of amphipathic antineoplastic polypeptide molecule
It is associated with lysine.The amino on the lysine of amphipathic antineoplastic polypeptide molecular end connection and sour response in step (2)
The functional group that can be reacted in functional molecular with amino is reacted, so as to which acid rings in coupling on amphipathic antineoplastic polypeptide molecule
Answer sexual function molecule.
Preferably, step (3) the neutral water environment is the phosphate buffer solution that pH value is 7.4.
As further optimal technical scheme, the preparation method of antineoplastic polypeptide Nano medication of the invention specifically includes
Following steps:
(1) using amino acid as raw material, the amphiphilic of lysine is connected with using solid-phase synthesis synthesizing hydrophobic peptide termini
Property antineoplastic polypeptide molecule;
(2) lysine and acid for making the hydrophobic peptides end of the amphipathic antineoplastic polypeptide molecule of step (1) synthesis ring
Sexual function molecule 3- (diethylamino) propyl dithiocarbamates isocyanates is answered to be coupled;
(3) by the product of step (2) pH value be 7.4 phosphate buffer solution in self assembly obtain it is described antitumor more
Peptide Nano medication.
Wherein, the NCO in above-mentioned steps (2) in 3- (diethylamino) propyl dithiocarbamate isocyanate molecule
It can react and be coupled together with the amino of lysine.
It is of the present invention to be obtained by hydrophilic anti-tumor polypeptide and with hydrophobic amino acid and the coupling of optional lysine
The process of amphipathic antineoplastic polypeptide molecule, solid phase synthesis process well known in the prior art can be used (for example, Lihong Liu
Deng, Nature Nanotechnology, 2009,4:457-463;And Ying Zhao etc., J Control Release,
2014,177:The method provided in 11-19) realize, in order to realize hydrophilic anti-tumor polypeptide and hydrophobic amino acid and
Connected in a specific way between optional lysine, by the amino not of the same race profit in raw material before synthesizing amphipathic peptide molecule
Protected and (carried out using the guard method of amino in the prior art) with chemical modification method.Due to the amino acid of amido protecting
Product can be purchased commercially, and therefore, the present invention completes using from the amino acid bought from gill biochemistry (Shanghai) Co., Ltd.
The present invention.The preparation process of antineoplastic polypeptide Nano medication of the present invention can use following detailed step to complete:
(1) present invention is purchased from gill biochemistry (Shanghai) Co., Ltd. for the amino acid of Peptide systhesis, purchases amino acid
Terminal amino group by Fmoc (tablet held before the breast by officials methoxycarbonyl group) protect, for synthesis hydrophilic antineoplastic polypeptide lysine side chain amino groups by
Boc (tertbutyloxycarbonyl) is protected, and the amino for the lysine side-chain of coupling function molecule is protected by CBZ (benzyloxycarbonyl group).
(2) by the end of first amino acid (terminal amino group is protected by Fmoc) of the Amphiphilic peptide molecule to be synthesized
(purpose for introducing CLEAR- amide resins is to fix the carboxyl terminal of amino acid to carboxyl, to make with CLEAR- amide resins
Its aminoterminal reacts) amino terminal connection, Fmoc protection groups are sloughed by 20% piperidines/DMF,
Then the amino acid being incorporated in using this on resin is used as amino group, same excessive next amino acid reaction containing activated carboxyl
Spreading peptide chain, aforesaid operations is repeated until all amino acid condensations finish, amino is protected amphipathic anti-on formation peptide chain
Oncopeptide.
(3) amphipathic antineoplastic polypeptide is sloughed into Fmoc protection groups with 20% piperidines/DMF, with catalysis
Hydrogenolysis method sloughs CBZ protection groups, sour response functional molecular is reacted with de- de-protected amino, so as to which acid is responded into sexual function
Molecule is connected on amphipathic antineoplastic polypeptide.
(4) peptide chain is cleaved from resin with the dichloromethane solution of high concentration trifluoroacetic acid, in C16Y fragments
Boc blocking groups will also remove simultaneously, by the processing such as purifying, that is, obtain being connected with the amphipathic anti-of sour response functional molecular
Oncopeptide.
(5) the resulting amphipathic antineoplastic polypeptide for being connected with sour response functional molecular is entered in neutral water environment
Row self assembly performance nanoparticle system, that is, obtain the antineoplastic polypeptide Nano medication.
The self assembly of amphipathic antineoplastic polypeptide of the present invention is entered using prior art well known to those skilled in the art
OK.
For the particle diameter of antineoplastic polypeptide Nano medication prepared by the present invention in 10-200nm, particle diameter is more uniform, is advantageous to swollen
The enrichment at knurl position, the targeting of medicine is improved, reduce the toxic side effect to normal cell.
On the other hand, it is anti-in preparation the invention provides antineoplastic polypeptide Nano medication as described in the first aspect of the invention
Application in tumour medicine.
Relative to prior art, the invention has the advantages that:
The antineoplastic polypeptide Nano medication good biocompatibility of the present invention, toxic side effect is low, has acid pH response, receives
Rice material is medicine in itself, and bioavilability is high.The antineoplastic polypeptide Nano medication of the present invention is using polypeptide and amino acid as original
Material is prepared, and has the biological safety of height.Compared with naked peptide, under neutral environment, antineoplastic polypeptide Nano medication shape
Into the nanostructured of high-sequential, conceal acceptor on polypeptide with reference to and site, so as to extend partly declining of circulating in vivo
Phase, stability is high, and can be enriched in tumor locus, in the weak acid environment of tumor locus, the nano-particle shape of Nano medication
State depolymerization, the receptor binding site on antineoplastic polypeptide is exposed, to have the function that antineoplaston, improved antitumor more
The bioavilability of peptide medicine.The preparation method of the present invention is simple, and covalence key is not generated in self assembling process, without back reaction,
The antineoplastic polypeptide Nano medication being prepared has broad application prospects.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the amphipathic antineoplastic polypeptide that coupling has DEAP in embodiment 1;
Fig. 2 is the mass spectrogram of the amphipathic antineoplastic polypeptide that coupling has DEAP in embodiment 1;
Fig. 3 A are Electronic Speculum shape appearance figure of the antineoplastic polypeptide Nano medication in neutral phosphate buffer liquid in embodiment 1;
Fig. 3 B are grain size distribution of the antineoplastic polypeptide Nano medication in neutral phosphate buffer liquid in embodiment 1;
Fig. 4 A are the faintly acid phosphate-buffered that the antineoplastic polypeptide Nano medication prepared in embodiment 1 is 6.8 in pH value
Electronic Speculum shape appearance figure in liquid;
Fig. 4 B are the faintly acid phosphate-buffered that the antineoplastic polypeptide Nano medication prepared in embodiment 1 is 6.8 in pH value
Grain size distribution in liquid;
Fig. 5 is to carry out tumor locus response measure to antineoplastic polypeptide Nano medication prepared by embodiment 1 in embodiment 8
Result figure;
Fig. 6 is the antineoplastic polypeptide Nano medication of the preparation of embodiment 1 determined in embodiment 9 in mouse blood circulation inside body
In stability result figure;
Fig. 7 is the suppression tumour growth determined in embodiment 10 to antineoplastic polypeptide Nano medication prepared by embodiment 1
Design sketch.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In the present embodiment, antineoplastic polypeptide Nano medication is prepared by the following method, methods described is:
From M.Lourdes Ponce etc., Cancer Research, 2003,63:The suppression tumour that 5060-5064 is provided
New vessels generate and the C16Y polypeptides of tumour growth (sequence since aminoterminal is:Aspartic acid-phenylalanine-rely ammonia
Acid-Ile-Phe-alanine-valine-Tyrosine-Isoleucine-lysine-Tyr-Arg) as parent
Water-based antineoplastic polypeptide, according to document (Lihong Liu etc., Nature Nanotechnology, 2009,4:457-463 and
Ying Zhao etc., J Control Release, 2014,177:Solid-phase synthesis 11-19) provided and peptide purification side
Method, the hydrophobic peptides of 8 leucines and 2 glycine compositions are connected on antineoplastic polypeptide C16Y, and it is more in hydrophobicity
The tripeptides that is formed by 3 lysines of amino terminal connection of peptide, then pass through amino on lysine (including terminal amino group and side
Chain amino) 4 3- (diethylamino) propyl dithiocarbamate isocyanate function molecules (DEAP) of connection, obtaining coupling has sour response
The amphipathic antineoplastic polypeptide of functional molecular.The building-up process is as follows:
(1) it is used to synthesize C16Y amino acid and leucine, the terminal amino group of glycine and lysine by Fmoc (tablets held before the breast by officials
Methoxycarbonyl group) protection, the lysine side chain amino groups for synthesizing C16Y are protected by Boc (tertbutyloxycarbonyl), for coupling function
The amino of the lysine side-chain of molecule is protected by CBZ (benzyloxycarbonyl group), and it is limited to be purchased from gill biochemical (Shanghai) with upper amino acid
Company.
(2) carboxyl and CLEAR- amide resins for making C16Y carboxyl-terminus amino acids (introduce the mesh of CLEAR- amide resins
Be to fix the carboxyl terminal of amino acid, to make its aminoterminal react) amino terminal connection, pass through 20% piperazine
Pyridine/DMF sloughs the Fmoc protection groups on the amino acid to expose amino, is then incorporated in resin with this
On amino acid as amino group, with excessive next amino acid reaction spreading peptide chain containing activated carboxyl, repeat above-mentioned
Operation finishes up to all amino acid condensations, forms the protected amphipathic antineoplastic polypeptide of amino on peptide chain.
(3) amphipathic antineoplastic polypeptide is sloughed into Fmoc protection groups with 20% piperidines/DMF, with catalysis
Hydrogenolysis method sloughs CBZ protection groups, sour response functional molecular DEAP is reacted with de- de-protected amino, so as to by sour response
Functional molecular DEAP is connected on amphipathic antineoplastic polypeptide.
(4) peptide chain is cleaved from resin with the dichloromethane solution of high concentration trifluoroacetic acid, in C16Y fragments
Boc blocking groups will also remove simultaneously, and by the processing such as purifying, that is, obtaining coupling has DEAP amphipathic antineoplastic polypeptide.
(5) the amphipathic antineoplastic polypeptide that taking 0.5mg couplings has DEAP is dissolved in 10 μ L dimethyl sulfoxide (DMSO)s, is subsequently added into
PH value to 1mL is in 7.4 phosphate buffer, and mixed liquor is ultrasonically treated in the ultrasonic washing instrument that power is 600W
2min.After ultrasound, sample obtains antineoplastic polypeptide Nano medication system after 2h is stored at room temperature.Dimethyl in system
Sulfoxide is removed by being dialysed in pH 7.4 phosphate buffer.
Confirm that the coupling that the present embodiment obtains has by means such as high performance liquid chromatography and LC-MS spectrometries
The structure of DEAP amphipathic antineoplastic polypeptide is:C16Y- (dipeptides of Formation of glycine)-(octapeptide that leucine is formed)-(relies
The tripeptides that propylhomoserin is formed)-(DEAP)4, Fig. 1 is the high-efficient liquid phase chromatogram of antineoplastic polypeptide, and Fig. 2 is the antineoplastic polypeptide of synthesis
Mass spectrogram, appearance time, peak area, height and the content number at each peak in Fig. 1 high-efficient liquid phase chromatogram are summarized in table 1
According to.
Table 1
The peak that main peak 3 is the antineoplastic polypeptide synthesized is drawn by Fig. 1 and Fig. 2 interpretation of result, can be seen by the result of table 1
Go out, the antineoplastic polypeptide purity of synthesis is more than 90%.
Utilize transmission electron microscope (U.S. FEI, Tecnai G2 20 S-TWIN, 200kV) and laser particle analyzer (Britain
Malvern, Zetasizer Nano ZS90) form and particle diameter table are carried out to obtained antineoplastic polypeptide Nano medication system
Sign, as shown in figure 3, wherein Fig. 3 A are the transmission electron microscope picture of antineoplastic polypeptide Nano medication system, it can be seen that preparing
Obtained antineoplastic polypeptide Nano medication is spherical in shape, and granular size is more uniform;Fig. 3 B are grain size distribution, gained antineoplastic polypeptide
The particle diameter distribution of Nano medication is 15-60nm, and average grain diameter is about 30nm, and dispersion index (PDI) is 0.373, with electron microscope institute
The result measured is consistent.
Embodiment 2
In the present embodiment, by synthetic method and step same as Example 1, realize in antineoplastic polypeptide
3 isoleucines and 2 methionine and 1 lysine are coupled on C16Y, and in the terminal amino group and side-chain amino group of lysine
On be connected to DEAP molecules, having obtained coupling has DEAP amphipathic antineoplastic polypeptide.Through self assembly same as Example 1
Journey obtains antineoplastic polypeptide Nano medication system.
Confirm that the coupling that the present embodiment obtains has the amphipathic of DEAP to resist by means such as high performance liquid chromatography and mass spectrums
The structure of oncopeptide is:C16Y- (tripeptides that isoleucine is formed)-(dipeptides that methionine is formed)-lysine-(DEAP)2。
Form and grain are carried out to obtained antineoplastic polypeptide Nano medication system using transmission electron microscope and laser particle analyzer
Footpath characterizes, the results showed that the antineoplastic polypeptide Nano medication being prepared is spherical in shape, and granular size is more uniform, and antineoplastic polypeptide is received
The particle diameter distribution of rice medicine is 40-200nm, and average grain diameter is about 150nm, and dispersion index (PDI) is 0.368.
Embodiment 3
In the present embodiment, by synthetic method and step same as Example 1, realize in antineoplastic polypeptide
20 alanine and 5 lysines are coupled on C16Y, and DEAP is connected on the terminal amino group and side-chain amino group of lysine
Molecule, having obtained coupling has DEAP amphipathic antineoplastic polypeptide.Obtained through self assembling process same as Example 1 antitumor
Polypeptide nano drug system.
Confirm that the coupling that the present embodiment obtains has the amphipathic of DEAP to resist by means such as high performance liquid chromatography and mass spectrums
The structure of oncopeptide is:C16Y- (polypeptide that 20 alanine are formed)-(polypeptide that 5 lysine is formed)-(DEAP)6。
Form and grain are carried out to obtained antineoplastic polypeptide Nano medication system using transmission electron microscope and laser particle analyzer
Footpath characterizes, the results showed that the antineoplastic polypeptide Nano medication being prepared is spherical in shape, and granular size is more uniform, and antineoplastic polypeptide is received
The particle diameter distribution of rice medicine is 30-160nm, and average grain diameter is about 100.5nm, and dispersion index (PDI) is 0.324.
Embodiment 4
In the present embodiment, by synthetic method and step same as Example 1, realize in antineoplastic polypeptide
20 valines, 10 tyrosine and 5 lysines are coupled on C16Y, and on the terminal amino group and side-chain amino group of lysine
DEAP molecules are connected to, having obtained coupling has DEAP amphipathic antineoplastic polypeptide.Through self assembling process same as Example 1
Obtain antineoplastic polypeptide Nano medication system.
Confirm that coupling that the present embodiment obtains has that DEAP's is amphipathic antitumor more by means such as mass spectrum and nuclear-magnetisms
The structure of peptide is:C16Y- (polypeptide that 20 valines are formed)-(polypeptide that 10 tyrosine is formed)-(5 lysines are formed
Polypeptide)-(DEAP)6。
Form and grain are carried out to obtained antineoplastic polypeptide Nano medication system using transmission electron microscope and laser particle analyzer
Footpath characterizes, the results showed that the antineoplastic polypeptide Nano medication being prepared is spherical in shape, and granular size is more uniform, and antineoplastic polypeptide is received
The particle diameter distribution of rice medicine is 10-180nm, and average grain diameter is about 123.6nm, and dispersion index (PDI) is 0.348.
Embodiment 5
In the present embodiment, by synthetic method and step same as Example 1, realize in antineoplastic polypeptide
40 leucines and 4 lysines are coupled on C16Y, and DEAP is connected on the terminal amino group and side-chain amino group of lysine
Molecule, having obtained coupling has DEAP amphipathic antineoplastic polypeptide.Obtained through self assembling process same as Example 1 antitumor
Polypeptide nano drug system.
Confirm that coupling that the present embodiment obtains has that DEAP's is amphipathic antitumor more by means such as mass spectrum and nuclear-magnetisms
The structure of peptide is:C16Y- (polypeptide that 40 leucines are formed)-(4 lysines form polypeptide)-(DEAP)5。
Form and grain are carried out to obtained antineoplastic polypeptide Nano medication system using transmission electron microscope and laser particle analyzer
Footpath characterizes, the results showed that the antineoplastic polypeptide Nano medication being prepared is spherical in shape, and granular size is more uniform, and antineoplastic polypeptide is received
The particle diameter distribution of rice medicine is 10-120nm, and average grain diameter is about 78.6nm, and dispersion index (PDI) is 0.311.
Embodiment 6
In the present embodiment, by synthetic method and step same as Example 1, realize in document
(Stephanie Filleur etc., Cancer Research, 2005,65:5144-5152) provide containing 11 amino acid
It is coupled on the peptide T GA (polypeptide can suppress Tumor Angiongesis and tumour growth) of Pigment epitheliumderived factor
10 leucines and 3 glycine and 2 lysines, and it is connected to DEAP on the terminal amino group and side-chain amino group of lysine
Molecule, having obtained coupling has DEAP amphipathic antineoplastic polypeptide.Obtained through self assembling process same as Example 1 antitumor
Polypeptide nano drug system.
Form and grain are carried out to obtained antineoplastic polypeptide Nano medication system using transmission electron microscope and laser particle analyzer
Footpath characterizes, the results showed that the antineoplastic polypeptide Nano medication being prepared is spherical in shape, and granular size is more uniform, and antineoplastic polypeptide is received
The particle diameter distribution of rice medicine is 10-60nm, and average grain diameter is about 21.04, and dispersion index (PDI) is 0.292.
Embodiment 7
The present embodiment purpose in measure antineoplastic polypeptide Nano medication self-assembling nanoparticles in slightly acidic solution
Pattern and particle diameter.
The pH value of the antineoplastic polypeptide Nano medication system sample obtained in embodiment 1 is adjusted to 6.8, is stored at room temperature 2h
Afterwards, particle diameter distribution is determined by transmission electron microscope observing pattern and with laser particle analyzer.As shown in Figure 4 A, in an acidic solution, it is more
Peptide is without obvious nanometer spherical structure, as shown in Figure 4 B, particle diameter distribution 4-18nm, average grain diameter 7nm.In addition will be anti-swollen
The pH value of knurl polypeptide nano drug system sample has been obtained with pH value is adjusted when being separately adjusted to angularly 6.7,7.0,7.1 and 7.2
The result similar to 6.8, in an acidic solution, antineoplastic polypeptide Nano medication is no longer that nanometer is spherical to this explanation, and is due to
Sour response molecule is carried after positive charge so that nanometer spherical structure produces repulsive force so that medicine is no longer collected as nanosphere.
Embodiment 8
The present embodiment purpose is to determine antineoplastic polypeptide Nano medication self-assembling nanoparticles in vivo to acidic cancer
The response of environment.
The coupling for taking the step of 0.5mg embodiments 1 (4) to obtain has DEAP amphipathic antineoplastic polypeptide, and (DEAP- is amphipathic anti-
Oncopeptide), with 0.1mg tetramethylrhodamines -5- isothiocyanates fluorescence molecule and 0.1mg quencher molecule co-dissolves in 10
In μ L dimethyl sulfoxide (DMSO)s, be subsequently added into 1mL pH value be 7.4 phosphate buffer in, by mixed liquor in power be 600W
Ultrasonic washing instrument in be ultrasonically treated 2min.After ultrasound, sample centrifuges 5min after 2h is stored at room temperature, in 10000g,
Supernatant is taken to be contained the amphipathic antineoplastic polypeptide self-assembled nanometers of DEAP- of fluorescence molecule and quencher molecule simultaneously
Grain, the nano particle is the spherical structure that size is more uniform, stable after measured.
The nano particle for taking 100 μ L to prepare, is injected in tumor-bearing mice body at tail vein, in 1h, 3h and 5h petty action
Thing living imaging instrument (the Cambridge Research&Instrumentation, Maestro in the U.S.TM) the internal fluorescence point of detection
Cloth, as shown in figure 5, fluorescence signal is distributed mainly on tumor locus, antineoplastic polypeptide Nano medication prepared by this explanation present invention
Energy responds weakly acidic tumor environment and depolymerization discharges fluorescence molecule.
Embodiment 9
The present embodiment purpose is steady in blood circulation in measure antineoplastic polypeptide Nano medication self-assembling nanoparticles
It is qualitative.
It is measured using the antineoplastic polypeptide Nano medication (being abbreviated as DEAP-C16Y) prepared in embodiment 1, with C16Y
Polypeptide is control sample, respectively takes 1 μm of ol C16Y and DEAP-C16Y, and 3 μm of ol fluorescence molecule Cy5.5 is coupled to respectively
On the amino of C16Y and DEAP-C16Y peptide molecules, the polypeptide of coupling fluorescence molecule is obtained.Cy5.5 C16Y polypeptides will be coupled
The pH value for being directly dissolved in 1mL is in 7.4 phosphate buffer;The DEAP-C16Y for being coupled Cy5.5 is dissolved in 10 μ L diformazans
In base sulfoxide, the pH value for being subsequently added into 1mL is in 7.4 phosphate buffer, by mixed liquor in the ultrasound that power is 600W
2min is ultrasonically treated in ripple cleaning device, the DEAP-C16Y self-assembling polypeptide nanometers for being coupled fluorescence molecule are obtained after being stored at room temperature 2h
Particle.Dimethyl sulfoxide (DMSO) and unnecessary fluorescence molecule in system are removed by being dialysed in pH 7.4 phosphate buffer
Go.
C16Y the and DEAP-C16Y self-assembling nanoparticles of fluorescence molecule will be coupled, BALB/c is injected at tail vein
In Mice Body, the μ L of mouse blood 30 are taken at tail vein respectively in 1h, 3h, 5h, 8h, 12h and 24h equi-time point, in 4000g from
After heart 10min, supernatant is taken to obtain blood plasma.The fluorescence signal in blood plasma is detected using small animal living body imager, with injecting fluorescence
The C16Y groups of mark compare, as shown in fig. 6, in the blood plasma of the DEAP-C16Y self-assembling nanoparticles groups of injection fluorescence labeling
The time significantly extends existing for fluorescence signal, antineoplastic polypeptide Nano medication (DEAP-C16Y) ratio prepared by this explanation present invention
C16Y is more stable in blood circulation in vivo.
Embodiment 10
The purpose of the present embodiment is to test the effect that self-assembling polypeptide nano particle suppresses tumour growth.
It is measured using the antineoplastic polypeptide Nano medication (being abbreviated as DEAP-C16Y) prepared in embodiment 1, with C16Y
Polypeptide is control sample.BALB/c nude mices are inoculated with MDA-MB-231 breast cancer cells at mammary fat pad, treat tumour growth
It is 100mm to volume3When, tail vein injection neutral phosphate (PBS) buffer solution, C16Y or DEAP-C16Y, wherein C16Y are every
Once, DEAP-C16Y injections in every two days once once set one group with injection in every three days, and wherein C16Y polypeptides dosage is equal for its injection
For 6.5 μm of ol/kg, PBS is to inject once for every three days, every group of 5 mouse.After handling 14 days and continuing observation one week, by mouse
Put to death, take out tumor tissues, weigh knurl weight.As shown in fig. 7, DEAP-C16Y suppresses tumour growth when injecting one time within every two days
Most pronounced effects, hence it is evident that injection in three days every better than DEAP-C16Y once and C16Y injection tumour inhibiting rates once daily, and
It is suitable that every three days of DEAP-C16Y injects the tumour inhibiting rate once injected daily once with C16Y, this explanation using DEAP-C16Y and
When C16Y treats to tumour, to reach identical therapeutic effect, the contained C16Y dosage identical situation in per injection
Under, the single C16Y of multiple injection, and DEAP-C16Y injections in every three days are once, reduce times for spraying, this also side
Reflect when injecting single C16Y, it is unstable when being circulated in vivo due to C16Y and cause utilization ratio of drug low, it is of the invention
Anti-tumor nano medicine overcomes this defect well, has good application prospect.
Applicant states that the present invention illustrates the antineoplastic polypeptide Nano medication of the present invention and its system by above-described embodiment
Preparation Method and application, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention has to rely on above-described embodiment
It could implement.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to raw material selected by the present invention
Equivalence replacement and the addition of auxiliary element, the selection of concrete mode etc., all fall within protection scope of the present invention and open scope
Within.
Claims (4)
1. a kind of antineoplastic polypeptide Nano medication, it is characterised in that the antineoplastic polypeptide Nano medication includes amphipathic anti-swollen
Knurl polypeptide and the sour response functional molecular with the coupling of amphipathic antineoplastic polypeptide;
The amphipathic antineoplastic polypeptide includes the hydrophilic anti-tumor polypeptide being coupled together by amido link and hydrophobicity is more
Peptide;The sour response functional molecular is 3- (diethylamino) propyl dithiocarbamate isocyanates;
The structure of the antineoplastic polypeptide Nano medication is as follows:C16Y- (dipeptides of Formation of glycine)-(the eight of leucine formation
Peptide)-(tripeptides that lysine is formed)-(DEAP)4;
Wherein C16Y is hydrophilic anti-tumor polypeptide, and the octapeptide composition hydrophobicity that the dipeptides and leucine of Formation of glycine are formed is more
Peptide, DEAP represent 3- (diethylamino) propyl dithiocarbamate isocyanates.
2. antineoplastic polypeptide Nano medication according to claim 1, it is characterised in that the antineoplastic polypeptide Nano medication
Particle diameter be 10-200nm.
3. a kind of preparation method of antineoplastic polypeptide Nano medication according to claim 1 or 2, it is characterised in that described
Method is:Using amino acid as raw material, synthesizing amphipathic antineoplastic polypeptide molecule, then draw on amphipathic antineoplastic polypeptide molecule
Enter sour response functional molecular, then carry out being self-assembly of the antineoplastic polypeptide Nano medication;
The preparation method comprises the following steps:
(1) terminal amino group for the amino acid of Peptide systhesis is protected by Fmoc, for synthesis hydrophilic antineoplastic polypeptide
Lysine side chain amino groups are protected by Boc, and the amino for the lysine side-chain of coupling function molecule is protected by CBZ;
(2) terminal carboxyl group by the terminal amino group for the Amphiphilic peptide molecule to be synthesized by Fmoc first amino acid protected
It is connected with the amino terminal of CLEAR- amide resins, Fmoc protection groups is sloughed by 20% piperidines/DMF, so
The amino acid being incorporated in afterwards using this on resin connects as amino group, same excessive next amino acid reaction containing activated carboxyl
Long peptide chain, aforesaid operations is repeated until all amino acid condensations finish, amino is protected amphipathic anti-swollen on formation peptide chain
Knurl polypeptide;
(3) amphipathic antineoplastic polypeptide is sloughed into Fmoc protection groups with 20% piperidines/DMF, uses catalytic hydrogenolysis
Method sloughs CBZ protection groups, sour response functional molecular is reacted with de- de-protected amino, so as to by sour response functional molecular
It is connected on amphipathic antineoplastic polypeptide;
(4) peptide chain is cleaved from resin with the dichloromethane solution of high concentration trifluoroacetic acid, the Boc in C16Y fragments is protected
Shield group will also remove simultaneously, by purification process, that is, obtain being connected with the amphipathic antitumor more of sour response functional molecular
Peptide;
(5) the resulting amphipathic antineoplastic polypeptide for being connected with sour response functional molecular is carried out certainly in neutral water environment
Assembling property nanoparticle system, that is, obtain the antineoplastic polypeptide Nano medication.
4. application of the antineoplastic polypeptide Nano medication according to claim 1 or 2 in antineoplastic is prepared.
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CN114230634B (en) * | 2022-02-23 | 2022-05-06 | 中山大学孙逸仙纪念医院 | Acid-responsive anticancer peptide and preparation method thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101353647A (en) * | 2008-09-10 | 2009-01-28 | 中国人民解放军第三军医大学 | Simulating retrovirus of target tumor, and preparation and use thereof |
CN103467579A (en) * | 2013-08-26 | 2013-12-25 | 华南理工大学 | Cation amphipathic self-assembly nano antibacterial peptide and application thereof |
CN103665114A (en) * | 2012-09-25 | 2014-03-26 | 国家纳米科学中心 | Peptide and preparation method and use thereof, and pharmaceutical composition and preparation method of pharmaceutical composition |
-
2015
- 2015-06-16 CN CN201510334405.3A patent/CN104940949B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101353647A (en) * | 2008-09-10 | 2009-01-28 | 中国人民解放军第三军医大学 | Simulating retrovirus of target tumor, and preparation and use thereof |
CN103665114A (en) * | 2012-09-25 | 2014-03-26 | 国家纳米科学中心 | Peptide and preparation method and use thereof, and pharmaceutical composition and preparation method of pharmaceutical composition |
CN103467579A (en) * | 2013-08-26 | 2013-12-25 | 华南理工大学 | Cation amphipathic self-assembly nano antibacterial peptide and application thereof |
Non-Patent Citations (2)
Title |
---|
Self-assembled peptide nanoparticles as tumor microenvironment activatable probes for tumor targeting and imaging;Ying Zhao;《Journal of Controlled Release》;20140110;第177卷;第11页右栏第2段;第12页左栏第2段,右栏第2段和第3段;第13页图1和第14页右栏第1段 * |
Structural plasticity of a transmembrane peptide allows self-assembly into biologically active nanoparticles;Sergey G. Tarasova;《PNAS》;20110614;第108卷(第24期);摘要,第9798页左栏第1段,表1和第9801页右栏第1段;第9802页左栏第2段和第3段 * |
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