CN101265331A - PEG modifying PHPMA material and preparation method thereof - Google Patents
PEG modifying PHPMA material and preparation method thereof Download PDFInfo
- Publication number
- CN101265331A CN101265331A CNA2007100643400A CN200710064340A CN101265331A CN 101265331 A CN101265331 A CN 101265331A CN A2007100643400 A CNA2007100643400 A CN A2007100643400A CN 200710064340 A CN200710064340 A CN 200710064340A CN 101265331 A CN101265331 A CN 101265331A
- Authority
- CN
- China
- Prior art keywords
- peg
- phpma
- hydroxyl
- molecular weight
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Polyethers (AREA)
Abstract
The invention discloses a PEG modified PHPMA material and a preparation method thereof. The PEG modified PHPMA material which is provided by the invention is N-(2'-hydroxyl) propyl methyl acrylamide (HPMA) and/or a copolymer of the derivative of the N-(2'-hydroxyl) propyl methyl acrylamide and polyethylene glycol (PEG). The PEG modified PHPMA material of the invention is a polymer which is formed by the copolymerization of the polyethylene glycol (PEG), poly-N-(2'-hydroxyl) propyl methyl acrylamide (PHPMA) and the derivative of the PHPMA, the copolymer can be obtained by adopting the reversible addition-fragmentation chain transfer (RAFT), the composition and the molecular weight are controllable, and the molecular weight distribution is narrow (the molecular weight distribution d is less than 1, 4). Such polymers can be applied in the targeting drug delivery, which can not only have high targeting property and good biocompatibility, but can also have the function of preventing the protein non-specific absorption after the PEG modification, so the PEG modified PHPMA material is a good drug targeting carrier with the good performance, in particular to the drug targeting carrier of an anti-tumor drug.
Description
Technical field
The present invention relates to modified polymer material, particularly relate to PEG modification PHPMA material and preparation method thereof.
Background technology
Tumour is the second largest disease that threatens human health at present, the mortality ratio height, exist curative ratio low and more after characteristics such as not good.For tumor treatment, mainly contain operation, chemotherapy and radiation three major types methods of treatment at present.In general, chemotherapy and radiation cooperates operation to carry out together, is used to kill the tumour cell that the operation back is remaining and shift.
Though chemotherapy and radiation has significant curative effect in oncotherapy, also there are a lot of problems.For chemotherapy, medicine also can nonselectively kill normal cell in the kill tumor cell, cause the side reaction of the sizable general of patient, has had a strong impact on the recovery of patient body and the enthusiasm of patient's partner treatment.For radiotherapy, because the penetration power of radioactive rays itself is limited, often can only be used for treating the tumour of shallow, and powerless for the tumour of deep tissues.
Utilization has the carrier of target function medicine is directly sent to lesions position kill tumor cell, can reach the purpose that improves curative effect, reduces side effect.Research about target medicine carrier, mainly be to adopt poly-N-(2 '-hydroxyl) propyl methyl acid amides (PHPMA) (to see document (1) J.Kopecek et al.HPMAcopolymer-anticancer drug conjugates:design at present as target medicine carrier, activity, and mechanism of action, EuropeanJournal of Pharmaceutics and Biopharmaceutics, 2000,50,61-81; (2) R.Duncan, TheDawning Era of Polymer Therapeutics, Nature Reviews Drug Discovery, 2003,2,347-360).PHPMA has tangible advantage as pharmaceutical carrier, and at first, it is a kind of water-soluble polymers; Secondly, it has extraordinary biocompatibility, not can with human body generation immune response; At last, it has EPR (enhanced infiltration and stop) effect, helps its gathering at tumor locus.But the PHPMA carrier also has tangible deficiency, as function singleness, do not have the albumen of preventing non-specific adsorption etc., causes the PHPMA pharmaceutical carrier can be in non-lesions position absorption and rich long-pending in the blood circulation process.The more important thing is, because common free radical polymerisation process is all adopted in the preparation of PHPMA carrier at present, resulting carrier molecule amount is uncontrollable, molecular weight distribution is very wide, have a strong impact on the EPR effect and the pharmacokinetics of polymer support, thereby further had influence on the result of treatment of medicine.
Summary of the invention
The purpose of this invention is to provide a kind of PEG modification PHPMA material and preparation method thereof.
PEG modification PHPMA material provided by the present invention is N-(2 '-hydroxyl) propyl methyl acid amides and/or the derivative of N-(2 '-hydroxyl) propyl methyl acid amides and the multipolymer of polyoxyethylene glycol (PEG).
Wherein, the number-average molecular weight of multipolymer is 2,000～100,000, and molecular weight distribution is at 1.05-1.4; The molar content of polyoxyethylene glycol component is 5～90%, and the molar content of N-(2 '-hydroxyl) propyl methyl acid amides and derivative component thereof is 10～95%.
PEG modification PHPMA preparation methods of the present invention comprises the steps:
1) preparation PEG macromolecular chain transfer agent
With N, N '-dicyclohexylcarbodiimide and 4-Dimethylamino pyridine are catalyzer, are that hydroxyl or amino PEG and 4-dithiobenzoic acid ester group-4-itrile group valeric acid react by end group, obtain PEG macromolecular chain transfer agent;
2) preparation PEG modification PHPMA material
In aqueous phase system, with 4,4 '-azo two (4-itrile group valeric acid) is an initiator, the derivative and the gained PEG macromolecular chain transfer agent of N-(2 '-hydroxyl) propyl methyl acid amides and/or N-(2 '-hydroxyl) propyl methyl acid amides are carried out copolymerization, obtain described PEG modification PHPMA material.
The described PEG number-average molecular weight of step 1) is 1,000～10,000, and the mol ratio of PEG and 4-dithiobenzoic acid ester group-4-itrile group valeric acid is 0.5～1: 1, and described temperature of reaction is a room temperature, and reaction solvent is toluene, tetrahydrofuran (THF) and chloroform.
Step 2) described aqueous phase system is selected from the mixed system of water, acetic acid-acetate salt buffer system, phosphoric acid-phosphate buffer or water and methyl alcohol.In above-mentioned preparation process, the derivative of N-(2 '-hydroxyl) propyl methyl acid amides and/or N-(2 '-hydroxyl) propyl methyl acid amides and the molar ratio of PEG macromolecular chain transfer agent are greater than 10; 1.Step 2) copolymerization carries out under argon gas or nitrogen atmosphere, and the copolymerization temperature is 60～100 ℃.
In the present invention, the structural formula of the derivative of N-(2 '-hydroxyl) propyl methyl acid amides is suc as formula I:
R wherein
1Be the polypeptid residue below the decapeptide of forming by natural amino acid, contain a plurality of carboxyls or amino, be included in amidation or the esterification carried out on this amino acid and modify if form the amino acid of this polypeptide.
Derivative commonly used has tyrosine acid amides Methacrylamide or glycine dipeptide methacrylamide etc.
PEG modification PHPMA material of the present invention is the polymer that the derivative copolymerization by polyoxyethylene glycol (PEG), poly-N-(2 '-hydroxyl) propyl methyl acid amides (PHPMA) and PHPMA forms, this multipolymer can adopt reversible addition fracture to shift the polymerization of (RAFT) polymerization process and obtain, its composition and molecular weight are controlled, number-average molecular weight is 2,000～100, between 000, narrow molecular weight distribution (molecular weight distribution d＜1.4).This base polymer is owing to have the PHPMA segment, can utilize the chemical structure characteristics of PHPMA or derivatives thereof, by in conjunction with bioactive moleculess such as polypeptide, antibody, perhaps rely on the EPR effect of PHPMA and derivative thereof itself, the target of realizing antitumor drug discharges, and has high target and excellent biological compatibility; Simultaneously, comprise the PEG block in the multipolymer, this makes this multipolymer have the function that prevents the albumen non-specific adsorption, is the target administration carrier of a kind of target medicine carrier of excellent property, particularly antitumor drug.
Embodiment
PEG modification PHPMA material of the present invention is the derivative (X) of N-(2 '-hydroxyl) propyl methyl acid amides (HPMA) and/or N-(2 '-hydroxyl) propyl methyl acid amides and the multipolymer of polyoxyethylene glycol (PEG).
Multipolymer of the present invention can shift (RAFT) polymerization process by reversible addition fracture and prepare:
1) preparation PEG macromolecular chain transfer agent
With N, N '-dicyclohexylcarbodiimide and 4-Dimethylamino pyridine are catalyzer, are that hydroxyl or amino PEG and 4-dithiobenzoic acid ester group-4-itrile group valeric acid react by end group, obtain PEG macromolecular chain transfer agent;
2) preparation PEG modification PHPMA material
In aqueous phase system, with 4,4 '-azo two (4-itrile group valeric acid) is an initiator, the derivative and the gained PEG macromolecular chain transfer agent of N-(2 '-hydroxyl) propyl methyl acid amides and/or N-(2 '-hydroxyl) propyl methyl acid amides are carried out copolymerization, obtain described PEG modification PHPMA material.
By telocopolymerization reaction times, monomer and the mol ratio of chain-transfer agent and the relative mol ratio of each component, can obtain different forming content, molecular weight is controlled and the block of narrow molecular weight distribution or random copolymers.Reaction is put into the liquid nitrogen termination reaction rapidly after finishing, and removes wherein small molecules by dialysis then, and last solvent evaporated obtains desired product.Preparation method of the present invention carries out in aqueous phase system, and the solvent of use comprises the mixed system of pure water, water buffered soln (acetic acid-acetate salt buffer system, phosphoric acid-phosphate buffer etc.) and water and methyl alcohol etc.
The number-average molecular weight of multipolymer of the present invention can be 2,000 to 100, accuracy controlling in 000 the scope, wherein the molecular weight of PEG component is 1,000～10, between 000, the molecular weight of PHPMA and derivative thereof is 1,000～100, between 000, number-average molecular weight can with water gel permeation chromatography (GPC) and
1The H NMR (Nuclear Magnetic Resonance) spectrum (
1H NMR) measures.Molecular weight distribution is narrow, between 1.05～1.40.The component of multipolymer of the present invention can be by changing the mole of each component when reinforced accuracy controlling recently, and wherein the molar content of PEG component is 5～90%, and the molar content of the component of PHPMA and derivative thereof is 10～95%.The mole of multipolymer is formed and can be passed through
1H NMR quantitatively determines.
The multipolymer for preparing by the inventive method can be two blocks, many blocks or random copolymers, can remember respectively and make PEG-b-PHPMA (A), PHPMA-b-PEG-b-PHPMA (B), PEG-PHPMA-PX (C) and PX-PHPMA-PEG-PHPMA-PX (D).Wherein, A and B are segmented copolymer, and C and D can be segmented copolymer, also can be at the intersegmental random copolymers of PHPMA-PX chain.When copolymerization, add monomer HPMA earlier, add monomer X after question response is finished again, can obtain the segmented copolymer of C or D; When copolymerization, add monomer HPMA and X simultaneously, can obtain at PHPMA-PX segmental random copolymers (C or D).As the PEG that uses one-ended hydroxy or single-ended amino during, will obtain copolymer A or C as reaction raw materials; And, will obtain multipolymer B or D as the PEG that uses both-end hydroxyl or double-end amino during as reaction raw materials.The PX part of such carrier can contain several different derivatives simultaneously.
The structural formula of above-mentioned four kinds of multipolymers is respectively suc as formula shown in II (A), formula III (B), formula IV (C) and the formula V (D):
(formula III)
Wherein, R represents the not labile substituting group of any one chance water, comprises various alkyl and aryl etc., and this group can be brought in the polymeric chain by the PEG raw material; R
1The substituted radical of expression on the HPMA is the polypeptid residue below the decapeptide of being made up of natural amino acid, contains a plurality of carboxyls or amino if form the amino acid of this polypeptide, also is included in the amidation carried out on this amino acid or esterification modified outcome etc.; Z represent an a kind of end with ester group or amide group link to each other with peg moiety, the other end and the segment that PHPMA partly links to each other, comprise various alkyl, aryl and contain heteroatomic substituting group etc.; Y represents a kind of group of the RAFT of having polymerization activity, and this group can be the various groups that contain one or more dithio ester group (Dithioester) or trithiocarbonate (Trithiocarbonate) or xanthate (Xanthate) or dithiocar-bamate (Dithiocarbamate); Subscript m, n represent that this segment is a block, and subscript x, y represent that this segment both may be a block, also may be for random.Group Y introduces by PEG macromolecular chain transfer agent, and copolyreaction is retained in the polymer chain end after finishing.
The invention will be further elaborated below by example, its objective is better understanding content of the present invention, and institute gives an actual example and do not limit protection scope of the present invention.
The preparation of embodiment 1, PEG-b-PHPMA
With number-average molecular weight is that 2000 one-ended hydroxy PEG 2.4g is dissolved in 40mL toluene, add 4-dithiobenzoic acid ester group-4-itrile group valeric acid (CPAD) 0.68g, 4-Dimethylamino pyridine (DMAP) 0.041g, treat to dissolve fully the back and add N, N '-dicyclohexylcarbodiimide (DCC) 0.74g, reaction is 90 hours under the stirring at room.Suction filtration, in the excessive ether of filtrate impouring, suction filtration, the gained precipitation is dissolved in small amount of toluene, uses ether sedimentation again, so triplicate.40 ℃ of vacuum-dryings 24 hours, products therefrom was the macromolecular chain transfer agent of PEG with throw out.
Get this chain-transfer agent 0.13g; HPMA 0.716g; 4,4 '-azo two (4-itrile group valeric acid) 5mg, pure water 6mL; in the vacuum reaction pipe; under freezing, vacuumize, return to room temperature then, charge into argon gas; with this is freezing-dissolve-applying argon gas process triplicate, under argon shield, place 70 ℃ of oil baths to react reaction tubes at last.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The molecular weight of this product and form can by water GPC and
1H NMR confirms jointly.
The different reaction times can obtain the molecular weight product different with block length.Reaction times, obtaining the multipolymer number-average molecular weight was 3000 when being 2h, and molecular weight distribution is 1.36, and the molar content of PEG component is 86%, and the molar content of PHPMA component is 14%; Reaction times, obtaining the multipolymer number-average molecular weight was 7100 when being 5h, and molecular weight distribution is 1.20, and the molar content of PEG component is 57%, and the molar content of PHPMA component is 43%; Reaction times, obtaining the multipolymer number-average molecular weight was 11000 when being 8h, and molecular weight distribution is 1.13, and the molar content of PEG component is 46%, and the molar content of PHPMA component is 54%; Reaction times, obtaining the multipolymer number-average molecular weight was 14000 when being 10h, and molecular weight distribution is 1.10, and the molar content of PEG component is 35%, and the molar content of PHPMA component is 65%; Reaction times, obtaining the multipolymer number-average molecular weight was 16500 when being 24h, and molecular weight distribution is 1.11, and the molar content of PEG component is 31%, and the molar content of PHPMA component is 69%.
The preparation of embodiment 2, PHPMA-b-PEG-b-PHPMA
The preparation method of this triblock copolymer is the same substantially with embodiment 1, just will original used number-average molecular weight be that 2000 one-ended hydroxy or amino PEG use instead to number-average molecular weight be 2000 both-end hydroxyl or amino PEG, because its both-end hydroxyl or amino, its consumption changes 1.2g in the present embodiment into, and the consumption of macromolecular chain transfer agent changes 0.065g into.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The composition of this product and molecular weight can by water GPC and
1H NMR confirms jointly.
The different reaction times can obtain forming the product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 4000 when being 2h, and molecular weight distribution is 1.40, and the molar content of PEG component is 77%, and the molar content of PHPMA component is 23%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 25000, molecular weight distribution is 1.15, the molar content of PEG component is 22%, and the molar content of PHPMA component is 78%, and the reaction times is when being 24h, obtaining the multipolymer number-average molecular weight is 30000, molecular weight distribution is 1.12, and the molar content of PEG component is 19%, and the molar content of PHPMA component is 81%.
The preparation 1 of embodiment 3, three block PEG-b-PHPMA-b-PX
Among this embodiment, PX is the polyglycine dipeptide methacrylamide.Take that the synthetic number-average molecular weight is 10 among the embodiment 1,000 PEG-b-PHPMA0.10g, glycine dipeptide methacrylamide 0.20g, 4,4 '-azo two (4-itrile group valeric acid) 2mg, acetic acid-sodium acetate buffer solution 3mL in the vacuum reaction pipe (acetate concentration 0.27moL/L in this acetic acid-sodium acetate buffer solution, sodium-acetate concentration 0.73moL/L, pH=5.2), under freezing, vacuumize, return to room temperature then, charge into argon gas, with this is freezing-dissolve-applying argon gas process triplicate.Under argon shield, place 70 ℃ of oil baths to react reaction tubes.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The structure of this product and form can by water GPC and
1H NMR confirms jointly.
The different reaction times can obtain each block length product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 15000 when being 5h, and molecular weight distribution is 1.16, and the molar content of PEG component is 36%, and the molar content of PHPMA component is 44%, and the molar content of PX component is 20%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 23000, and molecular weight distribution is 1.12, and the molar content of PEG component is 28%, the molar content of PHPMA component is 33%, the molar content of PX component is 39%, and the reaction times, obtaining the multipolymer number-average molecular weight was 30000 when being 24h, molecular weight distribution is 1.10, the molar content of PEG component is 23%, and the molar content of PHPMA component is 27%, and the molar content of PX component is 50%.
The preparation of embodiment 4, random PEG-PHPMA-PX
In this embodiment, PX is the polyglycine dipeptide methacrylamide.The macromolecular chain transfer agent for preparing PEG according to the method among the embodiment 1.Get this chain-transfer agent 0.13g, HPMA 0.358g, glycine dipeptide methacrylamide 0.50g, 4,4 '-azo two (4-itrile group valeric acid) 5mg, pure water 6mL, in the vacuum reaction pipe, under freezing, vacuumize, return to room temperature then, charge into argon gas, with this is freezing-dissolve-applying argon gas process triplicate.Under argon shield, place 70 ℃ of oil baths to react reaction tubes.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The structure of this product and form can by water GPC and
1HNMR confirms jointly.
The differential responses time can obtain forming the product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 7000 when being 5h, and molecular weight distribution is 1.21, and the molar content of PEG component is 61%, and the molar content of PHPMA component is 20%, and the molar content of PX component is 19%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 21000, and molecular weight distribution is 1.13, and the molar content of PEG component is 30%, the molar content of PHPMA component is 31%, the molar content of PX component is 39%, and the reaction times, obtaining the multipolymer number-average molecular weight was 32000 when being 24h, molecular weight distribution is 1.11, the molar content of PEG component is 21%, and the molar content of PHPMA component is 26%, and the molar content of PX component is 53%.
The preparation of embodiment 5, five block PX-b-PHPMA-b-PEG-b-PHPMA-b-PX
In this embodiment, PX is the polyglycine dipeptide methacrylamide.Take that the synthetic number-average molecular weight is 10 among the embodiment 2,000 PHPMA-b-PEG-b-PHPMA 0.05g, glycine dipeptide methacrylamide 0.20g, 4,4 '-azo two (4-itrile group valeric acid) 2mg, acetic acid-sodium acetate buffer solution 3mL (acetate concentration 0.27moL/L in this acetic acid-sodium acetate buffer solution in the vacuum reaction pipe, sodium-acetate concentration 0.73moL/L, pH=5.2), under freezing, vacuumize, return to room temperature then, charge into argon gas, with this is freezing-dissolve-applying argon gas process triplicate.Under argon shield, place 70 ℃ of oil baths to react reaction tubes.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The The Nomenclature Composition and Structure of Complexes of this product can by water GPC and
1H NMR confirms jointly.
The differential responses time can obtain each block length product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 20000 when being 5h, and molecular weight distribution is 1.27, and the molar content of PEG component is 30%, and the molar content of PHPMA component is 36%, and the molar content of PX component is 34%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 34000, and molecular weight distribution is 1.18, and the molar content of PEG component is 22%, the molar content of PHPMA component is 27%, the molar content of PX component is 51%, and the reaction times, obtaining the multipolymer number-average molecular weight was 47000 when being 24h, molecular weight distribution is 1.15, the molar content of PEG component is 16%, and the molar content of PHPMA component is 20%, and the molar content of PX component is 64%.
The preparation of embodiment 6, random PX-PHPMA-PEG-PHPMA-PX
In this embodiment, PX is the polyglycine dipeptide methacrylamide.The macromolecular chain transfer agent for preparing PEG according to the method among the embodiment 2.Get this chain-transfer agent 0.05g, HPMA 0.358g, glycine dipeptide methacrylamide 0.50g, 4,4 '-azo two (4-itrile group valeric acid) 5mg, pure water 6mL, in the vacuum reaction pipe, under freezing, vacuumize, return to room temperature then, charge into argon gas, with this is freezing-dissolve-applying argon gas process triplicate.Under argon shield, place 70 ℃ of oil baths to react reaction tubes.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The structure of this product and form can by water GPC and
1HNMR confirms jointly.
The differential responses time can obtain forming the product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 10000 when being 5h, and molecular weight distribution is 1.25, and the molar content of PEG component is 49%, and the molar content of PHPMA component is 26%, and the molar content of PX component is 25%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 41000, and molecular weight distribution is 1.18, and the molar content of PEG component is 17%, the molar content of PHPMA component is 34%, the molar content of PX component is 49%, and the reaction times, obtaining the multipolymer number-average molecular weight was 60000 when being 24h, molecular weight distribution is 1.13, the molar content of PEG component is 12%, and the molar content of PHPMA component is 28%, and the molar content of PX component is 60%.
The preparation of embodiment 7, three block PEG-PHPMA-PX
Among this embodiment, PX is a polytyrosine acid amides Methacrylamide.Take that the synthetic number-average molecular weight is 10 among the embodiment 1,000 PEG-b-PHPMA0.10g, tyrosine acid amides Methacrylamide 0.25g, 4,4 '-azo two (4-itrile group valeric acid) 2mg, acetic acid-sodium acetate buffer solution 3mL in the vacuum reaction pipe (acetate concentration 0.27moL/L in this acetic acid-sodium acetate buffer solution, sodium-acetate concentration 0.73moL/L, pH=5.2), under freezing, vacuumize, return to room temperature then, charge into argon gas, with this is freezing-dissolve-applying argon gas process triplicate.Under argon shield, place 70 ℃ of oil baths to react reaction tubes.During termination reaction reaction tubes is put into liquid nitrogen rapidly, remove wherein small molecules by dialysis then, last solvent evaporated obtains desired product.The structure of this product and form can by water GPC and
1HNMR confirms jointly.
The different reaction times can obtain each block length product different with molecular weight.Reaction times, obtaining the multipolymer number-average molecular weight was 18000 when being 5h, and molecular weight distribution is 1.18, and the molar content of PEG component is 34%, and the molar content of PHPMA component is 41%, and the molar content of PX component is 25%; Reaction times is when being 10h, obtaining the multipolymer number-average molecular weight is 26000, and molecular weight distribution is 1.12, and the molar content of PEG component is 27%, the molar content of PHPMA component is 34%, the molar content of PX component is 39%, and the reaction times, obtaining the multipolymer number-average molecular weight was 33000 when being 24h, molecular weight distribution is 1.13, the molar content of PEG component is 22%, and the molar content of PHPMA component is 29%, and the molar content of PX component is 49%.
Claims (10)
1. PEG modification PHPMA material is N-(2 '-hydroxyl) propyl methyl acid amides and/or the derivative of N-(2 '-hydroxyl) propyl methyl acid amides and the multipolymer of polyoxyethylene glycol (PEG).
2. PEG modification PHPMA material according to claim 1, it is characterized in that: the number-average molecular weight of described multipolymer is 2,000～100,000, and molecular weight distribution is at 1.05-1.4; The molar content of polyoxyethylene glycol component is 5～90%, and the molar content of N-(2 '-hydroxyl) propyl methyl acid amides and derivative component thereof is 10～95%.
3. PEG modification PHPMA material according to claim 1 is characterized in that: the structural formula of the derivative of described N-(2 '-hydroxyl) propyl methyl acid amides is:
(formula I)
R wherein
1Be the following polypeptid residue of 10 peptides or the derivative of polypeptid residue.
4. the described PEG modification of claim 1 PHPMA preparation methods comprises the steps:
1) preparation PEG macromolecular chain transfer agent
With N, N '-dicyclohexylcarbodiimide and 4-Dimethylamino pyridine are catalyzer, are that hydroxyl or amino PEG and 4-dithiobenzoic acid ester group-4-itrile group valeric acid react by end group, obtain PEG macromolecular chain transfer agent;
2) preparation PEG modification PHPMA material
In aqueous phase system, with 4,4 '-azo two (4-itrile group valeric acid) is an initiator, the derivative and the gained PEG macromolecular chain transfer agent of N-(2 '-hydroxyl) propyl methyl acid amides and/or N-(2 '-hydroxyl) propyl methyl acid amides are carried out copolymerization, obtain described PEG modification PHPMA material.
5. preparation method according to claim 4 is characterized in that: the described PEG number-average molecular weight of step 1) is 1,000～10,000, and the mol ratio of PEG and 4-dithiobenzoic acid ester group-4-itrile group valeric acid is 0.5～1: 1; Described temperature of reaction is a room temperature, and reaction solvent is toluene, tetrahydrofuran (THF) and chloroform.
6. preparation method according to claim 4 is characterized in that: step 2) described aqueous phase system is selected from the mixed system of water, acetic acid-acetate salt buffer system, phosphoric acid-phosphate buffer or water and methyl alcohol.
7. preparation method according to claim 4 is characterized in that: the derivative of N-(2 '-hydroxyl) propyl methyl acid amides and/or N-(2 '-hydroxyl) propyl methyl acid amides and the molar ratio of PEG macromolecular chain transfer agent were greater than 10: 1.
8. preparation method according to claim 4 is characterized in that: the structural formula of the derivative of described N-(2 '-hydroxyl) propyl methyl acid amides is:
R wherein
1Be the following polypeptid residue of 10 peptides or the derivative of polypeptid residue.
9. preparation method according to claim 8 is characterized in that: the derivative of described N-(2 '-hydroxyl) propyl methyl acid amides is tyrosine acid amides Methacrylamide or glycine dipeptide methacrylamide.
10. according to the arbitrary described preparation method of claim 4-9, it is characterized in that: step 2) copolymerization carries out under argon gas or nitrogen atmosphere; The copolymerization temperature is 60～100 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100643400A CN101265331B (en) | 2007-03-12 | 2007-03-12 | PEG modifying PHPMA material and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100643400A CN101265331B (en) | 2007-03-12 | 2007-03-12 | PEG modifying PHPMA material and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101265331A true CN101265331A (en) | 2008-09-17 |
| CN101265331B CN101265331B (en) | 2010-10-13 |
Family
ID=39988034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100643400A Expired - Fee Related CN101265331B (en) | 2007-03-12 | 2007-03-12 | PEG modifying PHPMA material and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101265331B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145932A (en) * | 2011-12-06 | 2013-06-12 | 中国科学院化学研究所 | Long-circulating anti-tumor targeting drug carrier and preparation method thereof |
| CN103936945A (en) * | 2013-01-23 | 2014-07-23 | 中国科学院化学研究所 | Novel efficient anti-tumor targeting drug carrier and preparation method thereof |
| CN108066771A (en) * | 2017-12-15 | 2018-05-25 | 北京思如诺科技有限公司 | One kind has high drug load environmental response type anti-tumor nano drug, carrier and preparation method |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9320781D0 (en) * | 1993-10-08 | 1993-12-01 | Erba Carlo Spa | Polymer-bound camptothecin derivatives |
| AU2004201277A1 (en) * | 1999-05-04 | 2004-04-29 | Access Pharmaceuticals Australia Pty Limited | Amplification of folate-mediated targeting to tumor cells using polymers |
| JP2003526244A (en) * | 2000-03-03 | 2003-09-02 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | Apparatus and method for transferring data from one device to another |
| US6436386B1 (en) * | 2000-11-14 | 2002-08-20 | Shearwater Corporation | Hydroxyapatite-targeting poly (ethylene glycol) and related polymers |
| CN101524549A (en) * | 2002-07-22 | 2009-09-09 | 匹斯美药物公开公司 | New anti-cancer compound |
| ES2641570T3 (en) * | 2004-03-31 | 2017-11-10 | University Of Utah Research Foundation | Macromolecular delivery systems for non-invasive imaging, evaluation and treatment of arthritis and other inflammatory diseases |
-
2007
- 2007-03-12 CN CN2007100643400A patent/CN101265331B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145932A (en) * | 2011-12-06 | 2013-06-12 | 中国科学院化学研究所 | Long-circulating anti-tumor targeting drug carrier and preparation method thereof |
| CN103936945A (en) * | 2013-01-23 | 2014-07-23 | 中国科学院化学研究所 | Novel efficient anti-tumor targeting drug carrier and preparation method thereof |
| CN108066771A (en) * | 2017-12-15 | 2018-05-25 | 北京思如诺科技有限公司 | One kind has high drug load environmental response type anti-tumor nano drug, carrier and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101265331B (en) | 2010-10-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100431491B1 (en) | Biodegradable poly(alkylene oxide)-poly(p-dioxanone)block copolymer soluble in organic solvents, and drug delivery composition comprising same | |
| WO1993024476A1 (en) | Water-soluble polymeric carriers for drug delivery | |
| JPH07508727A (en) | Polyoxymethylene-oxyethylene copolymer combined with biomolecules | |
| US9295734B2 (en) | Branched amphipathic block polymer and molecular aggregate and drug delivery system using same | |
| KR101262056B1 (en) | Glycol chitosan derivative, preparation method of the same and drug delivery system comprising the same | |
| EA016911B1 (en) | Polyglutamic acids functionalized by cationic groups and hydrophobic groups and applications thereof, in particular therapeutic applications thereof | |
| WO2011057224A2 (en) | Zwitterionic polymer bioconjugates and related methods | |
| KR20190081507A (en) | hydrogel comprising phenylboronic acid conjugated polymer | |
| CN107556497B (en) | A kind of preparation method and application of hybridized hydrogel material | |
| CN103145932A (en) | Long-circulating anti-tumor targeting drug carrier and preparation method thereof | |
| Gerrits et al. | Semiflexible polymer scaffolds: an overview of conjugation strategies | |
| CN101265331B (en) | PEG modifying PHPMA material and preparation method thereof | |
| CN107530279A (en) | The poly ion complexes of block copolymer and polyanion polymer containing poly- (L arginine) segment | |
| CN105327362B (en) | A kind of preparation method of the graphene targetable drug carriers of amphipathic nature polyalcohol brush modification | |
| CN108727583B (en) | Multi-arm targeted anticancer conjugate | |
| JP5105166B2 (en) | Method for producing polyether | |
| CN104371098B (en) | Multiple-limb hydrophilic polymer isocyanate derivates | |
| CN112933038A (en) | Drug-loaded temperature-sensitive hydrogel delivery system and preparation method and application thereof | |
| CN110628035A (en) | Enzyme and pH dual-responsive copolymer and preparation method and application thereof | |
| CN116082546A (en) | Aminopeptidase catalyzed hydrolysis induced charge turnover polymer and application thereof | |
| JPWO2004004794A1 (en) | Resin with fluid compatibility and biocompatibility | |
| Mahkam et al. | pH-sensitive hydrogel containing acetaminophen silyl ethers for colon-specific drug delivery | |
| CN107397962A (en) | A kind of poly- (L lysines) VAPG nucleic acid carriers of glucan g and its preparation method and application | |
| JP5189243B2 (en) | Drug complex and carrier for drug delivery | |
| CN108727582B (en) | Targeted anticancer conjugates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101013 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |