Naphthalene ring-based precise self-degradation amphiphilic block oligomer, and synthesis method and application thereof
阅读说明：本技术 基于萘环的精确自降解两亲性嵌段寡聚物、合成方法及其应用 (Naphthalene ring-based precise self-degradation amphiphilic block oligomer, and synthesis method and application thereof ) 是由 刘世勇 吕长柱 于 2020-07-24 设计创作，主要内容包括：本发明涉及基于萘环的精确自降解两亲性嵌段寡聚物、合成方法及其应用。具体地,本发明基于触发式自降解聚合物设计了具有不同聚合度的分子量精确的两亲性嵌段寡聚物。利用慢加水的方式进行组装,依靠萘环之间的Π-Π相互作用和氨基甲酸酯之间的氢键相互作用,通过改变聚合度,可以得到不同的高级形貌结构。并且由于引入不对称结构(萘环),可以得到具有螺旋结构的组装形貌。引入光响应触发基元后,在相应波长光的照射下,形成的组装结构可以发生解体。该寡聚物具有单一的分子量,组装体疏水部分是含有萘环的自降解基元,相对于传统苯环的自降解基元可以更加快速的降解。这种寡聚物还可用于制备单分子型光刻胶,得到特征尺寸更加小且均一的微结构。(The invention relates to a naphthalene ring-based precise self-degradation amphiphilic block oligomer, a synthesis method and application thereof. Specifically, the invention designs amphiphilic block oligomers with different polymerization degrees and precise molecular weights based on the triggered self-degradation polymer. The assembly is carried out by slowly adding water, and different high-grade morphological structures can be obtained by changing the polymerization degree by means of pi-pi interaction between naphthalene rings and hydrogen bond interaction between carbamate. And due to the introduction of an asymmetric structure (naphthalene ring), an assembly morphology with a helical structure can be obtained. After the light response trigger element is introduced, the formed assembly structure can be disintegrated under the irradiation of light with corresponding wavelength. The oligomer has single molecular weight, and the hydrophobic part of the assembly is a self-degradation element containing naphthalene ring, so that the oligomer can be degraded more quickly compared with the self-degradation element of the traditional benzene ring. The oligomer can also be used for preparing monomolecular photoresist to obtain a microstructure with smaller and uniform characteristic dimension.)
1. An amphiphilic block oligomer of formula 1,
wherein the content of the first and second substances,
n is 1, 2, 3 or 4, and
r is selected from: r1
R2
R3
2. A method of making the amphiphilic block oligomer of claim 1, the method comprising:
(1) reacting a monomer of formula (i) with a light-triggered motif of formula (ii), removing the protecting group of the obtained product under the action of p-toluenesulfonic acid to continue the reaction with the monomer to obtain an oligomer intermediate
(2) (iv) reacting the oligomer intermediate with a branched glycol moiety of formula (iii) to give the amphiphilic block oligomer
Wherein n is 1, 2, 3 or 4, and
r is selected from: r1
R2
R3
3. The method of claim 2, wherein
Reacting a monomer of formula (i) with a photo-triggering moiety of formula (ii) in the presence of dibutyl tin Dilaurate (DBTL) at 70-110 ℃ for 2-8 hours and
(iv) reacting the oligomer intermediate with a branched glycol moiety of formula (iii) in the presence of dibutyl tin Dilaurate (DBTL) at 70-110 ℃ for 2-8 hours;
preferably, the molar ratio of the monomer of formula (i) to the light trigger element of formula (ii) is 1:1 to 4: 1;
preferably, the molar ratio of the oligomer intermediate to the branched glycol moiety of formula (iii) is from 1:1 to 1: 4;
preferably, the reaction of the monomer of formula (i) with the photo-triggering moiety of formula (ii) is carried out under a nitrogen atmosphere;
preferably, the reaction of the oligomer intermediate with the branched glycol moiety of formula (iii) is carried out under a nitrogen atmosphere.
4. An assembly prepared by self-assembly of the amphiphilic block oligomer of claim 1.
5. The assembly of claim 4, wherein the oligomer is of formula (I)
The assembly is a sheet-like assembly,
preferably, the height of the lamellar assembly is 1 to 20nm, for example 5 nm.
6. The assembly of claim 4, wherein the oligomer is an oligomer of formula (II)
The assembly is a nanobelt-shaped assembly.
7. The assembly of claim 4, wherein the oligomer is an oligomer of formula (III)
The assembly is a long linear assembly,
preferably, the long linear assembly has a length of 50nm to 2000nm, and more preferably, the long linear assembly has a helical structure.
8. The assembly of claim 4, wherein the oligomer is of formula (IV)
The assembly is an assembly with chiral extinction effect,
preferably, the assembly has a chiral extinction effect, optical activity and a circular dichroism signal.
9. The amphiphilic block oligomer according to claim 1 or the assembly according to any one of claims 4-8, wherein the molecular chain of the oligomer is degraded or the assembly disintegrates under UV irradiation,
preferably, the wavelength of the ultraviolet light is 200nm to 400 nm.
10. A method of assembling in an aqueous solution to obtain an assembly according to any one of claims 4-8, the method comprising:
dissolving the oligomer of any one of claims 3-7 in a pure organic solvent, and slowly dripping water into the obtained solution, and then removing the organic solvent by dialysis to obtain an assembly with a corresponding morphological structure;
preferably, the organic solvent is selected from one or more of tetrahydrofuran, 1, 4-dioxane and DMF;
preferably, the concentration of the oligomer in the solution is 0.1-5 mg/mL;
preferably, the volume ratio of the water to the organic solvent is 1: 1-10: 1;
preferably, the time for dripping the water is 1-10 h.
Technical Field
The invention relates to the field of polymer synthetic chemistry, in particular to a synthetic preparation method of a naphthalene ring-based precise self-degradation oligomer, and researches the assembly characteristics of the oligomer.
Background
Self-assembly of amphiphilic block copolymers is a simple and general method for constructing nanomaterials from bottom to top in solution. By changing the molecular weight ratio of the hydrophobic part and the hydrophilic part of the block copolymer, assemblies with different geometrical morphologies including micelles, vesicles, cylindrical phases and lamellae can be obtained. Conventional block copolymers are generally linear-linear structures, and in order to expand the morphology of the assembly, one of the linear blocks is replaced by a branched topology, and such linear-branched block copolymers (LDBCs) may have an assembly structure different from that of the conventional block copolymers. The group Stupp project utilizes the LDBC to obtain a nano-belt-shaped assembly in dichloromethane through pi-pi stacking and intermolecular hydrogen bonding (J Am Chem Soc 2001,123(17), 4105-4106); chiral supramolecular assemblies with helical structures can be further obtained by introducing chiral alkyl chains (J Am Chem Soc 2005,127(22), 7992-3). The Gitsov topic group utilizes Atom Transfer Radical Polymerization (ATRP) to synthesize an amphiphilic LDBC, and can obtain assemblies with high-grade shapes such as worm-like micelles, bicontinuous phases and onion shapes by changing the branching degrees of good solvents and hydrophilic branched parts (Macromolecules 2019,52(15), 5563-5573).
In recent years, chemists developed a triggered Self-degradable Polymer (SIP), and the molecular backbone of the triggered Self-degradable Polymer can undergo cascade depolymerization similar to domino under a specific stimulation effect, so that an assembly is dissociated, and the molecule can be used in the fields of drug delivery carriers, Self-repairing materials, shape memory materials and the like. The Moore group utilizes SIP to manufacture a microcapsule with a core-shell structure, the shell is composed of crosslinked self-degradable polymer, the content is liquid self-repairing material, under the specific stimulation, the wall of the microcapsule shell is decomposed along with the molecular degradation of the self-degradable polymer through the observation of a scanning electron microscope, and the content is released (J Am Chem Soc 2010,132(30), 10266-. The group of subjects to which the applicant belongs is further expanded, and amphiphilic linear copolymers (J Amchem Soc 2014,136(20),7492-7) and branched copolymers (J Amchem Soc 2015,137(36),11645-55) are manufactured based on self-degradable polymers, so that stable assemblies are formed in aqueous solution, and programmed enzymatic reaction and ultra-sensitive monitoring are realized.
However, conventional self-degradable polymers are generally prepared by condensation polymerization, and the preparation method is simple and rapid, but the molecular weight distribution of the resulting polymers is generally broad, and thus precise control of molecules and assemblies is difficult to achieve. The polypeptide is an important molecule constituting a living body, and the accuracy of its molecular weight and amino acid sequence is very important for the realization of its function. The artificial synthesis of polypeptide usually uses solid phase synthesis method, and the obtained polypeptide has single molecular weight and precise sequence structure. In recent years, chemists have made many important advances in the field of precise polymer synthesis. The Lutz project group designed a monodisperse polyalkoxyamine amide by an iterative strategy using two selective chemical reactions and introduced a binary code in its sequence to encrypt, which molecule could then be decoded by tandem mass spectrometry (Nat Commun 2015, 6.). The highly topic group successfully synthesized a series of cation sequenced polymers with quaternary ammonium backbone of up to 12 repeat units and characterized their precise structure by alternating Menschutkin reaction and copper catalyzed azide-alkyne cycloaddition reaction (CuAAC) (J Am Chem Soc 2019,141(11), 4541-4546.).
In view of the above, the applicant designs a series of naphthalene ring-containing linear polyurethanes with different polymerization degrees and precise molecular weights based on the efficient coupling reaction of isocyanate and hydroxyl, and the main chain of the linear polyurethanes can be subjected to cascade depolymerization; and a precise amphiphilic LDBC is obtained by connecting hydrophilic branched glycol at the tail end of the LDBC. By means of slow water addition, LDBC with different polymerization degrees can form various assemblies with different morphologies in aqueous solution under the same assembly condition. This precise molecule is of great interest for exploring the mechanisms of assembly inherent to the molecule.
Disclosure of Invention
The invention designs a new route by using a method for synthesizing polypeptide with an accurate structure by protection-deprotection used in the traditional solid phase synthesis, synthesizes a series of naphthalene ring-based accurate self-degradation amphiphilic block oligomers with different polymerization degrees, and obtains assemblies with different high-grade morphological structures by using a cosolvent method. The assembly can be further disintegrated by illumination, so that the assembly can be used in the fields of drug transport carriers and photoresists.
In one aspect, the present invention provides a precisely self-degrading amphiphilic block oligomer based on naphthalene rings, said oligomer consisting of three parts: a) a light trigger element derived from 3, 4-dihydroxybenzaldehyde and containing two hydrophobic alkyl chains and an o-nitrobenzyloxycarbonyl group; b) a hydrophobic naphthalene ring based degradable repeating unit linked by carbamate linkages; c)
a)
Wherein the content of the first and second substances,
b)
wherein n is 0,1, 2, 3 or 4
c)
The accurate self-degradation amphiphilic block oligomer based on naphthalene ring has the following structure:
wherein the content of the first and second substances,
n is 1, 2, 3 or 4, and
r is selected from:
in one aspect, the present application also provides a method for synthesizing the above-mentioned precisely self-degradable amphiphilic block oligomer, the method comprising:
(1) reacting a monomer of formula (i) with a light-triggered motif of formula (ii), removing the protecting group of the obtained product under the action of p-toluenesulfonic acid to continue the reaction with the monomer to obtain an oligomer intermediate
(2) (iv) reacting the oligomer intermediate with a branched glycol moiety of formula (iii) to give the amphiphilic block oligomer
Wherein n is 1, 2, 3 or 4, and
r is selected from:
in some embodiments, the monomer of formula (i) is reacted with the photo-triggering moiety of formula (ii) in the presence of dibutyl tin Dilaurate (DBTL) at 70-110 ℃ for 2-8 hours.
In some embodiments, the oligomer intermediate is reacted with the branched glycol moiety of formula (iii) in the presence of dibutyl tin Dilaurate (DBTL) at 70-110 ℃ for 2-8 hours.
In some embodiments, the molar ratio of the monomer of formula (i) to the photo-triggering moiety of formula (ii) is from 1:1 to 4: 1.
In some embodiments, the molar ratio of oligomer intermediate to branched glycol moiety of formula (iii) is from 1:1 to 1: 4.
Preferably, the reaction of the monomer of formula (i) with the photo-triggering moiety of formula (ii) is carried out under a nitrogen atmosphere.
Preferably, the oligomer intermediate is reacted with the branched glycol moiety of formula (iii) under a nitrogen atmosphere.
Specifically, the main idea of the synthesis method is as follows: under the action of catalyst, isocyanate and hydroxyl can produce high-efficiency coupling reaction. One end of the monomer used is acyl azide which is a precursor of isocyanate, and the hydroxyl group at the other end is protected by tert-butyl dimethyl silicon group. Under the heating condition, acyl azide can be converted into isocyanate which can react with hydroxyl of oligomer to obtain a section of oligomer with tert-butyl dimethyl silicon base protective hydroxyl. Under the action of p-toluenesulfonic acid, protecting groups are removed, hydroxyl groups are exposed, and the reaction with monomers is continued. And repeating the steps to obtain a series of oligomers with different polymerization degrees.
The obtained serial oligomers with hydroxyl end continue to react with the hydrophilic branched glycol part with acyl azide end to obtain the final precise amphiphilic block oligomer.
In another aspect, the invention provides assemblies prepared by self-assembly of the amphiphilic block oligomers of the invention.
In another aspect, the present invention provides a method of assembling in an aqueous solution to obtain assemblies having different morphologies, the method comprising: the amphiphilic block oligomer is dissolved in a pure organic solvent, water is slowly dripped into the obtained solution, and then the organic solvent is removed through dialysis to obtain an assembly with a corresponding morphological structure.
In some embodiments, the organic solvent is selected from one or more of tetrahydrofuran, 1, 4-dioxane, and DMF.
In some embodiments, the concentration of the oligomer in the solution is 0.1-5 mg/mL.
In some embodiments, the volume ratio of water to organic solvent is from 1:1 to 10: 1.
In some embodiments, the time for dropping the water is 1 to 10 hours.
In some embodiments, the invention provides lamellar assemblies prepared by self-assembly of oligomers of formula (I) and methods of making the lamellar assemblies.
The method comprises the following steps: the oligomer of formula (I) is dissolved in a pure organic solvent (e.g. tetrahydrofuran), and water is slowly dropped into the resulting solution, followed by removal of the organic solvent (e.g. tetrahydrofuran) by dialysis to obtain a lamellar assembly.
In some embodiments, the lamellar assembly has a height of 1 to 20nm, such as 5 nm.
In some embodiments, the present invention provides a nanobelt-shaped assembly prepared by self-assembly of oligomers of formula (II) and a method for preparing the same.
The method comprises the following steps: the oligomer of formula (II) is dissolved in a pure organic solvent (e.g., tetrahydrofuran), and water is slowly dropped into the resulting solution, and then the organic solvent (e.g., tetrahydrofuran) is removed by dialysis to obtain a nanobelt-shaped assembly.
In some embodiments, the invention provides long linear assemblies prepared by self-assembly of oligomers of formula (III) and methods of making the long linear assemblies.
The method comprises the following steps: the oligomer of formula (III) is dissolved in a pure organic solvent (e.g. tetrahydrofuran), and water is slowly dropped into the resulting solution, followed by removal of the organic solvent (e.g. tetrahydrofuran) by dialysis to obtain a long linear assembly.
In some embodiments, the long linear assemblies have a length of 50nm to 2000 nm. For example, the length of the long linear assembly may be only about 100nm, or may be up to several micrometers. The resulting long linear assembly also has a pronounced helical structure.
In some embodiments, the invention provides an assembly with chiral extinction effect prepared by self-assembly of oligomers of formula (IV) (the hydrophobic core of the assembly introduces chiral citronellol) and a method of preparing the assembly with chiral extinction effect.
The method comprises the following steps: the oligomer of formula (IV) is dissolved in a pure organic solvent (e.g. tetrahydrofuran) and water is slowly added dropwise to the resulting solution, followed by removal of the organic solvent (e.g. tetrahydrofuran) by dialysis to obtain an assembly with chiral extinction effect.
In some embodiments, the assemblies have a strong chiral extinction effect, are optically active, and have a strong circular dichroism signal.
In one aspect, the oligomers and assemblies thereof of the present invention degrade under ultraviolet light irradiation. In some embodiments, both the oligomer and the assembly are substantially completely degraded after 30 minutes of uv irradiation.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a light trigger element synthesized in preparation example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of an intermediate synthesized in preparation example 2 of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of a naphthalene ring-containing self-degradation monomer synthesized in preparation example 2 of the present invention;
FIG. 4 is a NMR hydrogen spectrum of a hydrophilic branched glycol synthesized in preparation example 3 of the present invention;
FIG. 5 is a gel permeation chromatogram of a precisely self-degrading oligomer synthesized in preparative example 4 of the present invention;
FIG. 6 is a gel permeation chromatogram of a precisely self-degradable amphiphilic block oligomer synthesized in preparative example 5 of the present invention;
FIG. 7 is a matrix-assisted laser desorption time-of-flight mass spectrum of a precisely self-degradable amphiphilic block oligomer synthesized in preparation example 5 of the present invention;
FIG. 8a is a cryo-TEM image of the lamellar assembly prepared in assembly example 1 according to the present invention; FIG. 8b is an atomic force microscope photograph of the lamellar assembly prepared in Assembly example 1 of the present invention;
FIG. 9 is a TEM image of a nanobelt-shaped assembly prepared in Assembly example 2 of the present invention;
FIG. 10a is a cryo-transmission electron micrograph of a nanowire-shaped assembly prepared in Assembly example 3 according to the present invention; FIG. 10b is an atomic force microscope photograph of a nanowire-shaped assembly prepared in Assembly example 3 of the present invention;
FIG. 11 shows the results of circular dichroism measurements of the assemblies with chiral extinction effect prepared in assembly example 4 of the present invention;
FIG. 12 is a single chain degradation GPC trace of a precisely self-degrading amphiphilic block oligomer of the present invention;
FIG. 13 shows the results of fluorescence tracing of degradation release of Nile Red coated assemblies of the present invention from precisely self-degrading amphiphilic block oligomers.
Detailed Description
The invention relates to synthesis and assembly of a self-degradable oligomer with accurate polymerization degree based on naphthalene rings, wherein the main chain of the oligomer is connected by carbamate bonds, and 1, 4-electronic rearrangement can occur to generate cascade depolymerization under the triggering of a corresponding triggering event to generate carbon dioxide and para-aminonaphthalene methanol. Hydrophilic branched glycol segments are connected around the self-degradable oligomer to form an amphiphilic block copolymer, and the polymerization degree of the self-degradable oligomer is changed in the same assembly mode to obtain assemblies with different morphological structures.
Traditional self-degradable polymers are generally obtained through polycondensation, and generally have wide molecular weight distribution, so that the morphology obtained by assembly is not uniform enough, and the polymers prepared each time are difficult to be completely consistent, so that the repeatability is poor. The oligomer obtained by the iterative mode provided by the application has single molecular weight, high repeatability and uniform appearance obtained by assembly. And due to the introduction of naphthalene rings, compared with the traditional self-degradation polymer containing benzene rings, the degradation is faster. Therefore, the nano-silver-doped silicon dioxide has an application prospect of being used as a carrier for quickly releasing drugs and a novel monomolecular photoresist.
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.
Preparation example 1: synthesis of optical trigger elements
The optical trigger element used in the present invention is obtained by:
1) 3, 4-dihydroxybenzaldehyde (7.2mmol,1.00g), octadecyl bromide (15mmol,5.00g) and potassium carbonate (15mmol,1.20g) were dissolved in 50mL DMF, a catalytic amount of potassium iodide was added, and the reaction was stirred under nitrogen at 90 ℃ for 12 h. Cooled to room temperature, and the reaction was poured into 150mL of H2HCl (100:50), dichloromethane was added to extract, and the extract was dried over anhydrous sodium sulfate to remove the solvent. The crude product was recrystallized from ethanol to yield 3.8g of intermediate (82%).
2) The intermediate (3.1mmol, 2g) synthesized in the previous step was dispersed in 10mL of dichloromethane, 16mL of concentrated nitric acid was added dropwise under ice-bath conditions, and the reaction was continued for 4h at room temperature. The reaction solution is sequentially added with 5 percent NaHCO3The aqueous solution, water and saturated brine were washed, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2g (93%) of a green solid product.
3) The intermediate (2.9mmol, 2g) synthesized in the previous step was dissolved in 50mL THF, 5mL methanol was added, stirred in ice bath for 15min, sodium borohydride (2.9mmol, 0.11g) was slowly added thereto, reacted at room temperature in the dark for 5h, and purified by column chromatography using petroleum ether-ethyl acetate as eluent to give 1.75g (87%) of the final product. The structure is characterized by nuclear magnetic hydrogen spectrum, the result is shown in figure 1, and the structure of the synthesized light trigger element is proved.
Preparation example 2: synthesis of naphthalene ring-containing self-degradation monomer
The naphthalene ring-containing self-degradable monomer used in the present invention is obtained by:
1) 4-hydroxymethylnaphthoic acid (1.01g,5mmo1, synthesized according to J.Med.chem.2002,45, 5755-5775), imidazole (0.68g,10mmol), a catalytic amount of 4-dimethylaminopyridine were dissolved in 30mL of DMF and stirred in ice bath for 15 min. Tert-butyldimethylsilyl chloride (1.13g,7.5mmo1) was dissolved in 20mL of DMF, and the resulting solution was added dropwise to the reaction system using a constant pressure dropping funnel, followed by reaction at room temperature for 12 hours. A large amount of saturated brine was added thereto, followed by extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, and column chromatography with petroleum ether-ethyl acetate as eluent to give 1.42g (90%) of the product. The structure of the intermediate is characterized by nuclear magnetic hydrogen spectrum, and the result is shown in figure 2, which proves the structure of the synthesized intermediate.
2) The intermediate (5.4mmol, 1.7g) synthesized in the previous step was dissolved in 20mL of THF, and ice-cooled for 15min, to which triethylamine (6.5mmol, 0.66g) and diphenylphosphorylazide (6.5mmol, 1.79g) were slowly added in this order, followed by stirring at room temperature for 4 h. The reaction system is washed by water, saturated salt water and ethyl acetate in sequence, an organic phase is dried by anhydrous sodium sulfate, and then is separated and purified by column chromatography by taking petroleum ether-ethyl acetate as an eluent to obtain 1.47g (80%) of a final white solid product. The structure is characterized by nuclear magnetic hydrogen spectrum, and the result is shown in figure 3, which proves the structure of the synthesized naphthalene ring-containing self-degradation monomer.
Preparation example 3: synthesis of hydrophilic branched glycols
The hydrophilic branched glycols used in the present invention are obtained by:
1)
2) The intermediate (4.2mmol, 5.6g) synthesized in the previous step was dissolved in 100mL of methanol, heated to reflux, potassium hydroxide (8.4mmol, 0.47g) was added to the flask, and reacted at 70 ℃ for 12h under reflux. After cooling to room temperature, the pH was adjusted to 3 with 1M hydrochloric acid, extraction was performed with dichloromethane, and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 5.27g (95%) of a viscous liquid product.
3) The intermediate (0.38mmol, 0.5g) synthesized in the previous step was dissolved in 10mL of THF, and ice-cooled for 15min, to which triethylamine (0.45mmol, 0.05g) and diphenylphosphorylazide (0.45mmol, 0.12g) were slowly added in this order, followed by stirring at room temperature for 4 h. The reaction system was washed with water, saturated brine, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give 0.46g (90%) of the final viscous transparent liquid product. The structure is characterized by nuclear magnetic hydrogen spectrum, and the result is shown in figure 4, which proves the structure of the synthesized hydrophilic branched glycol.
Preparation example 4: precision self-degrading oligomer synthesis
The exact self-degrading oligomer of the terminal hydroxyl group used in the present invention is obtained by the following iterative manner:
the acyl azide functional group of the naphthalene ring self-degradation monomer is converted into isocyanate under the heating condition, and can react with a light trigger element with the terminal being hydroxyl under the action of a catalyst dibutyl tin dilaurate to obtain the oligomer with the terminal tert-butyl dimethyl silicon group protecting hydroxyl connected by a carbamate bond. The tert-butyl dimethyl silicon base can be removed by p-toluenesulfonic acid to obtain the oligomer with the terminal hydroxyl, and the method is continuously repeated to obtain the self-degradable oligomer with accurate molecular weight.
The general iterative preparation method is as follows: the light trigger (0.72mmol, 0.5g) from
The general method for deprotection of the hydroxyl groups is as follows: the above-mentioned terminal hydroxyl group-protected oligomer (0.2mmol, 0.2g) was dissolved in 10mL of a mixed solvent of THF: MeOH (10:1), p-toluenesulfonic acid (0.02mmol, 4mg) was slowly added under ice bath, reacted at room temperature for 4h, the reaction was precipitated in excess methanol, and the precipitation-dissolution cycle was performed 3 times to obtain 0.16g (93%) of a terminal hydroxyl group-exposed oligomer. The structure was characterized by Gel Permeation Chromatography (GPC), and the results are shown in fig. 5, demonstrating the structure of the synthesized precision self-degrading oligomer.
Preparation example 5: synthesis of precise self-degradable amphiphilic block oligomer
The precisely self-degradable amphiphilic block oligomer used in the present invention is obtained by:
the general preparation method is as follows (taking n ═ 4 as an example): the hydroxyl-terminated oligomer obtained in production example 4 (0.034mmol, 50mg), the hydrophilic branched glycol having a terminal hydroxyl group obtained in production example 3 (0.068mmol, 90mg), and 1 drop of dibutyltin dilaurate were dissolved in dry toluene, and reacted at 85 ℃ for 4 hours under nitrogen protection. Cooled to room temperature, the reaction precipitated in excess methanol, and the precipitate was separated by preparative gel permeation chromatography using a cycle to yield 40mg (43%) of the precision self-degrading amphiphilic block oligomer. The structure was characterized by Gel Permeation Chromatography (GPC), and the results are shown in fig. 6, demonstrating the structure of the synthesized intermediate. The structure was also confirmed by matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF), and the results are shown in FIG. 7.
Assembly example 1: preparation of a lamellar Assembly
1mg of the amphiphilic block oligomer (n ═ 2) in preparation example 5 was weighed out and dissolved in 1mL of a co-solvent dioxane (1mg/mL), and stirred at 500rpm, and 9mL of water was slowly added thereto at a rate of 1mL/h using a syringe pump. The solution was stirred for a further 2 hours, then transferred to a dialysis membrane and dialyzed against water to remove dioxane (molecular weight cut-off: 14000Da), dialyzed against pure water and replaced with water several times. The structure was confirmed by Cryo-transmission electron microscopy (Cryo-TEM) (FIG. 8a) and Atomic Force Microscopy (AFM) (FIG. 8b), respectively.
Assembly example 2: preparation of Nanocap Assembly
1mg of the amphiphilic block oligomer (n ═ 3) of preparation example 5 was weighed out and dissolved in 1mL of dioxane as a cosolvent (1mg/mL), and stirred at 500rpm, and 9mL of water was slowly added thereto at a rate of 1mL/h using a syringe pump. The solution was stirred for a further 2 hours, then transferred to a dialysis membrane and dialyzed against water to remove dioxane (molecular weight cut-off: 14000Da), dialyzed against pure water and replaced with water several times. A Cryo-transmission electron micrograph (Cryo-TEM) of the specimen is shown in FIG. 9.
Assembly example 3: preparation of nanowire-shaped Assembly
1mg of the amphiphilic block oligomer (n ═ 3) of preparation example 5 was weighed out and dissolved in 1mL of dioxane as a cosolvent (1mg/mL), and stirred at 500rpm, and 9mL of water was slowly added thereto at a rate of 1mL/h using a syringe pump. The solution was stirred for a further 2 hours, then transferred to a dialysis membrane and dialyzed against water to remove dioxane (molecular weight cut-off: 14000Da), dialyzed against pure water and replaced with water several times. The structure was confirmed by Cryo-transmission electron microscopy (Cryo-TEM) (FIG. 10a) and Atomic Force Microscopy (AFM) (FIG. 10b), respectively.
Assembly example 4: preparation of chiral assemblies
1mg of the below-indicated chiral center-introduced amphiphilic block oligomer was weighed out and dissolved in 1mL of dioxane as a cosolvent (1mg/mL), stirred at 500rpm, and 9mL of water was slowly added thereto at a rate of 1mL/h using a syringe pump. The solution was stirred for a further 2 hours, then transferred to a dialysis membrane and dialyzed against water to remove dioxane (molecular weight cut-off: 14000Da), dialyzed against pure water and replaced with water several times. The assembly was subjected to circular dichroism testing, and the results are shown in fig. 11.
Degradation example 1: precise self-degradation amphiphilic block oligomer single-chain horizontal degradation
5mg of the amphiphilic block oligomer of preparation example 5 (n ═ 3) was weighed out and dissolved in 1mL of THF: MeOH: H2O (8:1:1) (5mg/mL), adding monodisperse polystyrene (M24000 Da) as a standard sample, filtering the system through a 220nm organic filter membrane, irradiating the system for 30min in a quartz bottle by using an ultraviolet curing lamp (with the wavelength of 200-400 nm) and monitoring the degradation process by using Gel Permeation Chromatography (GPC) at intervals of 1h, 3h and 6 h. The degradation results monitored by GPC are shown in fig. 12.
Degradation example 2: degradation of precision self-degradable amphiphilic block oligomer assembly
A dioxane mother liquor of 1mM nile red was prepared, 10 μ L of a 1g/L solution of the amphiphilic block oligomer (n ═ 4) of preparation example 5 in a dioxane solution was added, 9mL of water was slowly added at 25 ℃ at a rate of 1mL/h, and then dioxane was removed by dialysis. Irradiating the assembly coated with Nile red by using an ultraviolet curing lamp (with the wavelength of 200-400 nm), and taking a sample every 5min to track the degradation process by using a fluorescence spectrometer. The degradation results monitored by fluorescence spectroscopy are shown in fig. 13.
The present invention has been described in detail above, but the present invention is not limited to the specific embodiments described herein. It will be understood by those skilled in the art that other modifications and variations may be made without departing from the scope of the invention. The scope of the invention is defined by the appended claims.