CN1683014A - Process for preparig dentritic poly lysine derivative carrier for gene therapy - Google Patents
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- CN1683014A CN1683014A CNA2005100162685A CN200510016268A CN1683014A CN 1683014 A CN1683014 A CN 1683014A CN A2005100162685 A CNA2005100162685 A CN A2005100162685A CN 200510016268 A CN200510016268 A CN 200510016268A CN 1683014 A CN1683014 A CN 1683014A
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Abstract
The preparation process of dentritic polylysine derivative includes the stepped repeated condensation reaction of fluorylmethoxylcarbonyl amino acid modified poly(4-hydroxymethylphenoxymethyl styrene) resin as solid phase synthesized medium and N, N-difluorylmethoxylcarbonyl lysine to produce 3G dentritic polylysine with protecting fluorylmethoxylcarbonyl radical; further reaction with carboxy radical containing compound to produce polylysine derivative resin with protecting radical; deprotection with piperidine/methane dichloride; cracking with trifluoroacetic acid to cut down the polylysine derivative from the resin; and precipitation in anhydrous ethyl ether to obtain the one-side branched polylysine derivative. The polylysine derivative thus prepared has high uniqueness and high biocompatibility, and may be used as nucleic acid carrying carrier for gene treating process and may be also used as carrier for antigen and diagnosis contrast.
Description
Technical field
The present invention relates to a kind of by aminoacid set out make up be used for gene therapy and biodegradable dendritic method, belong to the technology of preparing of non-viral gene treatment carrier.
Background technology
The gene therapy technology that the nineties grows up from last century has fundamentally changed the idea of traditional Drug therapy, and has brought hope for effecting a radical cure numerous single-gene disorder, tumor and heredopathias.Efficiently, An Quan gene therapy vector is a link primary in the gene therapy scheme.In the past in the quite a long time, be that the viral vector of representative plays a part very important in gene therapy always with retrovirus, adenovirus.1999, the important event of volunteer's death in the gene therapy process took place in the U.S., and the carrier of Shi Yonging was adenovirus vector at that time; After this similar situation has also taken place in France.The incident that these are a series of people have been produced for the safety of viral vector doubt, defectives such as the capacity that viral vector showed simultaneously is little, preparation difficulty, expense height have also limited its development.In this case, much more more and more the research of non-viral gene treatment carrier begin to be subjected to paying attention to.
Non-viral vector is a kind of controlled delivery of pharmaceutical agents release tech, and the therapeutic gene that utilizes synthetic or natural chemical compound will be considered as medicine imports target cell or tissue and expresses.Carrier commonly used comprises liposome, polymer, naked DNA etc.As a class non-viral gene delivery means commonly used in the research, polymer support many based on linear cationic polymer and by its surface amino groups with positive charge and the electrostatic attraction between the DNA negative charge make dna molecular be condensed into the complex (polyplex) of high stability, small particle diameter.This condensation that is caused by electrostatic interaction is regarded as the main means that plasmid is striden the film transportation always.Though the linear polymer carrier is more common in the laboratory research, its application clinically still rarely has report.Cause the one of the main reasons of this situation to be to there is certain molecular weight distribution, thereby caused the uncertainty on metabolic pathway and toxic difference and the pharmacology, thereby limited its application clinically.And dendritic has been avoided above-mentioned problem with its regular branching unit, exclusive synthesis mode, thereby shows huge medical application potentiality.People such as Denkewalter take the lead in from N
α, N
ε-two tertbutyloxycarbonyl lysines set out and adopt the liquid phase synthetic technology to obtain dendroid polylysine (US4,410,688).Soon, Dow chemical company also discloses the synthetic patent of dendroid polyaminoamide (PCT/US83/02052).People such as Haensel attempt being applied to cell transfecting process (Bioconjugate Chem, 4:372,1993) first.After this, people such as Szoka has announced that then the end modified Polyethylene Glycol of dendroid polyaminoamide, polysaccharide, small peptide promote the method (WO 95/02397) of nucleic acid transportation.Recently, U.S. Pat 2003/0096280 discloses avidin and the link coupled method of dendroid polyaminoamide.Handsome and rich cyclodextrin and the link coupled preparation technology of dendroid polyaminoamide of then having announced of basis history of horse arranged.Baidude has also reported the method (Macromolecules, 36:7100,2003) of liquid phase synthetic technology at dendroid polylysine surface coupling polysaccharide that adopt.Can improve the affinity of polymer/nucleic acid complexes and target cell and subcellular organelle thereof effectively by above-mentioned technological means, thereby realize high-throughout nucleic acid delivery.Fundamentally, high efficiency nucleic acid delivery is realized under less nucleic acid grain diameter often.And virus genomic efficient assembling shows, said process is a power-actuated result of multiple effect (Annu Rev Biochem, 67:1,1998), but not single electrostatic interaction.
Summary of the invention
The object of the present invention is to provide a kind of method of synthesizing the dendroid poly-D-lysine derivant that constitutes by highly branched polypeptide chain, unicity with polymer support molecule method for preparing, that pass through the unitary chemical modification preparation of top layer branch is higher, and has better biocompatibility, it can be used as the carrier of delivery nucleic acid substances in the gene therapy process, and the carrier that also can be used as antigen, diagnostic contrast agents is applied.
The present invention is realized that by following technical proposals a kind of preparation method that is used for the dendroid polylysine derivative carrier of gene therapy is characterized in that comprising following process,
(1) with volume ratio be 25～80% piperidines/dichloromethane solution with modify density be 0.02～4.0mmol/g the amino acid whose 4-hydroxymethyl of fluorenylmethyloxycarbonyl Phenoxymethyl polystyrene resin 4～40 ℃ down reaction sloughed fluorenylmethyloxycarbonyl (Fmoc) blocking group in 5～120 minutes, use dichloromethane and washing with alcohol to neutral then;
(2) the 4-hydroxymethyl Phenoxymethyl polystyrene resin of the modified amino acid of deprotection is joined by every gram resin add the following substances amount: 0.1～12mmol N
α, N
εIn-two fluorenylmethyloxycarbonyl lysines, 0.4～20ml dimethyl formamide (DMF) and 10～530mg N-hydroxybenzotriazole (HOBt) mixed solution, and then add 0.1～5ml 1,3-DIC (DIC) obtains contain the resin of generation polylysine with dichloromethane, washing with alcohol 4-40 ℃ of reaction after 2-96 hour; The resin that will contain generation polylysine then joins the synthetic resin that contains secondary polylysine, wherein N in the above-mentioned reactant liquor of preparing again
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.2～25mmol; The resin that contains secondary polylysine that obtains of reaction joins the synthetic resin that contains three generations's polylysine, wherein N in the reactant liquor of new preparation after dichloromethane, washing with alcohol
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.3～50mmol;
(3) be that three generations's polylysine resin reaction under 4～40 ℃ that 25～80% piperidines/dichloromethane solution and fluorenylmethyloxycarbonyl group protect was sloughed the fluorenylmethyloxycarbonyl blocking group in 5～120 minutes with volume ratio, use dichloromethane and washing with alcohol then to neutral; The resin of deprotection is joined by every gram resin adding following substances amount: in the carboxylic chemical compound of 0.4～40mmol, 1～20mlDMF and the 50～530mg HOBt mixed solution, and then add 0.3～6ml DIC, reacted 2-120 hour down at 4～40 ℃;
(4) volume ratio is trifluoroacetic acid/dichloromethane solution and the reaction 10-180min under 4～40 ℃ of the resin behind the deprotection of 0.5-5;
(5) at last with dichloromethane solution flushing resin several times, merger filtrate, rotary evaporation to volume no longer changes the back and adds a large amount of absolute ethers and centrifugal collection, and resultant precipitation is product.
In the above-mentioned building-up process on the resin the amino acid modified density of fluorenylmethyloxycarbonyl be 0.1～2.0mmol/g, N
α, N
ε-two fluorenylmethyloxycarbonyl lysine additions are every gram resin 0.4～10mmol, and the volume of DMF is every gram resin 1.0～12ml, and the consumption of HOBt is every gram resin 50～300mg, and the addition of DIC is every gram resin 0.2～6ml; N in synthetic two, three generations's polylysine resin process
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.6～20mmol; Piperidines and methylene chloride volume ratio is 30～70% in the deprotecting regent, and the deprotection process is carried out 20～80min under 15～30 ℃; The carboxylated compound addition was every gram resin 1～30mmol during surface branch elementary layer was modified, and the volume of DMF is every gram resin 2～14ml, and the consumption of HOBt is every gram resin 80～400mg, and the addition of DIC is every gram resin 0.5～5ml; In the product cutting process, trifluoroacetic acid is 0.8～3 with the methylene chloride volume ratio, is reflected at 15～30 ℃ and continues 30-120min down.
Obtain by said method that the polymer support biological degradability is good, toxicity is little, have boundless actual application prospect.
Below the present invention is described in detail.
Key technology of the present invention has 6 points: the one, and the selection of solid phase synthesis process.Dendroid polylysine synthetic all adopted the synthetic method that liquid phase is synthetic and derive from, as being the liquid-phase synthesis process of carrier with the Polyethylene Glycol.The distinguishing feature of these methods is in the building-up process owing to need not sterically hindered little (as the use of linear polyethylene glycol) of carrier (synthetic as liquid phase) or carrier, so aggregate velocity is very fast; On the other hand, this has also caused the yield of subsequent separation process complexity and product low.Though and solid phase synthesis process of the present invention slightly is inferior to liquid phase on aggregate velocity synthetic, its follow-up treatment step is very simple, rapidly, thereby part has remedied the deficiency of aggregate velocity.The 2nd, the determining of synthesis material resin.Synthesize and independently to synthesize with resin, also can adopt market-oriented product, the amino acid modified density of 100～200 orders, fluorenylmethyloxycarbonyl as Shanghai gill biochemical corp is that the Wang resin of 0.5mmol/g or the amino acid modified density of fluorenylmethyloxycarbonyl of Sigma company are the Wang resin of 0.8mmol/g, and related aminoacid can be any one aminoacid.The 3rd, N
α, N
εThe preparation of-two fluorenylmethyloxycarbonyl lysines.Highly purified N
α, N
ε-two fluorenylmethyloxycarbonyl lysines are the key factors that obtain the single product of molecular weight.Present commercially available N
α, N
ε-two fluorenylmethyloxycarbonyl lysine purity are generally between 80～90%.The present invention adopts homemade N
α, N
ε-two fluorenylmethyloxycarbonyl lysines synthesize, its preparation process is as follows: after being dissolved in lysine in the dioxane aqueous solution transferring pH to 10.0 with sodium hydroxide under ice bath, dropwise add the fluorenylmethyloxycarbonyl butanimide that is dissolved in dioxane and react and control pH value of solution 10.0; Transfer pH to 8.0～8.5 subsequently, reaction is spent the night; Reacting coarse product is adding ether and regulating pH to 3 under ice bath after extracted with diethyl ether, collects the ether layer behind the oscillation extraction and steam ether under 50 ℃, and the white oily liquids that obtains is through ethyl acetate and petroleum ether recrystallization, and lyophilization can get product.The 4th, the selection of finishing reagent.The reagent that is used for modifying branch unit, top layer can be organic acid, also fluorenylmethyloxycarbonyl aminoacid etc.The 5th, the selection of aminoacid blocking group.Amino acid whose blocking group is Fmoc in the building-up process of the present invention, and it goes to protect step simple and the product that is incorporated on the resin is come off.The 6th, the determining of product collection method.The present invention adopts acid condition trifluoroacetic acid cleaved products, and cutting efficiency is than higher.After concentrating, cleaved products directly promptly obtains product through the absolute ether precipitation.
The specific embodiment
Following example will give further instruction to method provided by the invention.
Embodiment 1
Getting 100～200 orders, fluorenylmethyloxycarbonyl glycine, to modify density be the Wang resin 0.5g of 0.5mmol/g, after the swelling, adds 50% piperidines/dichloromethane solution reaction 40min in dichloromethane; With ethanol 2 times, 4 washing resins of dichloromethane are to neutral.Resin behind the deprotection adds the N of 1mmol
α, N
εIn-two fluorenylmethyloxycarbonyl lysines, 1ml DMF and the 34mg HOBt mixed solution, add 0.15ml DIC and 1.85ml dichloromethane again, reacted 24 hours; Resin after reaction finishes obtains to contain the resin (Fmoc) of generation product through draining and washed with dichloromethane
2-Lys-Gly-Wang resin; Repeat the resin that above-mentioned building-up process can obtain to contain secondary polylysine product, N in the building-up process
α, N
εThe addition of-two fluorenylmethyloxycarbonyl lysines is that addition 2mmol, DMF and HOBt is respectively 2ml and 68mg, and the adding volume of DIC and dichloromethane is 0.3ml and 3.7ml, reacts 48 hours; The synthesis condition that contains the resin of three generations's polylysine product equally is N
α, N
εThe addition of-two fluorenylmethyloxycarbonyl lysines is that the addition of 4mmol, DMF and HOBt is respectively 4ml and 136mg, and the adding volume of DIC and dichloromethane is 0.6ml and 7.4ml, reacts 72 hours.The resin adding volume ratio of the resulting three generations's of containing polylysine product is 1 trifluoroacetic acid/dichloromethane solution and the reaction 60min under 15 ℃ of the resin behind the deprotection; wash resin 3 times with dichloromethane solution at last; merger filtrate; rotary evaporation to volume no longer changes the back and adds a large amount of absolute ethers and centrifugal collection, and resultant precipitation is product (((Fmoc)
2-Lys)
2-Lys)
2-Lys-Gly, yield are 74.3%.Measure the molecular weight [M+Na] of this product with MALDI-TOF
+[M+K]
+Be respectively 2776.7 and 2791.6;
1The H-NMR analysis result is: 1.0-1.7 (γ-, δ-, β-H, Lys), 2.97 (ε-H, Lys), 3.78 (α-H, Gly), 3.9 (α-H, Lys), 4.2-4.3 and 7.3-7.9 (Fmoc-H).
Embodiment 2
The resin that contains three generations's polylysine product that embodiment 1 obtains adds 50% piperidines/dichloromethane solution reaction 90min; With ethanol 2 times, 4 washing resins of dichloromethane are to neutral.Resin behind the deprotection adds in fluorenylmethyloxycarbonyl phenylalanine, 4ml DMF and the 136mg HOBt mixed solution of 4mmol, adds 0.6ml DIC and 7.4ml dichloromethane again, reacts 72 hours.Reaction finishes the liquid phase in the system of back, adds 50% piperidines/dichloromethane solution reaction 90min then; With ethanol 2 times, 4 washing resins of dichloromethane are to neutral; Resin adding volume ratio behind the deprotection is 1 trifluoroacetic acid/dichloromethane solution and the reaction 60min under 15 ℃ of the resin behind the deprotection; wash resin 3 times with dichloromethane solution at last; merger filtrate; rotary evaporation to volume no longer changes the back and adds a large amount of absolute ethers and centrifugal collection, and resultant precipitation is product (((Phe)
2-Lys)
2-Lys)
2-Lys-Gly, single step yield are 93%.Measure the molecular weight [M+H] of this product with MALDI-TOF
+[M+Na]
+Be respectively 2150.4 and 2173.6;
1The H-NMR analysis result is: 1.0-1.7 (γ-, δ-, β-, Lys), 2.97 (ε-H, Lys), 3.21 (β-H, Phe), 3.78 (α-H, Gly), 3.9 (α-H, Lys), 7.2-7.4 (Benz-H, Phe).
Embodiment 3
The resin that contains three generations's polylysine product that embodiment 1 obtains adds 50% piperidines/dichloromethane solution reaction 90min; With ethanol 2 times, 4 washing resins of dichloromethane are to neutral.Resin behind the deprotection adds in acetic acid, 4ml DMF and the 136mg HOBt mixed solution of 4mmol, adds 0.6ml DIC and 7.4ml dichloromethane again, reacts 72 hours.After finishing, reaction discards the liquid phase in the system; add volume ratio then and be 1 trifluoroacetic acid/dichloromethane solution and the resin behind the deprotection at 15 ℃ of reaction 60min down; wash resin 3 times with dichloromethane solution at last; merger filtrate; rotary evaporation to volume no longer changes the back and adds a large amount of absolute ethers and centrifugal collection, and resultant precipitation is product (((Ac)
2-Lys)
2-Lys)
2-Lys-Gly, single step yield are 97%.Measure the molecular weight [M+H] of this product with MALDI-TOF
+[M+Na]
+Be respectively 1437.1 and 1460.6;
1The H-NMR analysis result is: 1.0-1.7 (γ-, δ-, β-, Lys), 1.76-1.85 (α-H, Ac), 2.97 (ε-H, Lys), 3.78 (α-H, Gly), 3.9 (α-H, Lys).
Claims (2)
1. a preparation method that is used for the dendroid polylysine derivative carrier of gene therapy is characterized in that comprising following process,
(1) with volume ratio be 25～80% piperidines/dichloromethane solution with modify density be 0.02～4.0mmol/g the amino acid whose 4-hydroxymethyl of fluorenylmethyloxycarbonyl Phenoxymethyl polystyrene resin 4～40 ℃ down reaction sloughed the fluorenylmethyloxycarbonyl blocking group in 5～120 minutes, use dichloromethane and washing with alcohol to neutral then;
(2) the 4-hydroxymethyl Phenoxymethyl polystyrene resin of the modified amino acid of deprotection is joined by every gram resin add the following substances amount: 0.1～12mmol N
α, N
εIn-two fluorenylmethyloxycarbonyl lysines, 0.4～20ml dimethyl formamide and the 10～530mg N-hydroxybenzotriazole mixed solution, and then add 0.1～5ml 1, the 3-DIC obtains contain the resin of generation polylysine with dichloromethane, washing with alcohol 4-40 ℃ of reaction after 2-96 hour; The resin that will contain generation polylysine then joins the synthetic resin that contains secondary polylysine, wherein N in the above-mentioned reactant liquor of preparing again
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.2～25mmol; The resin that contains secondary polylysine that obtains of reaction joins the synthetic resin that contains three generations's polylysine, wherein N in the reactant liquor of new preparation after dichloromethane, washing with alcohol
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.3～50mmol;
(3) be that three generations's polylysine resin reaction under 4～40 ℃ that 25～80% piperidines/dichloromethane solution and fluorenylmethyloxycarbonyl group protect was sloughed the fluorenylmethyloxycarbonyl blocking group in 5～120 minutes with volume ratio, use dichloromethane and washing with alcohol then to neutral; The resin of deprotection is joined by every gram resin adding following substances amount: in the carboxylic chemical compound of 0.4～40mmol, 1～20ml dimethyl formamide and the 50～530mg N-hydroxybenzotriazole mixed solution, and then add 0.3～6ml 1, the 3-DIC was reacted 2-120 hour down at 4～40 ℃;
(4) volume ratio is trifluoroacetic acid/dichloromethane solution and the reaction 10-180min under 4～40 ℃ of the resin behind the deprotection of 0.5-5;
(5) at last with dichloromethane solution flushing resin several times, merger filtrate, rotary evaporation to volume no longer changes the back and adds a large amount of absolute ethers and centrifugal collection, and resultant precipitation is product.
2. by the described preparation method that is used for the dendroid polylysine derivative carrier of gene therapy of claim 1, it is characterized in that: in the building-up process on the resin the amino acid modified density of fluorenylmethyloxycarbonyl be 0.1～2.0mmol/g, the volume of dimethyl formamide is every gram resin 1.0～12ml, the consumption of N-hydroxybenzotriazole is every gram resin 50～300mg, 1, the addition of 3-DIC is every gram resin 0.2～6ml; N in the synthetic generation polylysine resin process
α, N
ε-two fluorenylmethyloxycarbonyl lysine additions are every gram resin 0.4～10mmol, N in the synthetic secondary polylysine resin process
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.4～16mmol; N in synthetic three generations's polylysine resin process
α, N
ε-two fluorenylmethyloxycarbonyl lysine consumptions are every gram resin 0.6～40mmol; Piperidines and methylene chloride volume ratio is 30～70% in the deprotecting regent, and the deprotection process is carried out 20～80min under 15～30 ℃; The carboxylated compound addition was every gram resin 1～30mmol during surface branch elementary layer was modified, the volume of dimethyl formamide is every gram resin 2～14ml, the consumption of N-hydroxybenzotriazole is every gram resin 80～400mg, 1, the addition of 3-DIC is every gram resin 0.5～5ml; In the product cutting process, trifluoroacetic acid is 0.8～3 with the methylene chloride volume ratio, is reflected at 15～30 ℃ and continues 30-120min down.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190713A (en) * | 2010-03-12 | 2011-09-21 | 北京元森康泰医药研究有限公司 | Synthetic peptide and application thereof |
| CN102604114A (en) * | 2012-01-10 | 2012-07-25 | 中山大学 | Star-shaped cationic polymer containing dendriform polylysine element and preparation method thereof |
| WO2012159263A1 (en) * | 2011-05-24 | 2012-11-29 | Dai Lijun | Enzyme-degradable polymer and application thereof |
| CN111808278A (en) * | 2019-04-11 | 2020-10-23 | 中山大学 | Branched antibacterial polyamino acid and preparation method and application thereof |
-
2005
- 2005-03-07 CN CNA2005100162685A patent/CN1683014A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190713A (en) * | 2010-03-12 | 2011-09-21 | 北京元森康泰医药研究有限公司 | Synthetic peptide and application thereof |
| WO2012159263A1 (en) * | 2011-05-24 | 2012-11-29 | Dai Lijun | Enzyme-degradable polymer and application thereof |
| CN102958938A (en) * | 2011-05-24 | 2013-03-06 | 戴立军 | Enzyme-degradable polymer and application thereof |
| CN102958938B (en) * | 2011-05-24 | 2014-08-27 | 戴立军 | Enzyme-degradable polymer and application thereof |
| US9200033B2 (en) | 2011-05-24 | 2015-12-01 | Karebay Biochem Inc. | Enzyme-degradable polymer and application thereof |
| CN102604114A (en) * | 2012-01-10 | 2012-07-25 | 中山大学 | Star-shaped cationic polymer containing dendriform polylysine element and preparation method thereof |
| CN102604114B (en) * | 2012-01-10 | 2014-06-25 | 中山大学 | Star-shaped cationic polymer containing dendriform polylysine element and preparation method thereof |
| CN111808278A (en) * | 2019-04-11 | 2020-10-23 | 中山大学 | Branched antibacterial polyamino acid and preparation method and application thereof |
| CN111808278B (en) * | 2019-04-11 | 2021-12-21 | 中山大学 | Branched antibacterial polyamino acid and preparation method and application thereof |
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