CN104151284B - Synthetic method and the application of a kind of Methacrylamide ortho acid esters monomer and acid-sensitive amphipathic segmented copolymer thereof - Google Patents
Synthetic method and the application of a kind of Methacrylamide ortho acid esters monomer and acid-sensitive amphipathic segmented copolymer thereof Download PDFInfo
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Abstract
The invention discloses synthetic method and the application of the new monomer of a kind of Methacrylamide ortho esters class and acid-sensitive amphipathic segmented copolymer thereof, belong to polymer support and slow controlled-release material technical field. The new single structure of described Methacrylamide ortho esters class is as shown in chemical formula I; The structure that contains two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters by the synthetic side chain of the described new monomer of Methacrylamide ortho esters class is as shown in chemical formula II. Utilize side chain to contain the micella that in two pentacyclic acid-sensitive amphipathic segmented copolymer aqueous solution of ortho esters, self assembly forms and can carry in vivo the medicine (as antitumor taxol) that is insoluble in water. Side chain of the present invention has good sensitivity to acid containing two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, and biocompatibility and biodegradability, have a good application prospect in targeted therapy field.
Description
Technical field
The present invention relates to synthetic method and the application of the new monomer of a kind of Methacrylamide ortho esters class and acid-sensitive amphipathic segmented copolymer thereof, belong to polymer support and slow controlled-release material technical field.
Background technology
The mankind's life and health in cancer serious harm, has been listed in the mankind's No. second killer. For the treatment of tumour, antineoplastic exists obvious deficiency mostly at present: targeting is not obvious, and therapeutic process often can cause irreversible infringement to body normal structure, reduces the immunocompetence of human body, thus delay treatment. Therefore, select suitable pharmaceutical carrier just to become the key that improves antineoplastic curative effect.
Utilize polymer micelle to carry cancer target performance that cancer therapy drug improves medicine and overcome tumor cell drug resistance and caused and study widely interest. PH responsive polymer micella mainly forms micella by parents' Self-Assembling of Block Copolymer and is prepared from, in copolymer, contain the chemical bond of fast hydrolyzing under acid condition, as hydrazone key, second two acetal bonds, amido link, original acid ester key etc., wherein the polymer taking original acid ester key as sensitive group can obtain (Chinese patent CN103588752 Chinese patent CN101880265A) by less step and simple reaction at present, but these polymer are degraded slowly in sour environment, after embedding medicinal, discharge slowly, cause drug effect to reduce.
Summary of the invention
The object of the invention is exactly synthetic method and the application for the new monomer of a kind of Methacrylamide ortho esters class and acid-sensitive amphipathic segmented copolymer thereof are provided.
For achieving the above object, the present invention is by the following technical solutions:
The structure of the synthetic new monomer of Methacrylamide ortho esters class of the present invention is as shown in chemical formula I:
The synthetic line of the new monomer of methacrylic acid ortho esters class of the present invention (Formula I) is as follows:
In formula, 1 is 2,2, the fluoro-N-{2-methoxyl group-[1 of 2-tri-, 3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen base)]-ethyl }-acetamide, the 2nd, 2-[2-methoxyl group-[1,3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)] ethamine.
The synthetic method of the metering system alkene acid amides new monomer of ortho esters class of the present invention (Formula I), comprises the following steps:
(1) under the effect of catalyst, 4,4 '-dimethylene oxygen-bis--(2-methoxyl group-1,3-dioxolane) reacts with N-(2-hydroxyethyl) trifluoroacetamide, and its mol ratio is 1:1-1.2, at 130 DEG C, reacts 6h; Reaction system adds acetic acid ethyl dissolution, wash through aqueous sodium carbonate, the dry pure compound 2 that obtains, 2, the fluoro-N-{2-methoxyl group-[1 of 2-tri-, 3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen base)]-ethyl }-acetamide, be directly used in next step reaction;
(2) by 2,2, the fluoro-N-{2-methoxyl group of 2-tri--[1,3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl }-acetamide is dissolved in organic solvent, add the sodium hydroxide solution of 1.0-2.0M, stirred overnight at room temperature, dichloromethane extraction, the dry pure compound 2-[2-methoxyl group-[1 that obtains, 3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)] ethamine;
(3) by 2-[2-methoxyl group-[1, 3] dioxolanes-4-(2-methoxyl group-[1, 3] dioxolanes-4-methylene oxygen)] ethamine, methacrylic acid N-succinimide ester and DMAP are dissolved in organic solvent, its mol ratio is 1:(1-1.1): 1, lucifuge room temperature reaction 24-48 hour, evaporate to dryness is removed after organic solvent, add ethyl acetate, wash through aqueous sodium carbonate, crude product separates through silica gel column chromatography, obtain product N-{2-[2-methoxyl group-[1, 3] dioxolanes-4-(2-methoxyl group-[1, 3] dioxolanes-4-methylene oxygen)]-ethyl }-2-methyl acrylamide monomer,
Catalyst described in step (1) is the mixture of p-methyl benzenesulfonic acid pyridiniujm or p-methyl benzenesulfonic acid and pyridine, and both mol ratios are 1:1.1-2, and the mol ratio of catalyst and hydroxyl is 0.001-0.01:1;
Organic solvent described in step (2) and step (3) is acetonitrile, oxolane, chloroform, carrene or dioxane;
It is ethyl acetate that silica gel described in step (3) separates leacheate.
The present invention contains two pentacyclic acid-sensitive amphipathic segmented copolymer structures of ortho esters as shown in chemical formula II by the synthetic side chain of the new monomer of Methacrylamide ortho esters class (Formula I):
In formula, X represents numerical value 20-120.
Side chain of the present invention is as follows containing the synthetic line of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters (chemical formula II):
Side chain of the present invention is containing the synthetic method of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, concrete steps are as follows: by the new monomer of Methacrylamide ortho esters class, macromolecular chain transfer agent, initator, accurately weigh and put into dry glass polymerization pipe, its molar ratio is (20-200): 1:(0.1-0.5), logical nitrogen tube sealing after degassed 30 minutes, then polymerization pipe is placed into polymerization in the oil bath of 50-80 DEG C, react after 2-24 hour, by reactants dissolved in organic solvent, ice ether sedimentation for crude product, filter collecting precipitation, under room temperature, vacuum drying obtains target copolymer.
Described macromolecular chain transfer agent structure is three sulfo-polyethylene glycols compounds of chemical formula III, and its molecular weight is 5400.
Described side chain is 20-120 containing the degree of polymerization of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters; Described organic solvent is oxolane, methyl alcohol, ethanol, acetonitrile, acetone, chloroform, DMF, the one in dioxane, benzene, toluene, paraxylene; Described initator is 2,2-azo-bis-isobutyl cyanide.
Side chain of the present invention forms micellar structure containing two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters (chemical formula II) self assembly in the aqueous solution, cause micella size difference according to close hydrophobic block ratio difference, and in self assembling process carrying medicament.
A kind of polymeric micelle medicine composition, comprise a kind of structure as shown in Formulae II side chain containing two pentacyclic acid-sensitive amphipathic block polymer micelles of ortho esters, and at least one is incorporated in the activating agent in this micella; Wherein said activating agent is selected from anti-inflammatory agent, cancer chemotherapeutic drug, immunodepressant, metabolic drug, Claritin, hepatosis treating medicine, nervous system medicine or circulation system disease medicine.
The method that described activating agent is incorporated in Amphipathilic block polymer micelle comprises stirring, heating, ultrasonic wave, solvent evaporation or infiltration processing.
Described cancer chemotherapeutic drug is selected from taxol, adriamycin, cyclosporin or BCNU.
The invention has the beneficial effects as follows that synthetic side chain has good sensitivity to acid containing two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, biocompatibility and biodegradability, under sour environment, degraded rapidly, can discharge faster the medicine being embedded in wherein, have a good application prospect in targeted therapy field.
Brief description of the drawings
Fig. 1 is N-{2-[2-methoxyl group in embodiment 1-[1,3] dioxolanes-4-(the sub-methoxyl group of 2-methoxyl group-[1,3] dioxolanes-4-)]-ethyl }-2-methyl acrylamide monomer1HNMR and13CNMR spectrogram.
Fig. 2 is that the original acid ester key hydrolysis that in embodiment 5, block copolymer pH relies on changes.
Fig. 3 is that the average-size of block copolymer micelle in embodiment 7 distributes.
Fig. 4 is the change in size that in embodiment 7, block copolymer micelle pH relies on.
Fig. 5 is block copolymer micelle vitro cytotoxicity test in embodiment 8.
Fig. 6 is block copolymer micelle vitro drug release test in embodiment 9.
Detailed description of the invention
Embodiment 1
N-{2-[2-methoxyl group-[1,3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl } synthetic method of-2-methyl acrylamide monomer, realizes by following step:
(1) 2, the fluoro-N-{2-methoxyl group of 2,2-tri--[1,3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl } preparation of-acetamide:
Under the effect of pyridine-tosilate, 4,4 '-dimethylene oxygen-bis--(2-methoxyl group-1,3-dioxolane) reacts with N-(2-hydroxyethyl) trifluoroacetamide, and its mol ratio is 1:1-1.2, at 130 DEG C, reacts 6h; Reaction system adds acetic acid ethyl dissolution, through 10% sodium carbonate liquor washing, the dry pure compound 2 that obtains, 2, the fluoro-N-{2-methoxyl group-[1 of 2-tri-, 3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl }-acetamide, be directly used in next step reaction.1HNMR(400MHz，CDCl3,δ,ppm):2.0-2.18(m,NH2-CH2)3.27-3.28(m,3H,O-CH3),3.43-3.710(m,6H,CH—
CH2-CH,N-CH2-CH2),3.68-4.13(m,4H,O-CH2-CH),4.25-4.40(m,2H,O-CH-CH2),5.7-5.83(q,2H,O-CH-O)。
(2) 2, the fluoro-N-{2-methoxyl group of 2,2-tri--[1,3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl } preparation of-acetamide:
By 2,2, the fluoro-N-{2-methoxyl group of 2-tri--[1,3] dioxolanes-2-[4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl }-acetamide is dissolved in oxolane, add the sodium hydroxide solution of 1.0-2.0M, stirred overnight at room temperature, dichloromethane extraction, the dry pure compound 2-[2-methoxyl group-[1 that obtains, 3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)] ethamine. 1HNMR (400MHz, CDCl3):1.48(s,CH2-NH2),2.86-2.89(m,NH2-CH2),3.32-3.33(m,3H,CH3O),3.51-3.71(6H,CH—CH2-CH,N-CH2-CH2),3.80-4.18(m,4H,O-CH2-CH),4.32-4.52(m,2H,O-CH-CH2),5.74-5.86(q,2H,O-CH-O)。
(3) N-{2-[2-methoxyl group-[1,3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl } preparation of-2-Methacrylamide:
By 2-[2-methoxyl group-[1, 3] dioxolanes-4-(2-methoxyl group-[1, 3] dioxolanes-4-methylene oxygen)] ethamine, methacrylic acid N-succinimide ester and DMAP are dissolved in acetonitrile, its mol ratio is 1:(1-1.1): 1, lucifuge room temperature reaction 24-48 hour, evaporate to dryness is removed after acetonitrile, add ethyl acetate, wash through aqueous sodium carbonate, crude product separates (leacheate: ethyl acetate) through silica gel column chromatography, obtain product N-{2-[2-methoxyl group-[1, 3] dioxolanes-4-(2-methoxyl group-[1, 3] dioxolanes-4-methylene oxygen)]-ethyl }-2-methyl acrylamide monomer.1HNMR(400MHz,CDCl3,δ,ppm):1.97(s,3H,C-CH3),3.32-3.33(m,3H,O-CH3),3.48-3.75(m,8H,CH2-O-CH2,O-CH2-CH2-NH),3.77-4.2(m,4H,CH-O-CH2-CH),4.28-4.51(m,2H,O-CH-CH2),5.34-5.36(m,H,C＝CH2),5.71-5.76(m,2H,CH-(O)3),5.84-5.86(m,H,C＝CH2),6.30-6.38(d,H,CO-NH).13CNMR(400MHz,CDCl3,δ,ppm):18.49,42.27,63.13,65.64,66.02,71.62,72.55,74.05,75.02,115.40,115.89,119.81,139.70,168.49.ESI-MScalcdfor(C12H20O5),347.16；foundm/z,370.00(M+Na+)。
Embodiment 2
By 1.00g (2.88mmoL) N-{2-[2-methoxyl group-[1, 3] dioxolanes-4-(2-methoxyl group-[1, 3] dioxolanes-4-methylene oxygen)]-ethyl }-2-Methacrylamide, polyethylene glycol macromole evocating agent 0.52g (0.096mmoL), 2, 2-azo-bis-isobutyl cyanide 3.15mg (0.0192mmoL) accurately weighs the glass polymerization pipe of putting into dried and clean, then add N, dinethylformamide (2.5mL), the logical nitrogen of polymerization system tube sealing after degassed 30 minutes, polymerisation tube is put into 70 DEG C of oil bath heated polymerizables, react after 24 hours, reactant mixture is dissolved in to N, in dinethylformamide, then be added dropwise in ice ether, collect precipitum, use again the drip washing of a small amount of ice ether, product vacuum drying to constant weight obtains target copolymer p 1, this polymer property is in table 1.
Embodiment 3
By 1g (2.88mmoL) N-{2-[2-methoxyl group-[1,3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl }-2-Methacrylamide, polyethylene glycol macromole evocating agent 0.26g (0.048mmoL), 2,2-azo-bis-isobutyl cyanide 1.58mg (9.6 × 10-3MmoL) accurately weigh the glass polymerization pipe of putting into dried and clean, then add N, dinethylformamide (2.5mL), the logical nitrogen of polymerization system tube sealing after degassed 30 minutes, polymerisation tube is put into 70 DEG C of oil bath heated polymerizables, react after 24 hours, reactant mixture is dissolved in to N, in dinethylformamide, then be added dropwise in ice ether, collect precipitum, then use the drip washing of a small amount of ice ether, product vacuum drying to constant weight obtains target copolymer p 2, and this polymer property is in table 1.
Embodiment 4
By 1g (2.88mmoL) N-{2-[2-methoxyl group-[1,3] dioxolanes-4-(2-methoxyl group-[1,3] dioxolanes-4-methylene oxygen)]-ethyl }-2-Methacrylamide, polyethylene glycol macromole evocating agent 0.17g (0.032mmoL), 2,2-azo-bis-isobutyl cyanide 1.05mg (6.4 × 10-3MmoL) accurately weigh the glass polymerization pipe of putting into dried and clean, then add N, dinethylformamide (2.5mL), the logical nitrogen of polymerization system tube sealing after degassed 30 minutes, polymerisation tube is put into 70 DEG C of oil bath heated polymerizables, react after 24 hours, reactant mixture is dissolved in to N, in dinethylformamide, then be added dropwise in ice ether, collect precipitum, then use the drip washing of a small amount of ice ether, product vacuum drying to constant weight obtains target copolymer p 3, and this polymer property is in table 1.
The property representation of block copolymer P1-P3 in table 1 embodiment 2,3,4
A: recorded by GPC; B: calculated by 1HNMR
Embodiment 5
Polymer relies on the mensuration of pH degraded:
Copolymer p 2, respectively at pH=7.4, in 6,5,4 deuterated phosphate buffer, is configured to the micellar solution of 5mg/mL, in NMR (ADVANCE400) setup times, surveys1HNMR, taking ortho esters peak, 5.77-5.82 place as characteristic peak, after hydrolysis, 8.14 and 8.19 places are detected peaks, observe ortho esters hydrolysis rate, as Fig. 2. As can be seen from Fig., the esterolytic speed of corresponding ortho acid and its change in size have certain relation, and the variation of size depends on the esterolytic speed of ortho acid.
Embodiment 6
The preparation of block copolymer micelle:
Each block copolymer P1-P3 100mg is dissolved in to 1mLDMSO (adding a small amount of triethylamine), then the phosphate buffer of agitation and dropping 10mL50mMpH=7.4, dropwise rear vigorous stirring 8 hours, it is in 3500 bag filter that solution is transferred to molecular cut off, the dialysis 48 hours using water (adding a small amount of triethylamine) as dislysate, then solution in bag is transferred in 50mL centrifuge tube, freeze drying, obtains block copolymer micelle.
Embodiment 7
The mensuration of polymer micelle dimensional measurement and dependence pH change in size:
By copolymer micelle P1-P3 respectively at pH=7.4,, in 4 phosphate buffer, be configured to the micellar solution of 2mg/mL, solution is crossed 0.45 micron of filter, each solution in setup times, is measured its copolymer micelle change in size in Malvern ParticleSizer (MalvernZetasizerNanoZS), with pH=7.4 respectively, 0 hour time, be of a size of original dimension, P1-P3 average-size is respectively 166,180,192nm (Fig. 3). As can be seen from Figure 4, P2 micella is at pH=4, and under sour environment, when 48h, micella size approaches the size of polyethylene glycol macromole evocating agent, infers the rear complete disintegration of micellar structure of ortho esters degraded.
Embodiment 8
Cell toxicity test:
NIH3T3 cell (10000/hole) is inoculated in 96 well culture plates, cultivates 24 hours Fusion of Cells degree 60-80% under 37 DEG C and 5% carbon dioxide conditions. Copolymer solution is added and above-mentionedly inoculated, cultivate 96 orifice plates of NIH3T3 cell, continue to cultivate 24 hours. Every hole adds 20 microlitre MTT (5mg/mL), after 4 hours, draws culture medium, and every hole adds 150 microlitre DMSO, jolting 10 minutes, and in ELIASA (the multi-functional ELIASA of ThermoScientific), 570nm measures A value. Click formula and calculate cells survival rate: cells survival rate (%)=(Asample-Ablank)/(Acontrol-Ablank) × 100%. As can be seen from Figure 5, the survival rate of NIH3T3 cell is than control group, even under the condition of higher concentration 5mg/mL, cell survival rate, all 90%, proves that copolymer does not almost have cytotoxicity.
Embodiment 9
The 30mg copolymer p of embodiment 2 gained 1 is dissolved in 1mL methyl-sulfoxide and (adds a small amount of triethylamine) with hydrophobic drug model drug Nile red 10mg, stirring and dissolving mixes, then slowly drip the phosphate buffer of 10 times of volumes, after dropwising, continue and stir 8-24 hour, solution centrifugal, it is dialysis 2 days in 3500 bag filters that supernatant is transferred to molecular cut off, and solution freeze drying in bag filter obtains the micella of load module medicine Nile red. This micella is respectively got to 10mg, be dissolved in respectively in the phosphate buffer of 5mL50mMpH=7.4 and pH=5, be transferred to molecular cut off and be in 20000 dialysis tubing, and be placed in dialysis in corresponding buffer solution 300mL. Measure in predetermined time the amount that Nile red discharges from micella. As can be seen from Figure 6, the model drug Nile red of load discharges comparatively fast in micro-acid environment pH=5, only needs 11h just can discharge half, and in the time of 48h, due to the disintegration of micellar structure, Nile red almost discharges completely.
Claims (9)
1. a Methacrylamide ortho acid esters monomer, is characterized in that, its structure is as shown in chemical formula I:
2. contain two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters by the synthetic side chain of Methacrylamide ortho acid esters monomer claimed in claim 1, it is characterized in that, its structure is as shown in chemical formula II:
In formula, X represents numerical value 20-120.
3. a side chain as claimed in claim 2 is containing the synthetic method of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, it is characterized in that, concrete steps are as follows: by Methacrylamide ortho acid esters monomer, macromolecular chain transfer agent, initator, accurately weigh and put into dry glass polymerization pipe, its molar ratio is (20-200): 1:(0.1-0.5), logical nitrogen tube sealing after degassed 30 minutes, then polymerization pipe is placed into polymerization in the oil bath of 50-80 DEG C, react after 2-24 hour, by reactants dissolved in organic solvent, ice ether sedimentation for crude product, filter collecting precipitation, under room temperature, vacuum drying obtains target copolymer.
4. side chain according to claim 3 is containing the synthetic method of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, it is characterized in that, described macromolecular chain transfer agent structure is three sulfo-polyethylene glycols compounds of chemical formula III, and its molecular weight is 5400;
5. side chain according to claim 3, containing the synthetic method of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, is characterized in that, described side chain is 20-120 containing the degree of polymerization of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters; Described organic solvent is oxolane, methyl alcohol, ethanol, acetonitrile, acetone, chloroform, DMF, the one in dioxane, benzene, toluene, paraxylene; Described initator is 2,2-azodiisobutyronitrile.
6. a side chain as claimed in claim 2 is containing the application of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, it is characterized in that, described side chain forms micellar structure containing the self assembly in the aqueous solution of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, cause micella size difference according to close hydrophobic block ratio difference, and in self assembling process carrying medicament.
7. a polymeric micelle medicine composition, is characterized in that, comprise the micella of a kind of side chain as claimed in claim 2 containing two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters, and at least one is incorporated in the activating agent in this micella; Wherein said activating agent is selected from anti-inflammatory agent, cancer chemotherapeutic drug, immunodepressant, metabolic drug, Claritin, hepatosis treating medicine, nervous system medicine or circulation system disease medicine.
8. polymeric micelle medicine composition according to claim 7, is characterized in that, described cancer chemotherapeutic drug is selected from taxol, adriamycin, cyclosporin or BCNU.
9. polymeric micelle medicine composition according to claim 7, it is characterized in that, described activating agent is incorporated into side chain and comprises stirring, heating, ultrasonic wave, solvent evaporation or infiltration processing containing the method in the micella of two pentacyclic acid-sensitive amphipathic segmented copolymers of ortho esters.
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|---|---|---|---|---|
| CN101880265A (en) * | 2010-06-09 | 2010-11-10 | 江南大学 | Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof |
| CN103588749A (en) * | 2013-10-30 | 2014-02-19 | 安徽大学 | Novel methacrylamide monomer, preparation method of pH sensitive polycation genetic vector of methacrylamide monomer and application thereof |
-
2014
- 2014-06-04 CN CN201410245302.5A patent/CN104151284B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880265A (en) * | 2010-06-09 | 2010-11-10 | 江南大学 | Acid-sensitive polymeric micelle pharmaceutical composition and preparation method thereof |
| CN103588749A (en) * | 2013-10-30 | 2014-02-19 | 安徽大学 | Novel methacrylamide monomer, preparation method of pH sensitive polycation genetic vector of methacrylamide monomer and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Amphiphilic Block Copolymers Bearing Ortho Ester Side-Chains: pH-Dependent Hydrolysis and Self-Assembly in Water;Rupei Tang, et al.;《Macromol. Biosci》;20101231;第10卷;第192-201页 * |
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| CN104151284A (en) | 2014-11-19 |
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