CN103656679B - A kind of preparation method of nano-particle - Google Patents
A kind of preparation method of nano-particle Download PDFInfo
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Abstract
The invention provides a kind of preparation method of nano-particle, comprise the following steps: 1) polycation macromolecule be dissolved in ultra-pure water or be mixed with said polycation solution without RNase enzyme water, nucleic acid drug is dissolved in ultra-pure water or is mixed with nucleic acid solution without RNase enzyme water; 2) join in described nucleic acid solution by described said polycation solution, evenly, incubated at room temperature, obtains polyplexes in piping and druming repeatedly; 3) block macromolecular be dissolved in ultra-pure water or be mixed with block macromolecular solution without in RNase enzyme water, described block macromolecular solution is slowly added to described step 2) in the polyplexes granule prepared, piping and druming evenly, leave standstill, make it fully wrap up, the nano-particle wrapped up by block macromolecular can be obtained.Compared with prior art, nano-particle prepared by the present invention can get rid of the obstacle that cationic particle circulates in vivo, improves body-internal-circulation efficiency, meanwhile, also can grafting targeting group, realize sick cell targeting in body, and effectively improve Targeting Effect.
Description
The divisional application that the application is application number is 201210163285.1, invention and created name is " preparation method of a kind of block macromolecular and synthetic method and nano-particle ", the applying date is the Chinese invention patent application on May 23rd, 2012.
Technical field
The present invention relates to biological technical field, particularly the preparation method of a kind of block macromolecular and synthetic method and nano-particle.
Background technology
SiRNA is the RNA molecule of one section of 21-25 base pair, is found in the mechanism that unicellular organism resists virus attack.Unicellular organism goes out one section of complementary with it siRNA for the mRNA sequent synthesis of intrusive viruses, initiatively in conjunction with mRNA, thus the copying of blocking virus.If this with pathogen gene one to one jamming exposure area be used for developing the medicine for the treatment of human diseases, will fundamentally change new drug discovery pattern traditional at present, bring the revolution of drug therapy techniques.SiRNA, because of the target spot specificity of its uniqueness, structure designability and metabolism safety, becomes the first candidate of the revolutionary new drug of the next generation that scientific circles generally have an optimistic view of.But, to so far, the shortage of delivery vehicles in an efficient body, but the druggability of siRNA is caused to be restricted (Castanotto, D. & Rossi, J.J.ThepromisesandpitfallsofRNA-interference-basedtherap eutics.Nature457,426-433 (2009) .).And focusing mostly in following a few class for the carrier of nucleic acid substances conveying at present: (1) physics imports: physics introductory technique is the method for gene introduction applied at first, namely adopt electroporation or particle bombardment technology etc., genes of interest is directly delivered in body or the method for target position.These methods are without the need to using genophore, but general very low, the complicated operation of transfection efficiency, also larger to the damage of tissue.(2) viral vector: at present for viral vector research more be slow virus carrier, adenovirus vector, although viral vector has higher in-vitro transfection active, but its immunogenicity is carry in body to bring huge potential safety hazard with easily leading mutagenic shortcoming.(3) non-virus carrier: the advantage of non-virus carrier is mainly, under the condition of transfection activity ensureing expection, greatly can reduce immunogenicity and many inflammatory reactions that viral vector brings, it is generally following several carrier design: (a) cationic-liposome; (b) polycation gene carrier.And study the modification more mainly concentrating on polycation gene carrier and cationic-liposome at present, make it the targeted being applicable to genetic stew.Cationic-liposome has higher inside and outside transfection activity, but, positive charge due to surface affects the normal distribution in its body, simultaneously, owing to selecting cation lipid, immunogenicity and inflammatory reaction also become one of inevitable shortcoming (Gao, K. & Huang in animal experiment, L.NonviralmethodsforsiRNAdelivery.Molecularpharmaceutics 6,651-658 (2008) .).Polycation gene carrier develops comparatively ripe at present, existing elaborate report in many documents.In addition, in gene delivery carrier, the RONDEL of comparatively successfully example CALANDOPharmaceuticals company employing
tMtechnology, with the cyclodextrin be connected with cationic gene carriers, 12 diamantane (obsolete) for carrier material, is that targeting group carries out package delivery to genetic stew with transferrins, with the treatment solid tumor that is administered systemically, at present just in the clinical I phase tests.But, be difficult to ensure that targeting group is on the surface of structure in structural design, and cyclodextrin can lower toxicity, but this structure increases and can reduce transfection activity, there is the design itself contradiction of a toxicity and transfection activity, simultaneously, it connects and is difficult to realize Non-toxic degraded (Davis in vivo, M.E.ThefirsttargeteddeliveryofsiRNAinhumansviaaself-asse mbling, cyclodextrinpolymer-basednanoparticle:fromconcepttoclini c.Molecularpharmaceutics6,659-668 (2009) .).
The nucleic acid drug carrier be used for the treatment of must complete following five steps with simple as far as possible structure: the A) cohesion of nucleic acid, B) nucleic acid is to targeting, the C of sick cell) endocytosis of nucleic acid is escaped, D) the nucleic acid release of starching at sick cell and E) the Non-toxic metabolism of carrier self.In prior art, A, C, D, E in the pH response degradable poly cation using human endogenous's property monomer and the known drug metabolite of safety to build and its simple structure effective implemention above-mentioned steps.But in the face of the multiformity (step B) of sick cell, its versatility but greatly discount.The self assembly of Polyplex particle surface film is the difficult problem not yet properly settled.Neutral phospholipid is not adsorbed in the chemical driving force on Polyplex surface.People's nineteen nineties such as Huang Lipopolyplex(LPD-II of building of the unit price negative charge phospholipid reported for the middle period) physical stability of skin covering of the surface is not good enough.Although the Lipopolyplex that two valency negative charge phospholipid of its nearest report build greatly improves skin covering of the surface physical stability, the too much negative charge of outer surface may affect the attachment of nano-particle for sick cell.Equally, much research and propose Poly-cation and the covalently bound polycationic gene nano grain surface positive charge that makes of PEG effectively shields, but, after covalently bound PEG, the compound ability of gene is but obviously affected.
Summary of the invention
The first object of the present invention is to provide a kind of block macromolecular, there is too much positive charge with the outer surface solving Polyplex particle surface film of the prior art thus affect the attachment of Polyplex granule for sick cell, and the technical matters of Targeting Effect difference.
The second object of the present invention is the synthetic method providing a kind of block macromolecular.
The third object of the present invention is the preparation method providing a kind of nano-particle.
The object of the invention is achieved through the following technical solutions:
A kind of block macromolecular, comprise the first block, the second block and the 3rd block that connect successively, described first block and described 3rd block are hydrophilic block, and described second block is hydrophobic block.
Preferably, described first block can be selected from PEG or PEO.
Preferably, the optional one from polylactic acid (PLA), PGA (PGA), polymeric polyglycolide-polylactide copolymer (PLGA) or polycaprolactone (PCL) of described second block.
Preferably, described 3rd block is selected from can provide the molecule of negative charge or can with the compound that the molecule covalent of negative charge can be provided to be connected by chemical reaction.
Preferably, describedly can comprise polyhydroxy molecule with the compound that the molecule covalent of negative charge can be provided to be connected by chemical reaction, described polyhydroxy molecule can be selected from the one of glycerol, ethylene glycol, fructose, glucose, lactose, maltose, sucrose or xylitol.
Preferably, the described molecule of negative charge that can provide comprises multi-carboxy compound, and described multi-carboxy compound can be selected from malic acid or citric acid.
Preferably, also comprise targeting group or fluorescence molecule, described targeting group or described fluorescence molecule are connected with described first block.
Preferably, described targeting group can be selected from one or more of albumen, polypeptide, antibody or micromolecule targeting group.
Preferably, described albumen is optional from transferrins or Asialoglycoprotein; Described polypeptide can be selected from RGD or insulin; Described micromolecule targeting group can be selected from the one of folic acid, biotin or galactose.
Preferably, described fluorescence molecule can be selected from the one of rhodamine, FITC, NBD, cy5.5 or FAM.
A synthetic method for block macromolecular, comprises the following steps:
1) take PEG as initiator, at Sn (oct)
2catalysis under, under 80 ~ 140 DEG C of conditions, cause ring-opening polymerisation in dry toluene, add caprolactone, 6 ~ 24h is carried out in reaction, synthesis PEG-PCL block;
2) take oxalyl chloride as bridging agent, first the PEG-PCL block synthesized in described step 1) is dissolved in anhydrous methylene chloride, again PEG-PCL block solution is slowly dropwise added in oxalyl chloride, dropping temperature is ice bath, room temperature is returned to after being added dropwise to complete, solvent and excessive oxalyl chloride is extracted after 2 ~ 12h, obtain intermediate product: the PEG-PCL that hydroxyl terminal activates through acyl chlorides, then intermediate product is dissolved in anhydrous methylene chloride, again intermediate product solution is dropwise added in a large amount of maltotrioses dissolved by DMF, dropping temperature is ice bath, room temperature is returned to after being added dropwise to complete, after 2 ~ 12h, decompression extracts solvent, with the bag filter dialysis removing maltotriose that molecular cut off is 1000 ~ 10000, dialysis time is 12 ~ 48h, pre-freeze, lyophilizing obtains PEG-PCL-Maltotriose block macromolecular.
A preparation method for nano-particle, comprises the following steps:
1) polycation macromolecule be dissolved in ultra-pure water or be mixed with said polycation solution without RNase enzyme water, nucleic acid drug being dissolved in ultra-pure water or being mixed with nucleic acid solution without RNase enzyme water;
2) join in described nucleic acid solution by described said polycation solution, evenly, incubated at room temperature, obtains polyplexes in piping and druming repeatedly;
3) above-mentioned block macromolecular be dissolved in ultra-pure water or be mixed with block macromolecular solution without in RNase enzyme water, described block macromolecular solution is slowly added to described step 2) in the polyplexes granule prepared, piping and druming evenly, leave standstill, make it fully wrap up, the nano-particle wrapped up by block macromolecular can be obtained.
Preferably, described nucleic acid drug is DNA or RNA.
Compared with prior art, block macromolecular of the present invention effectively can shield the electric charge on the cationic particle surfaces such as polycationic gene composite particles, get rid of the obstacle that cationic particle circulates in vivo, improve body-internal-circulation efficiency, simultaneously, also can grafting targeting group, realize sick cell targeting in body, and effectively improve Targeting Effect.
Accompanying drawing explanation
Fig. 1 is block macromolecular structure of the present invention and synthetic method schematic diagram;
Fig. 2 is the nuclear magnetic spectrogram of block macromolecular of the present invention;
Fig. 3 is the nuclear magnetic spectrogram of block macromolecular of the present invention;
Fig. 4 be nano-particle of the present invention prepare schematic diagram;
Fig. 5 be nano-particle of the present invention prepare schematic diagram;
Fig. 6 is the schematic diagram of the fluorescent co-location method structure verification of nano-particle of the present invention;
Fig. 7 is nano particle diameter of the present invention and Zeta potential variation diagram (wherein ABC refers to the block macromolecular without carboxylation, and ABCH refers to the block macromolecular of end through carboxylation);
Fig. 8 is that the cytotoxicity of block macromolecular of the present invention detects schematic diagram;
Fig. 9 is toxicity in vivo and the circulation result schematic diagram of nano-particle of the present invention;
Figure 10 is the tumor-targeting effect schematic diagram of block macromolecular of the present invention.
Detailed description of the invention
The present invention is described in detail below in conjunction with embodiment.Embodiment is implemented under premised on technical solution of the present invention, gives detailed embodiment and concrete operating process.But illustrated embodiment is not intended to limit protection scope of the present invention.
The physicochemical property characterizing method of the present invention to the nano-particle that block macromolecular and polyplexes are formed comprises: transmission electron microscope, dynamic light scattering and zeta point bit test.The DNA that the cellular uptake of the nano-particle prepared by this programme, gene transfection and small animal living body imaging are selected is green fluorescent protein plasmid; The cell that relevant toxicity test is selected is HepG2 cell, Hela cell, BRL-3A cell and SMMC-7721 cell; The animal that distribution in vivo is selected is BALB/c nude mice.
The synthetic method of embodiment 1 block macromolecular PEG-PCL-maltotriose-COOH
The synthetic route of block macromolecular PEG-PCL-maltotriose-COOH as shown in Figure 1.Whole reaction is carried out in the environment of anhydrous and oxygen-free, get a certain amount of PEG, polycaprolactone, stannous octoate in three-necked bottle, add the dry toluene of existing system, stirring reaction 24 hours at 120 DEG C, add ether sedimentation after having reacted, then add dichloromethane and dissolve, then use ether sedimentation, three times repeatedly, obtain PEG-PCL block macromolecular.
Then PEG-PCL is dissolved in dichloromethane, add excessive oxalul chloride in reaction bulb, under the condition of anhydrous and oxygen-free ice bath, PEG-PCL dropwise is joined in reaction bulb, room temperature is returned to after being added dropwise to complete, stir, after 12h, decompression extracts remaining oxalyl chloride, then add the PEG-PCL that dichloromethane dissolving end activates through acyl chlorides, under ice bath, end is added in excessive maltotriose slowly through the PEG-PCL dropwise that acyl chlorides activates and (be dissolved in a small amount of DMF), reaction is carried out under the condition of anhydrous and oxygen-free, room temperature is returned to after being added dropwise to complete, after 12h, decompression extracts solvent, in the bag filter of molecular cut off 7000, dialyse and remove unreacted maltotriose in 24 hours.Pre-freeze, then in freeze dryer, lyophilizing obtains white powder.
Obtained white powder is dissolved in anhydrous methylene chloride, join in excessive oxalyl chloride, slowly drip in ice bath, room temperature is returned to after being added dropwise to complete, stirring reaction, terminate rear decompression removing excessive oxalul chloride, then add water hydrolysis, in molecular cut off be 3500 retain a small amount of small molecule segment of centrifugal removing in centrifuge tube, lyophilizing obtains finished product.
Its
1h-NMR collection of illustrative plates is as shown in Figure 2,3:
1h-NMR collection of illustrative plates (DMSO-d
6, 400MHz): its peak ownership is shown in Fig. 2, Fig. 3, wherein, chemical shift is the peak of maltotriose hydroxyl hydrogen in 4-6 interval, and the peak of skeleton hydrogen on sugared ring is between chemical shift 3-4, cover by high molecular peak, so the judgement using the hydroxyl peak of maltotriose as synthesis result.Through the block macromolecular maltotriose of carboxylation hydroxyl peak partial disappearance or weaken, indicating section hydroxyl is by carboxyl substituted.
The preparation of embodiment 2 nano-particle
Get a certain amount of polycation macromolecule (for PEI) and plasmid DNA, owing to investigating nanoparticle structure and electron screening situation, therefore select mass ratio 1:5(pDNA:PEI) be prepared into polyplexes sample, then add block macromolecular, abundant compound.Concrete steps are shown in Fig. 4,5.
The sign of embodiment 3 nano-particle
According to nano-particle prepared by above-mentioned preparation method, logical fluorescent co-location characterizes it, specific practice is as follows, PEI and FITC is connected by covalent bond, and use the hydrophobic PCL block of nilered labelling block macromolecular simultaneously, the fluorescent grain of preparation is fixed in PVA hydrogel, and carries out crosslinking curing by " freezing-room temperature " repeatedly circulation, restriction granule two dimensional motion in the horizontal plane.Observed result is shown in Fig. 6, and red (nilered) and green (FITC) occurs in same position and overlap, and demonstrates the formation of nano-particle.
The particle diameter of embodiment 4 nano-particle and the sign of surface potential
By the mensuration of particle diameter and current potential, nano-particle result is characterized, the change of current potential, through parcel after-potential at about 0mV, simultaneously, macromolecule current potential without carboxylation does not obviously reduce, intuitively can prove that block macromolecular material of the present invention can shielded packaged food thus, and particle size distribution is relatively more even, the results are shown in Figure 7.
The Cytotoxic investigation of embodiment 5 block macromolecular
Adopt mtt assay to measure cytotoxicity, select HepG2, HeLa, BRL-3A, SMMC-7721 cell to investigate cytotoxicity, turn 96 porocyte plates with the cell density in 8000/hole, be placed in overnight incubation in 37 DEG C of 5% cell culture incubator.Preparation 1,2,3,4,6, the block macromolecular solution of the serial variable concentrations of 8mg/mL, every hole adds 100 μ L, diluent media is DMEM high glucose medium (serum-free is without phenol red), 96 porocyte plates are taken out from incubator, suck culture fluid, every hole 100 μ L phosphate buffered solution are rinsed once, then discard phosphate buffered solution, the block macromolecular solution of variable concentrations is joined in cell plates successively, parallel assay 6 holes.Be placed in cell culture incubator and cultivate 4 hours.Then, suck culture fluid, every hole 100 μ L phosphate buffered solution are rinsed once, then discard phosphate buffered solution, every hole adds 100 μ LDMEM high glucose mediums (serum-free is without phenol red) and 25 μ LMTT solution (5mg/mL), continues in incubator and cultivates.After 6 hours, suck culture fluid, every hole adds 100 μ L dimethyl sulfoxide, places abundant molten first and praises, and adopts multi-functional microplate reader working sample at the absorbance (with 630nm place for contrast) at 570nm and 630nm place.Known through test, block macromolecular material toxicity is lower, substantially nontoxic in Gamma Magnitude, the results are shown in Figure 8.
Embodiment 6 body-internal-circulation is investigated
According to nano-particle prepared by preceding method, respectively by polyplexes with nano-particle after wrapping up through mouse tail vein injection, single dose gives the complex of the pDNA plasmid of 1mg/kg body weight, its compositely proportional and method ditto described in, by the covalently bound labelling of block macromolecular fluorescent dye rhodamine, after tail vein injection, all there is acute death in the mice of polyplexes group, and it is steady for the Bearing Mice Life sign of the nano-particle of injection after designed block macromolecular parcel, through 24 as a child, cervical dislocation puts to death mice, core respectively, liver, spleen, lung, kidney carries out frozen section observation, to inject equal-volume normal saline group for blank, through fluorescence microscope, can see liver, spleen, all there is the gathering of partial particulate in lung place, the results are shown in Figure 9, prove after parcel, polyplexes surface charge obtains effective neutralization, achieve body-internal-circulation.
The cancer target of embodiment 7 block macromolecular is investigated
Select biotin to be that targeting group and block macromolecular carry out covalently bound, investigate its tumor-targeting, the BALB/c nude mice in 5 week age is raised one week at SPF level Animal House, then carries out Subcutaneous tumor inoculation with SMMC-7721 cell, treat that tumor grows to 200mm
3after, the gene composite of single dose injection pDNA, dosage 1mg/kg body weight, preparation method and ratio the same, the gene granule that the nano-particle preparing the block macromolecular parcel connected without targeting group respectively wraps up with the macromolecule taking biotin as targeting group, and carry out fluorescence tracing in vivo with the fluorescence block macromolecular that rhodamine is covalently bound, with the normal saline group of same volume for blank, carry out tumor-targeting investigation.Through mouse tail vein injection administration, the accumulation of mouse tumor part fluorescence volume is observed respectively at 4h, 12h, 24h after administration, granule prepared by investigation is at the Targeting Effect of tumor tissues, gene granule after targeting group connects is in the accumulation of tumor locus apparently higher than without Connecting groups, and concrete outcome is shown in Figure 10.
Be only several specific embodiments of the application above, but the application is not limited thereto, the changes that any person skilled in the art can think of, all should drops in the protection domain of the application.
Claims (2)
1. a preparation method for nano-particle, is characterized in that, comprises the following steps:
1) polycation macromolecule be dissolved in ultra-pure water or be mixed with said polycation solution without RNase enzyme water, nucleic acid drug being dissolved in ultra-pure water or being mixed with nucleic acid solution without RNase enzyme water;
2) join in described nucleic acid solution by described said polycation solution, evenly, incubated at room temperature, obtains polyplexes in piping and druming repeatedly;
3) block macromolecular be dissolved in ultra-pure water or be mixed with block macromolecular solution without in RNase enzyme water, described block macromolecular solution is slowly added to described step 2) in the polyplexes granule prepared, piping and druming evenly, leave standstill, make it fully wrap up, the nano-particle wrapped up by block macromolecular can be obtained;
Wherein, described block macromolecular comprises the first block, the second block and the 3rd block that connect successively, and described first block and described 3rd block are hydrophilic block, and described second block is hydrophobic block;
The synthetic method of described block macromolecular comprises the following steps:
1) take PEG as initiator, at Sn (oct)
2catalysis under, under 80 ~ 140 DEG C of conditions, cause ring-opening polymerisation in dry toluene, add caprolactone, 6 ~ 24h is carried out in reaction, synthesis PEG-PCL block;
2) take oxalyl chloride as bridging agent, first by described step 1) in synthesis PEG-PCL block be dissolved in anhydrous methylene chloride, again PEG-PCL block solution is slowly dropwise added in oxalyl chloride, the temperature conditions dripped is ice bath, room temperature is returned to after being added dropwise to complete, solvent and excessive oxalyl chloride is extracted after 2 ~ 12h, obtain intermediate product: the PEG-PCL that hydroxyl terminal activates through acyl chlorides, then intermediate product is dissolved in anhydrous methylene chloride, again intermediate product solution is dropwise added in a large amount of maltotrioses dissolved by DMF, the temperature conditions dripped is ice bath, room temperature is returned to after being added dropwise to complete, after 2 ~ 12h, decompression extracts solvent, with the bag filter dialysis removing maltotriose that molecular cut off is 1000 ~ 10000, dialysis time is 12 ~ 48h, pre-freeze, lyophilizing obtains PEG-PCL-Maltotriose block macromolecular.
2. the preparation method of nano-particle as claimed in claim 1, it is characterized in that, described nucleic acid drug is DNA or RNA.
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| WO2001074413A1 (en) * | 2000-04-04 | 2001-10-11 | Boston Scientific Limited | Medical devices suitable for gene therapy regimens |
| CN1324374A (en) * | 1998-10-01 | 2001-11-28 | 麦克罗梅德公司 | Biodegradable low molecular weight triblock polyester polyethylene glocol copolymers having reverse thermal gelation properties |
| CN102083972A (en) * | 2008-01-25 | 2011-06-01 | 金拓 | Polycationic gene carriers formed of endogenous amino group-bearing monomers |
| CN102443169A (en) * | 2011-10-14 | 2012-05-09 | 上海交通大学 | Preparation process of ammonia-ester-bond cross-linked poly(ethylene imine) polycation carrier |
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| CN1324374A (en) * | 1998-10-01 | 2001-11-28 | 麦克罗梅德公司 | Biodegradable low molecular weight triblock polyester polyethylene glocol copolymers having reverse thermal gelation properties |
| WO2001074413A1 (en) * | 2000-04-04 | 2001-10-11 | Boston Scientific Limited | Medical devices suitable for gene therapy regimens |
| CN102083972A (en) * | 2008-01-25 | 2011-06-01 | 金拓 | Polycationic gene carriers formed of endogenous amino group-bearing monomers |
| CN102443169A (en) * | 2011-10-14 | 2012-05-09 | 上海交通大学 | Preparation process of ammonia-ester-bond cross-linked poly(ethylene imine) polycation carrier |
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