CN107266384B - N- carboxyl inner-acid anhydride monomer and polyaminoacid based on 2- aminohexadecanoic acid and preparation method thereof - Google Patents
N- carboxyl inner-acid anhydride monomer and polyaminoacid based on 2- aminohexadecanoic acid and preparation method thereof Download PDFInfo
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- CN107266384B CN107266384B CN201710517904.5A CN201710517904A CN107266384B CN 107266384 B CN107266384 B CN 107266384B CN 201710517904 A CN201710517904 A CN 201710517904A CN 107266384 B CN107266384 B CN 107266384B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
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- A—HUMAN NECESSITIES
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/40—Polyamides containing oxygen in the form of ether groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
Abstract
The N- carboxyl inner-acid anhydride monomer and polyaminoacid that the invention discloses a kind of based on 2- aminohexadecanoic acid and preparation method thereof.2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride monomer is prepared first, polymer is prepared by monomer again, resulting polymers molecular weight distribution is relatively narrow and has excellent biocompatibility, it can be used for controlled drug delivery systems, stablize long circulating in the polymer micelle and polymer vesicle Nano medication support of the cRGD modification of preparation, it is enriched in tumor tissues height and efficiently enters cell, drug is released in the cell, cancer cell is specifically efficiently killed, effectively inhibits subcutaneous and in situ tumor growth without causing apparent toxic side effect.
Description
Technical field
The present invention relates to a kind of biodegradable materials based on 2- aminohexadecanoic acid, and in particular to a kind of 2- amino ten
Six alkanoic acid-N- carboxyl inner-acid anhydrides and its synthesis, and the polymerization by its ring-opening polymerisation polymer prepared and polymer preparation
Object micella and vesica.
Background technique
Polyaminoacid is controllable and wide due to lower with immunogenicity, good degradation property and mechanical performance and performance
It is general to be applied to the fields such as medicine controlled releasing, organizational project and regenerative medicine.But it is polymerize by a-amino acid-N- carboxyl inner-acid anhydride
Obtained hydrophobic polyamino acids (such as: poly- leucine, polyphenylalanine, poly- isoleucine and poly- methionine etc.) are organic molten
Dissolubility in agent is very poor, and then leads to polymerize that uncontrollable, resulting polymers molecular weight is smaller.So researcher is usually logical
Later the mode modified modifies hydrophobicity base in the side chain of the hydrophilic polymers such as polyglutamic acid, polylysine or poly-aspartate
Group is to obtain hydrophobic polymer blocks.But this mode will generally pass through the processes such as a series of protection and deprotection,
Lower so as to cause ultimate yield, consuming time is long for synthesis.
It is therefore desirable to which studying synthesis not only has strong-hydrophobicity but also has the poly- amino of hydrophobicity of preferable solvent selection window
Acid；And these polyaminoacid have good solvent selectivity and synthesis controllability, and preparing resulting amphiphilic polymer can
The targeted therapy of the polymer micelle or vesica of target drug-carrying for tumour is prepared.
Summary of the invention
The object of the present invention is to provide a kind of 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride monomers and preparation method thereof, and
Block copolymer polyaminoacid is prepared by ring-opening polymerisation with 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride, these polymer energy
By being self-assembly of polymer micelle and polymer vesicle.
In order to achieve the above objectives, the technical solution adopted by the present invention is that: a kind of 2- amino hexadecane with Formulas I structure
Acid-N- carboxyl inner-acid anhydride:
Formula I.
The invention discloses the preparation methods of above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride, include the following steps, with
2- aminohexadecanoic acid, firpene, triphosgene are reactant, react in organic solvent such as anhydrous tetrahydro furan, institute is prepared
State 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride.
In above-mentioned technical proposal, the molar ratio of 2- aminohexadecanoic acid, firpene and triphosgene is 2: 4~6: 1~2；Institute
The time for stating reaction is 1~2 hour, and the temperature of reaction is 30~70 DEG C.Preferably, 2- aminohexadecanoic acid, australene and three
The molar ratio of phosgene is 2: 3: 1.
In above-mentioned technical proposal, specific reaction process is as follows:
2- aminohexadecanoic acid, triphosgene and australene are added in anhydrous tetrahydro furan, stirred evenly, at 50 DEG C
After reaction 1 hour, by concentrated by rotary evaporation after reaction solution cooled to room temperature, crude product then is obtained with petroleum ether precipitation；Again will
The anhydrous tetrahydrofuran of the crude product and petroleum ether recrystallize 2-3 times, finally obtain white powdery solids, as 2- amino
Hexadecanoic acid-N- carboxyl inner-acid anhydride (APA-NCA).
Above-mentioned preparation method can be expressed as follows:
The invention also discloses a kind of polyaminoacid, including are free of targeted molecular polyaminoacid or the poly- ammonia containing targeted molecular
Base acid；It is described without targeted molecular polyaminoacid by above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride in the presence of initiator
It is prepared；The polyaminoacid containing targeted molecular is by above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride in initiator and target
It is prepared in the presence of to molecule.
In polyaminoacid molecular structure prepared by the present invention, the molecular weight of initiator segment is 2000~10000, (2- ammonia
Base hexadecanoic acid) segment molecular weight be 1000~50000.
The invention also discloses a kind of preparation methods of polyaminoacid, by sour in above-mentioned 2- aminohexadecanoic acid-N- carboxyl
Acid anhydride is prepared with initiator ring-opening polymerisation；Or by above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride initiator open loop
Targeted molecular is coupled after polymerization to be prepared.
Preferably, the invention discloses by above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride polyethylene glycol compound
For the block copolymer polyaminoacid of initiator polymerization preparation, wherein the molecular weight of polyethylene glycol segment is 2000-10000, is gathered
The molecular weight of (2- aminohexadecanoic acid) segment is 1000~50000.
The polyethylene glycol compound can be methoxy poly (ethylene glycol) amino, the methoxy poly (ethylene glycol) of different molecular weight
Silazane, acrylate polyethylene glycol amino, acrylate polyethylene glycol silazane, allyl polyglycol amino, allyl
Polyethylene glycol silazane, maleimide polyethylene glycol amino, maleimide polyethylene glycol silazane, nitrine polyethylene glycol ammonia
Base, nitrine polyethylene glycol silazane, alkynyl polyethylene glycol amino, alkynyl polyethylene glycol silazane, biotin polyethylene glycol amino,
Biotin polyethylene glycol silazane.Preferably, the block copolymer is used by above-mentioned 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride
Polyethylene glycol is that initiator is prepared through ring-opening polymerisation, and chemical structural formula is as shown in Formula II:
Formula II.
In above-mentioned technical proposal, R is the end functional groups of polyethylene glycol compound initiator, the preferably poly- second two of the present invention
Alcohol amino initiator.Molecular formula is shown in formula III:
Formula III
Wherein, R is,,,Or。
The preparation process of above-mentioned polyaminoacid is in organic solvent such as N,N-dimethylformamide (DMF), methylene chloride
(DCM), it is carried out in chloroform, tetrahydrofuran (THF), the preferred n,N-Dimethylformamide of the present invention makees solvent.
The end of the hydrophilic section PEG for the polymer that the present invention obtains can obtain containing target with the selectively targeted molecule of chemical coupling
To molecule polyaminoacid, including small peptide (cRGD, cNGQ, CC-9, CPP33, CPP44 etc.), small molecule targeted molecular (folic acid, fennel
Fragrant amide etc.), antibody and antibody fragment, polysaccharide and monosaccharide etc..
Polymer prepared by the present invention can be applied to prepare polymer nanostructures, including polymer micelle and polymeric bladder
Bubble, and drug can be contained, Nano medication is obtained, in conjunction with decentralized medium such as buffer, obtains Nano medication system.
The invention also discloses a kind of polymer nanostructures and preparation method thereof, are free of the poly- amino of targeted molecular by above-mentioned
Acid and/or polyaminoacid containing targeted molecular are prepared；Or it is received above-mentioned without what targeted molecular polyaminoacid was prepared
It is coupled targeted molecular again after rice structure, the polymer nanostructures are prepared.
The invention also discloses a kind of Nano medication, including above-mentioned polymer nanostructures and drug, including polypeptide and
Pharmaceutical grade protein, hydrophobicity chemical drug and hydrophily chemical drug.
The invention also discloses a kind of preparation method of Nano medication, by it is above-mentioned without targeted molecular polyaminoacid and/or
Polyaminoacid containing targeted molecular, medicine preparation obtain the Nano medication；Or it is above-mentioned without targeted molecular polyaminoacid with
It is coupled targeted molecular again after the medicament-carried nano structure that medicine preparation obtains, the Nano medication is prepared.
The invention also discloses a kind of Nano medication systems and preparation method thereof, including above-mentioned Nano medication and dispersion to be situated between
Matter；Above-mentioned Nano medication and decentralized medium are mixed, the Nano medication system is obtained；Decentralized medium can for buffer or
Person's physiological saline etc..
The invention also discloses 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride, polyaminoacid, polymer nanostructures or
Nano medication application in preparation of anti-tumor drugs.
Polymer of the invention has suitable hydrophobe ratio, therefore a system can be prepared by solvent displacement
Column size controllable polymer micelle and polymer vesicle.Specific preparation method can be with are as follows:
Polymer micelle and vesica are prepared by solvent displacement.Dissolve a polymer in N,N-dimethylformamide
(DMF) or in tetrahydrofuran (THF), then polymer solution is added drop-wise to dropwise in water either PB, finally with retention molecule
Partial size can be obtained in the polymer micelle or vesica of 50-200 nm for 7000 bag filter dialysis removing organic solvent in amount.It can
Selectively targeted polymer micelle or vesica is prepared by the ratio for adjusting above-mentioned targeting and non-targeted polymer.Target
Introducing to molecule can also be realized, such as in micella after polymer micelle or vesica prepare by post-decoration method
Or the end PEG of vesicle surface introduces small peptide (cRGD, cNGQ, CC-9, CPP33, CPP44 etc.), small molecule targeted molecular (folic acid,
Anisamide etc.), antibody and antibody fragment, polysaccharide and monosaccharide etc..
Due to the application of above-mentioned technical proposal, compared with the prior art, the invention has the following advantages:
A-amino acid-N- carboxyl inner-acid anhydride prepared by the present invention is a kind of long chain lipid inner-acid anhydride monomer, can be by opening
Cyclopolymerization obtains the controllable polyester peptide of performance, such polyaminoacid has broader solvent compared to other hydrophobic polyamino acids
Select window and better dissolubility；
The present invention using polyethylene glycol is initiator, obtains by ring-opening polymerisation that molecular weight is controllable, molecular weight distribution is relatively narrow
Polymer enriches the type of amphiphilic biocompatible polymer；
Polymer disclosed by the invention have excellent biocompatibility, can prepare (cancer target) polymer micelle and
Vesica can be used for the efficient loading of peptide and protein drug, hydrophobicity chemical drug and hydrophily chemical drug；
Polyaminoacid disclosed by the invention is a kind of polyester peptide, can assemble and form nanostructure, while can load hydrophobicity
Chemical drug (such as Irinotecan) a variety of drugs are used for the treatment of kinds cancer, are also used as a kind of auxiliary material and are linked on antigen to use
In the preparation of anti-cancer vaccine, a nanometer medical research field can be widely applied to；
Preparation method of the present invention is simple, raw materials used from a wealth of sources, to have a good application prospect.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum of APA-NCA and nuclear-magnetism carbon spectrogram in embodiment one；
Fig. 2 is PEG in embodiment two5k-b-PAPA3.5kNucleus magnetic hydrogen spectrum figure；
Fig. 3 is AA-PEG in embodiment three6k-b-PAPA4.2kNucleus magnetic hydrogen spectrum figure；
Fig. 4 is cRGD-PEG in embodiment three6k-b-PAPA4.2kNucleus magnetic hydrogen spectrum figure；
Fig. 5 is the particle diameter distribution (A) and transmitted electron for the polymer micelle that cRGD is modified in example IV and embodiment five
Microscope figure (B), serum stability (C) and release in vitro (D)；
Fig. 6 is the particle diameter distribution (A) and transmitted electron for the polymer vesicle that cRGD is modified in embodiment six and embodiment seven
Microscope figure (B), serum stability (C) and release in vitro (D)；
Fig. 7 is that eight hollow polymer micella of embodiment is thin to L929 l cell and B16F10 murine melanoma
The cytotoxicity result figure (B) of born of the same parents (A) and empty polymer vesicle to L929 l cell and A549 human lung carcinoma cell；
Fig. 8 is that Docetaxel polymer micelle is carried in embodiment nine to the cell toxicant of B16F10 mouse melanin tumor cell
Property (A), and carry adriamycin polymer vesicle to the cytotoxicity (B) of A549 human lung carcinoma cell；
Fig. 9 be in embodiment ten polymer micelle (A) and vesica (B) in the intracorporal blood circulation result of study figure of mouse；
Figure 10 is 11 drug-carrying polymer micelle of embodiment in the intracorporal biology point of lotus B16F10 murine melanoma mouse
Cloth result of study figure (A) and drug holding theca bubble are in the intracorporal biodistribution research result figure (B) of lotus A549-Luc human lung cancer mouse；
Figure 11 is that the target polymer micella DTX-cRGD-PMs of DTX is carried in embodiment 12 in lotus mouse B16F10 black
The plain intracorporal tumor suppression situation map of tumor C57/BL6 mouse, wherein A is tumor growth curve, and B is tumour picture after mouse treatment, and C is
Changes of weight, D curve for survival；
Figure 12 is that the target polymer vesica Dox-cRGD-LPPs of Dox is carried in embodiment 13 in lotus people's A549-Luc lung
The intracorporal tumor suppression situation map of cancer in situ tumor nude mice, wherein A is tumor growth curve, and B is mouse weight variation, and C is bent for survival
Line.
Specific embodiment
With reference to the accompanying drawing and embodiment the invention will be further described:
The synthesis of one 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride (APA-NCA) of embodiment
(1) the 2- aminohexadecanoic acid accurately weighed (3 g, 11 mmol) is placed in three handled by anhydrous and oxygen-free
In neck round-bottom flask, anhydrous THF(100 mL is added), reaction system is placed in 50 DEG C of oil bath and is stirred evenly, then by solid
Triphosgene (1.64 g, 5.5 mmol) and australene (α-pinene, 2.7 mL, 16.5 mmol) are added in reaction solution；Reaction 1
With by concentrated by rotary evaporation after reaction solution cooled to room temperature after h, APA-NCA crude product is obtained with petroleum ether precipitation later；Again will
Crude product is dissolved in THF, is then spin-dried for solution, obtains the product of white, then recrystallized three times with anhydrous THF and petroleum ether,
Finally obtaining solid in the powder of brilliant white is APA-NCA(1.65 g, yield 50%).
APA-NCA nuclear-magnetism characterization is shown in attached drawing 1,1H NMR (400 MHz, DMSO-d 6 ): δ 9.07 (s, 1 H, -
CHNHCO-), 4.41 (m, 1 H, -COCHNH-), 1.65 (d, 2 H, -CH2CH2CH-), 1.29 (d, 2 H, -
CH2CH2CH3-), 0.84 (t, 3 H, -CH2CH3); 13C NMR (100 MHz, DMSO-d 6 ): δ 171.66,
151.96, 57.04, 31.33, 30.95, 29.06, 28.91, 28.76, 28.43, 24.26, 22.12, 13.93;
The elemental analysis of APA-NCA be C, 68.65; H, 10.51;N, 4.71 (it is theoretical: C, 68.37; H, 10.07; N,
4.65).Mass spectrum: [M+Na]+320.2202；It is (theoretical: 320.2205).
Two PEG- of embodimentbThe preparation of-PAPA polyamino acid block copolymer
The present invention is prepared for different poly- of two kinds of PAPA chain lengths using Amino End Group polyethylene glycol as initiator, by ring-opening polymerisation
Close object PEG-b-PAPA.To synthesize PEG5k-b-PAPA3.5kFor: in N2Under environment, by macromole evocating agent polyethylene glycol amino
(M n =5000 g/mL, 100 mg, 0.02 mmol) DMF solution be added in closed reactor, under stirring conditions will
APA-NCA(94 mg, 0.32 mmol) DMF solution be added closed reactor, 48 h are reacted in 35 DEG C of constant temperature oil bath extremely
APA-NCA monomer polymerize completely (to reaction infrared monitoring, 1841 cm of carbonyl absorption peak of APA-NCA monomer acid anhydrides-1Disappear
It loses, shows that polymerization is complete)；Polymer solution precipitates in no water-ice ether, arrives product by what filtering, normal-temperature vacuum were dried
PEG5k-b-PAPA3.5k.Yield: 91%.PEG-bThe nuclear-magnetism characterization of-PAPA block copolymer is shown in attached drawing 2.By changing initiator
With monomeric charge ratio, the polymer (table 1) of different molecular weight and composition can conveniently be prepared.Meanwhile PAPA polyaminoacid is equal
Polymers and PEG-b- PAPA copolymer has shown good dissolubility (table 2) in chloroform and tetrahydrofuran solvent.
The characterization of 1 polyamino acid copolymer of table
A: it uses1The calculated result of H NMR analysis end group；The calculated result of b:GPC.
The deliquescent characterization of 2 polyaminoacid of table
| Solvent | PAPA | PEG5K-b-PAPA3.5K | PEG5K-b-PAPA9.8K |
| Chloroform | +++ | +++ | +++ |
| Tetrahydrofuran | ++ | ++ | ++ |
| N,N-dimethylformamide | - | + | - |
| Dimethyl sulfoxide | - | - | - |
| Acetone | - | - | - |
+++: very good dissolving;++: good dissolving;+: it can dissolve under certain condition;: it is insoluble.
The PEG- of three cRGD of embodiment modificationb- PAPA polymer (cRGD-PEG-b- PAPA) synthesis
The present invention has synthesized two kinds of different cRGD-PEG- of PAPA chain lengthb- PAPA polymer.To synthesize cRGD-PEG6k-b-PAPA4.2kFor: the polyethylene glycol amino (AA-PEG-NH modified with acrylic acid2,MThe g/mol of w=6000) it is used as macromolecular
Then initiator prepares polymer by two method of embodiment.CRGD-PEG is prepared in two steps6k-b-PAPA4.2k.Firstly, AA-
PEG6k-b-PAPA4.2kThe preparation of polymer: in N2Under environment, by macromole evocating agent polyalkylene glycol acrylate amino (M n =
6000 g/mol, 100 mg, 0.0167 mmol) DMF solution be added in closed reactor, under stirring conditions will
APA-NCA(79.4 mg, 0.267 mmol) DMF solution be added closed reactor, react 48 in 35 DEG C of constant temperature oil bath
H polymerize completely (to reaction infrared monitoring, 1841 cm of carbonyl absorption peak of APA-NCA monomer acid anhydrides to APA-NCA monomer-1Disappear
It loses, shows that polymerization is complete)；Polymer solution precipitates in no water-ice ether, arrives product by what filtering, normal-temperature vacuum were dried
AA-PEG6k-b-PAPA4.2k。AA-PEG6k-b-PAPA4.2kThe nuclear-magnetism characterization of block copolymer is shown in attached drawing 3.Then, pass through luminous point
Hit chemical method preparation cRGD-PEG6k-b-PAPA4.2k.In N2Above-mentioned polymer is dissolved in DMF under environment, then by cRGD-SH and
Photoinitiator I2959 is added in polymer solution；Then reaction is transferred in ultra-violet curing case under condition of ice bath in 365 nm
Ultraviolet light in react 20 minutes.After reaction, by polymer solution molecular cut off be 3500 bag filter in DMF
Dialyse 24 h, changes saturating 48 h of distilled water later, and finally freeze-drying obtains white solid.Yield: 83%.cRGD-PEG6k-b-
PAPA4.2kThe nuclear-magnetism characterization of block copolymer is shown in attached drawing 4.
The reaction of embodiment two and embodiment three can be expressed as follows, and A is embodiment two, and B is embodiment three.
Example IV PEG-bThe preparation of-PAPA polymer micelle
Under stirring, PB buffer solution or ultrapure water are dripped into PEG dropwise5k-b-PAPA3.5kN, N- dimethyl methyl
In amide (DMF) solution, the above-mentioned solution of bag filter dialysis for being then 7000 with molecular cut off removes organic solvent, dialyses
Journey carries out in the PB buffer or pure water of pH=7.4.Finally, polymer is measured by dynamic light scattering particle size analyzer (DLS)
The size of micella is 78 nm, and particle diameter distribution is relatively narrow.
And the preparation of cRGD targeting micella is then by PEG5k-b-PAPA3.5kAnd cRGD-PEG6k-b-PAPA4.2kBy centainly rubbing
You are dissolved in 1 mL DMF ratio, are then made with above-mentioned dialysis.The PEG molecular weight of target polymer is than non-targeted polymerization
The PEG of object will be grown, to guarantee that targeted molecular can preferably be exposed to micellar surface.Polymer micelle surface cRGD density can pass through
Adjust the cRGD-PEG containing cRGD6k-b-PAPA4.2kThe ratio of polymer controls.With the cRGD-PEG for containing 20% molar concentration6k-b-PAPA4.2kMicella size obtained containing targeted molecular is smaller (80 nm), and particle diameter distribution is relatively narrow (Fig. 5 A).By Fig. 5 B it is found that
It is solid spherical structure that TEM, which measures the polymer micelle,.Moreover, polymer micelle in 10% fetal calf serum environment have compared with
Good stability (Fig. 5 C).
Five polymer micelle of embodiment loads Docetaxel and release in vitro
The preparation of carrier micelle is similar with the preparation method for preparing polymer micelle with solvent displacement.Specifically, will
mPEG5k-b-PAPA3.5kAnd cRGD-PEG6k-b-PAPA4.2k4:1 is dissolved in DMF (5 mg/mL) in molar ratio.By polymer
Solution and Docetaxel (DTX, 10 mg/mL, DMF) mixing are placed in ampoule, then PB(pH=7.4,10 mM) is slow
It rushes solution or ultrapure water to drip to dropwise wherein, the above-mentioned solution of bag filter dialysis for being then 7000 with molecular cut off removes organic
Solvent and free drug, dialysis procedure carry out in the PB buffer or pure water of pH=7.4.It is finally measured with DLS and carries medicine glue
The partial size of beam is 60 nm or so, and particle diameter distribution is in 0.18-0.19.The efficiency that contains of HPLC measurement DTX is 74%(table 3).It obtains
Carrier micelle be named as DTX-cRGD-PMs, indicate the drug contained be DTX, targeted molecular cRGD.
The extracorporeal releasing experiment of DTX shakes (200 rpm) progress in 37 DEG C of constant-temperature tables, and every group is done three Duplicate Samples.
The targeting micella of DTX is carried in PB (10 mM, pH 7.4), the concentration of micella is 0.2 mg/mL, and 0.5 mL is taken to be put into release
In bag filter (MWCO:12,000), 25 mL of dialysis medium of response is added in each test tube, takes out in predetermined time interval
5.0 mL bag filter external agencies are used as test, while 5.0 mL response medium is added into test tube.Solution is measured using HPLC
Drug concentration.Attached drawing 5D is the relationship of DTX cumulative release amount and time, and as can be seen from the figure carrier micelle can pass through diffusion
Effect release drug.
Table 3 carries the characterization of Docetaxel micella (theoretical drugloading rate is 15%)
A: it is measured by dynamic light scattering；B: it is measured by HPLC；C: it is measured by electrophoresis.
Six PEG- of embodimentbThe preparation of-PAPA polymer vesicle
Under stirring, by PEG5k-b-PAPA9.8kTHF solution dripped in PB buffer solution or ultrapure water dropwise, so
The above-mentioned solution of bag filter dialysis for being afterwards 7000 with molecular cut off removes organic solvent, and PB of the dialysis procedure in pH=7.4 is buffered
It is carried out in liquid or pure water.It finally, is 80 nm by the size that dynamic light scattering particle size analyzer (DLS) measures polymer vesicle,
Particle diameter distribution is relatively narrow.
And cRGD target polymer vesica is then by PEG5k-b-PAPA9.8kAnd cRGD-PEG6k-b-PAPA10kBy mole
It is dissolved in THF than 4:1, is made into the solution of 2 mg/mL.Polymer solution is dripped to dropwise in PB or pure water under stirring,
Then dialysis removes organic solvent.It is 80 nm by the size that dynamic light scattering particle size analyzer (DLS) measures polymer vesicle,
Particle diameter distribution is relatively narrow (Fig. 6 A).By Fig. 6 B it is found that it is hollow ball-shape structure that TEM, which measures polymer vesicle,.Moreover, polymer vesicle
It is still maintained in 10% fetal calf serum environment and stablizes (Fig. 6 C).
Seven polymer vesicle of embodiment carries hydrophilic medicament DOXHCl and release in vitro
By PEG5k-b-PAPA9.8kAnd cRGD-PEG6k-b-PAPA10k4:1 is dissolved in THF in molar ratio, is made into 2 mg/
The solution of mL.200 μ L of polymer solution is dripped to dropwise in the citrate buffer solution (10 mM, pH 4.0) of 800 μ L, so
Afterwards with oversaturated Na2HPO3PH is adjusted to 7.8 ~ 8.0, then DOXHCl is added in solution again, and is placed on 37 DEG C of shaking tables
It is shaken in (200 rpm) overnight；Finally dialyse in dialysis medium (PB, 10 mM, pH 7.4) 8 h, changes five dialyzates.It carries
The partial size of the polymer vesicle of the medicine (10 ~ 20 wt.%) of different proportion is in 80-90 nm, and particle diameter distribution is in 0.17-0.20.Fluorescence
The efficiency that contains that spectrometer measures DOXHCl is 68-84%, obtains Dox-cRGD-LPPs(table 4).DOXHCl's releases in vitro
Experiment is put with embodiment five.DOXHCl cumulative release amount and the relationship of time can be seen that DOXHCl can be by own
Diffusion cross-film discharges (Fig. 6 D).The PEG molecular weight of target polymer than non-targeted polymer PEG long, to guarantee target
The surface of polymer vesicle can be preferably exposed to molecule.The two can be prepared by different proportion mixing shows to have different targetings
The polymer micelle of molecular density.In the present invention, the targeting ratio of micelle volume and vesicle system preferentially selects 20 wt.%.
The characterization of the load adriablastina target vesica of table 4
A: it is measured by Fluorescence Spectrometer；B: it is measured by dynamic light scattering；C: it is measured by electrophoresis.
Eight mtt assay of embodiment tests the cytotoxicity of empty polymer micelle and vesica
Mtt assay uses mouse melanoma cells (B16F10) human lung carcinoma cell (A549) and mouse fibroblast cell (L929).
With 5 × 103By cell kind in 96 orifice plates, every 100 μ L of hole is supported after 24 hours to cell adherent 70% or so a/mL.Then, real
It tests in each hole of group and is separately added into the micella containing various concentration (0.1-1.0 mg/mL) or vesica sample (with the sky of example IV
For polymer micelle and the empty polymer vesicle of embodiment six), separately set cell blank control wells and culture medium blank well (multiple 4
Hole).After culture 24 hours, MTT(5.0 mg/mL is added in every hole) 10 μ L, 150 μ L are added in every hole after continuing culture 4 hours
Crystallization that DMSO dissolution generates, surveys absorbance value with microplate reader at 570 nm, with the zeroing of culture medium blank well, calculates cell
Survival rate.Attached drawing 7A is polymer micelle to the cytotoxicity result of L929 and B16F10, it can be seen that dense when polymer micelle
For degree from when 0.1 increasing to 1.0 mg/mL, the survival rate of B16F10 is still higher than 90%, illustrates that the polymer micelle has good biology
Compatibility.The measurement of the cytotoxicity of polymer vesicle is similar in this, sees attached drawing 7B, and the equal very little of toxicity has good biology
Compatibility.
Nine mtt assay of embodiment surveys drug-carrying polymer micelle to B16F10 melanoma cells and drug-carrying polymer vesica pair
The toxicity of A549 lung carcinoma cell
Test object be embodiment five DTX-cRGD-PMs and embodiment seven Dox-cRGD-LPPs, no targeting
DTX-PMs and free DTX, Dox-LPPs the and Lipo-DOX group difference of no targeting is as a control group.The culture and implementation of cell
Example eight is identical, and nanoparticle or drug with culture medium after cell co-culture 4 hours, is renewed continue that MTT is added after being incubated for 44 h, locates
Reason and measurement absorbance are the same as embodiment eight.Experimental result is referring to attached drawing 8.DTX-cRGD-PMs is thin to B16F10 as the result is shown by Fig. 8 A
Half lethal concentration (the IC of born of the same parents50) it is 0.15 μ g/mL, it is 2.6 times smaller than the half lethal concentration of DTX-PMs；Attached drawing 8B is drug holding theca bubble
Toxicity test to A549 cell is as a result, as can be seen from the figure Dox-cRGD-LPPs is to the half lethal concentration of A549 cell
15.17 μ g/mL are far below Lipo-Dox, 1 times smaller than the half lethal concentration of Dox-LPPs.Illustrate micella and vesica of the invention
Drug can be transmitted into the cell well, and effectively discharged, finally kill cancer cell, and target micella and targeting vesica
Effect it is more preferable.
The blood circulation of embodiment ten targeting and non-targeted micella and vesica
All zoopery operations meet University Of Suzhou's animal experimental center regulation.It is 18 ~ 20 grams of left sides that weight is selected in experiment
The right side, 4 ~ 6 week old Balb/C mouse.The micella PMs-Cy5 of Cy5 label is by PEG5k-b-PAPA3.5kAnd PEG5k-b-PAPA3.5k-Cy5
It is mixed with by 1:1, the micellar particle size for the Cy5 label that this ratio is formed is 60 nm, particle diameter distribution 0.19.cRGD-PMs-
Cy5 micella is by cRGD-PEG6k-b-PAPA4.2kAnd PEG5k-b-PAPA3.5k- Cy5 is mixed with by 1:1, the polymer of formation
Micellar particle size is 60 nm or so, particle diameter distribution 0.18.By PMs-Cy5 and cRGD-PMs-Cy5 with crossing tail vein injection to small
In mouse body (Cy5 concentration is 4 μM), about 10 μ L of blood is taken in 0,0.25,0.5,1,2,4,8,12 and 24 hour fixed point, passes through residual quantity
Method accurately calculates blood weight, then plus 100 μ L concentration are led to for 1% Qula and 600 μ L DMF extract 24 h；It is then centrifuged for
After (20000 rpm, 20 min), supernatant liquor is taken, the amount of each time point Cy5 is measured by Fluorescence Spectrometer.It is horizontal in Fig. 9 A
Coordinate is the time, and ordinate is the total Cy5 injection volume (ID %/g) of the Cy5 Zhan in every gram of blood.By Fig. 9 A it is found that targeting polymerization
Object micella, non-targeted polymer micelle are respectively 2.73 and 2.33 hours in mouse intracorporal elimination half-life period, so of the invention
Polymer micelle in Mice Body stablize, have longer cycle times.
It is same as above, Dox-LPPs and Dox-cRGD-LPPs is passed through into (the administration of DOX in tail vein injection to Mice Body
Amount is 10 mg/kg), about 10 μ L of blood is taken in 0,0.25,0.5,1,2,4,8,12 and 24 hour fixed point, it is accurate by difference assay
Blood weight is calculated, then plus 100 μ L concentration are led to for 1% Qula and 600 μ L DMF extract 24 h；It is then centrifuged for (20000
Rpm, 20 min) after, supernatant liquor is taken, the amount of each time point DOX is measured by Fluorescence Spectrometer.When abscissa is in Fig. 9 B
Between, ordinate is the total DOX injection volume (ID %/g) of the DOX Zhan in every gram of blood.By Fig. 9 B it is found that target polymer vesica,
Non-targeted polymer vesicle is respectively 3.74,3.33 hours in mouse intracorporal elimination half-life period, so polymer of the invention
Vesica is stablized in Mice Body, there is longer cycle times.
11 DTX-PMs and DTX-cRGD-PMs polymer micelle of embodiment in lotus B16F10 melanoma mouse and
Dox-LPPs and Dox-cRGD-LPPs polymer vesicle is distributed in the vivo biodistribution of the original position lotus people A549-Luc lung cancer in mice
Animal is with embodiment ten, in the black sub-cutaneous injections 8 × 10 of C57BL/67A B16F10 mouse melanoma cells, about
Tumor size is 200 mm after 7 ~ 8 days3Start to test when left and right.DTX-PMs and DTX-cRGD-PMs and free DTX are passed through
In tail vein injection to Mice Body (DTX:10 mg/kg), mouse is put to death after 6 h, by tumour and the heart, liver, spleen, lung and nephridial tissue
It takes out, the anhydrous methanol of 500 μ L is added after cleaning weighing, the extraction of 500 μ L anhydrous methanols is added after grinding by refiner
24 h.Finally, centrifugation (20000 rpm, 20 min), takes supernatant, the amount of DTX in all samples is surveyed with high performance liquid chromatography.
Abscissa is histoorgan in Figure 10 A, and ordinate is the total DTX injection volume (ID%/g) of DTX Zhan in every gram of tumour or tissue.
It is respectively 2.9,7.9 and 1.3 that DTX-PMs, DTX-cRGD-PMs and free DTX, which inject 6 hours DTX amounts in tumor accumulation,
ID%/g, DTX-cRGD-PMs are respectively 2.5 times and 5.5 times of DTX-PMs and DTX, illustrate that DTX-cRGD-PMs passes through active target
It is more to being enriched in tumor locus.
The lobe of the lung in-situ injection 8 × 10 on the left of nude mice7A A549-Luc human lung carcinoma cell, through mouse living body after about 10 days
It is 10 that imager, which detects mouse lung bioluminescence intensity,6When start to test.By Dox-LPPs, Dox-cRGD-LPPs and commercialization
Lipo-Dox puts to death mouse after 6 h by (DoxHCl:10 mg/kg) in tail vein injection to Mice Body, by mouse core,
Liver, spleen, lung and nephridial tissue are taken out, and the Qula that the concentration that 500 μ L are added after cleaning weighing is 1% leads to solution, are ground by refiner
500 μ L N,N-dimethylformamides are added after broken extracts 24 h.Finally, centrifugation (20000 rpm, 20 min), takes supernatant
Liquid surveys the amount of Dox in all samples with Fluorescence Spectrometer.In Figure 10 B abscissa be histoorgan, ordinate be every gram of tumour or
The total Dox injection volume (ID%/g) of Dox Zhan in tissue.Dox-LPPs, Dox-cRGD-LPPs and Lipo-Dox inject 6 hours after
The Dox amount of tumor accumulation is respectively 3.4,6.1 and 4.3 ID%/g, illustrates Dox-cRGD-LPPs by active targeting in tumour portion
Position enrichment is more.
More low dosage administrations of embodiment 12 DTX-cRGD-PMs and DTX-PMs and single high dose administration are in lotus
Tumor killing effect, changes of weight and survival rate in the mouse of B16F10 subcutaneous melanoma
The inoculation of tumour and tail vein administration are with embodiment 11, and after inoculation four days, tumor size is 30 ~ 50 mm3
When start to test.By DTX-cRGD-PMs (single-dose), DTX-cRGD-PMs (multi-dose 40&80 mg/
Kg), DTX-PMs, DTX and PBS were arrived at the 0th, 2,4,6 day (single-dose group was only given at the 0th day) by tail vein injection respectively
In Mice Body (DTX dose is 10 mg/kg).At 0 ~ 10 day, the weight and gross tumor volume of every two days measurement mouse, gross tumor volume
Calculation method: V=(L × W2)/2, (the wherein length and width that L, W are respectively tumour).The existence of continuous observation mouse is to 40
It.As shown in Figure 11, at the tenth day, DTX-cRGD-PMs treatment group tumors are significantly suppressed, and DTX-PMs group is swollen
Tumor has certain growth, and free DTX is not obvious the inhibitory effect of tumour；And for single-bolus high-dose administration group, 40 mg/
Kg group is bad to the inhibitory effect of tumour, and 80 mg/kg groups show excellent tumor killing effect, and each group tumor size photo
Further demonstrate the conclusion.And the weight of each treatment group mouse shows the mouse under this dosage without significant change
Well-tolerated, toxic side effect are low.In terms of the survival rate of mouse, DTX-cRGD-PMs(multi-dose), DTX-cRGD-PMs
(single-dose 40), DTX-cRGD-PMs(single-dose 80), the median survival of DTX-PMs, DTX and PBS group point
It Wei not 35 d, 13 d, 23 d, 27 d, 9 d, 9 d.
Tumor suppression of embodiment 13 DOX-cRGD-LPPs and DOX-LPPs in the mouse of the original position lotus A549-Luc lung cancer
Effect, changes of weight and survival rate
Animal injects 5 × 10 with embodiment 11, in the nude mice of 5 week old on the lobe of the lung of left side6A549-Luc human lung cancer
Cell can start to test when tumour fluorescence value is about 105 ~ 106 after about 2 ~ 3 weeks.By Dox-cRGD-LPPs, Dox-
LPPs, Lipo-Dox and PBS respectively the 0th, 4,8,12 day by tail vein injection to Mice Body (DOXHCl injection volume:
Dox-cRGD-LPPs, Dox-LPPs group are 10.0 mg/kg；Lipo-Dox group is 7.5 mg/kg).At the 0th ~ 20 day, every 4 days
The weight of mouse is weighed, and biodiversity resources are carried out to mouse, the size of tumour is monitored by fluorescent value.It can by Figure 12
Know, at the 20th day, Dox-cRGD-LPPs treatment group tumors were significantly suppressed, and Dox-LPPs and Lipo-Dox group
Tumour has certain growth.By observation, Dox-cRGD-LPPs, Dox-LPPs mouse survival intermediate value are respectively the left side 36d, 24 d
It is right.
With PEG3.5k-b-PAPA7k、PEG5k-b-PAPA13k、PEG7.5k-b-PAPA21k、PEG10k-b-PAPA50kBased on make
Standby polymer vesicle, target polymer vesica, the survival rate of test cell are both greater than 90%, and the equal very little of toxicity has good
Biocompatibility；The partial size of adriamycin polymer vesicle is carried in 80 rans, theory carries encapsulation rate when medicine is 20% and reaches 83%
More than；Half lethal concentration to A549 cell is 15 μ g/mL or so；It is small that 3.2 are both greater than in mouse intracorporal elimination half-life period
When；Dox amount after the injection of Dox-LPPs and Dox-cRGD-LPPs polymer vesicle Nano medication 6 hours in tumor accumulation is distinguished
Greater than 3.2 ID%/g, 6.0 ID%/g, mouse survival intermediate value is respectively 36d, 24 d or so.
With PEG10k-b-PAPA8k、PEG7.5k-b-PAPA6k、PEG5k-b-PAPA5k、PEG3.5k-b-PAPA4kBased on prepare
Polymer micelle, target polymer micella, the survival rate of test cell is both greater than 90%, and the equal very little of toxicity has good life
Object compatibility；The partial size of the polymer micelle of docetaxel is carried in 60 rans, theory carries encapsulation rate when medicine is 15% and reaches
70% or more；To the half lethal concentration (IC of B16F10 cell50) it is 0.15 μ g/mL or so；In mouse intracorporal elimination half-life period
Both greater than 2.2 hours；In tumor accumulation after the injection of DTX-PMs and DTX-cRGD-PMs polymer micelle Nano medication 6 hours
DTX amount is respectively greater than 2.8 ID%/g, 7.8 ID%/g, and mouse survival intermediate value is respectively 35d, 26 d or so.
Claims (9)
1. a kind of 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride with structure shown in formula I:
Formula I.
2. 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride according to claim 1, which is characterized in that the 2- amino 16
The preparation method of alkanoic acid-N- carboxyl inner-acid anhydride includes the following steps, using 2- aminohexadecanoic acid, firpene, triphosgene as reactant,
It reacts in organic solvent, the 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride is prepared.
3. a kind of polyaminoacid, which is characterized in that the polyaminoacid includes without targeted molecular polyaminoacid or containing targeting
Molecule polyaminoacid；The targeted molecular polyaminoacid that is free of is by 2- aminohexadecanoic acid-N- carboxyl described in claim 1
Acid anhydrides is prepared in the presence of initiator；The polyaminoacid containing targeted molecular is by 2- amino 16 described in claim 1
Alkanoic acid-N- carboxyl inner-acid anhydride is prepared in the presence of initiator and targeted molecular；The initiator is that polyethylene glycol amino draws
Send out agent.
4. polyaminoacid according to claim 3, which is characterized in that the polyaminoacid is by 2- ammonia described in claim 1
Base hexadecanoic acid-N- carboxyl inner-acid anhydride is prepared with initiator ring-opening polymerisation；Or by 2- amino ten described in claim 1
Targeted molecular is coupled after six alkanoic acid-N- carboxyl inner-acid anhydride initiator ring-opening polymerisations to be prepared.
5. a kind of polymer nanostructures, which is characterized in that the polymer nanostructures are free of target by as claimed in claim 3
It is prepared to molecule polyaminoacid and/or polyaminoacid containing targeted molecular；Or as claimed in claim 3 without targeting point
Sub- polyaminoacid, which is prepared after nanostructure, to be coupled targeted molecular again the polymer nanostructures is prepared.
6. a kind of Nano medication, which is characterized in that the Nano medication include polymer nanostructures described in claim 5 and
Drug.
7. a kind of preparation method of Nano medication, which is characterized in that be free of targeted molecular polyaminoacid by as claimed in claim 3
And/or polyaminoacid containing targeted molecular, medicine preparation obtain the Nano medication；Or target is free of as claimed in claim 3
It is coupled targeted molecular again after obtaining medicament-carried nano structure to molecule polyaminoacid and medicine preparation, the Nano medication is prepared.
8. a kind of Nano medication system, which is characterized in that the Nano medication system include Nano medication described in claim 6 with
And decentralized medium.
9. polyaminoacid, claim described in 2- aminohexadecanoic acid-N- carboxyl inner-acid anhydride, claim 3 described in claim 1
Nano medication application in preparation of anti-tumor drugs described in 5 polymer nanostructures or claim 6.
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