A method for in situ synthesis of unimolecular micelles via pH-responsive dynamic covalent boronate bonds promoted by electrostatic interactions

Abstract

The present invention discloses a method for in-situ synthesis of single-molecule micelles by electrostatically promoted pH-responsive dynamic covalent borate ester bonds. The original supramolecular micelles are mixed micelles of sodium dodecyl sulfate surfactant and dodecyl maltodextrin surfactant. The biphenylboronic acid linker molecules are anchored on the surface of the mixed micelles through electrostatic interaction with SDS to promote BTEAB and DM to form dynamic covalent single-molecule micelles. The pH of the borate ester in the single-molecule micelles is 1.17kJ / cm2. K a =8.37, across p K a The narrow pH range has pH-responsive function, an S-L two-phase system is obtained at pH ≤ 8.0, and a unimolecular micellar solution is obtained at pH ≥ 8.8. The phase behavior caused by pH swing, the change of BTEAB concentration in the solution, the interaction at different pH values, and the fluorescence spectrum measurement of BTEAB itself indicate that the unimolecular micelles synthesized in situ with pH-responsive dynamic covalent borate bonds promoted by electrostatic interaction are successfully prepared.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparing small molecule surfactant micelles by in-situ covalently linking the surfactant with a double-headed linker molecule to generate single-molecule micelles, and specifically relates to a method for in-situ synthesis of single-molecule micelles by pH-responsive dynamic covalent borate bonds promoted by electrostatic interaction. Background Art

[0002] The microstructure of surfactant micelles, composed of a polar shell and a hydrophobic core, plays an irreplaceable and important role in biomimetics, pharmaceuticals, and a wide range of other industrial and daily applications. Due to the coexistence of polar and non-polar heterogeneous microenvironments within micelles, most applications involve solubilization of micelles or loading of guest molecules. The weak intermolecular interactions that drive the formation of micelle supramolecules determine that micelles and monomers are in a dynamic equilibrium state in solution. This property means that micelles are at risk of guest molecule leakage due to dissociation in complex fluids, thus limiting their application in certain fields. Using dynamic covalent bonds to connect the molecules that constitute micelles in situ can greatly avoid micelle dissociation while retaining the main advantages of micelles, thereby expanding the application of surfactant micelles. Unimolecular micelles are structurally characterized by nanometer size and porosity. However, because the alkyl chains within the hydrophobic core are in a sol phase, their pore size has multi-level variability, which falls into the category of soft materials. Therefore, unimolecular micelles as carriers have the advantages of both supramolecular micelles and porous nanoparticles, and have huge application potential and broad expansion space.

[0003] The in situ synthesis of single-molecule micelles from small-molecule surfactant micelles is a new concept and technology. Typical single-molecule micelle preparation techniques are based on classical polymer synthesis, which involves extensive synthetic work and costs. Another approach is to synthesize single-molecule micelles by in situ ligation based on polymer micelles. These single-molecule micelles are larger in size, have unclear hydrophobic and hydrophilic domains, and have random ligation sites along the polymer chain. Summary of the Invention

[0004] The technical problem solved by the present invention is to provide a method for preparing unimolecular micelles based on in situ covalent linkage of small molecule surfactant mixed micelles. The method designs and synthesizes a biphenylboronic acid linker molecule (BTEAB) with an ethylenediammonium spacer group, which can be anchored on the surface of negatively charged micelles (such as SDS micelles) through positive charge sites. At a pH greater than the pK a When the BTEAB micelles are surrounded by borate anions, if pure SDS micelles are replaced by mixed micelles of SDS and DM (maltodextrin surfactant), the electrostatically anchored BTEAB reacts with DM to form boric acid diol esters, thus obtaining pH-responsive, dynamically covalently cross-linked unimolecular micelles.

[0005] The present invention adopts the following technical solution to solve the above technical problems, which is a method for in situ synthesis of single-molecule micelles with dynamic covalent borate bonds in response to pH promoted by electrostatic interaction. The method is characterized in that the specific process is as follows: the original supramolecular micelle is a mixed micelle of sodium dodecyl sulfate (SDS) surfactant and dodecyl maltodextrin (DM) surfactant, and the biphenylboronic acid linker molecule (BTEAB) is anchored on the surface of the mixed micelle through electrostatic interaction with SDS, promoting the formation of dynamic covalent single-molecule micelles between BTEAB and DM, and the pK of the borate in the single-molecule micelle is 0. a =8.37, across pK a The narrow pH range has pH response function, pH ≤ 8.0 to obtain SL two-phase system, pH ≥ 8.8 to obtain unimolecular micelle solution, the structural formula of the unimolecular micelle is:

[0006]

[0007] It is further defined that the molar ratio of the sodium lauryl sulfate surfactant to the lauryl maltodextrin surfactant in the mixed micelles is 2:1, and the surface of the mixed micelles is rich in negative charges and hydroxyl groups.

[0008] It is further defined that the synthetic route of the biphenylboronic acid linker molecule is:

[0009]

[0010] It is further defined that the interaction between BTEAB and SDS / DM mixed micelles is as follows: the two quaternary ammonium cations of BTEAB electrostatically interact with the sulfate anions of SDS in the mixed micelles, anchoring the BTEAB ions on the surface of the mixed micelles; the two boronic acid head groups of BTEAB react with the polyhydroxyl groups of DM to form pH-responsive dynamically covalently bonded borate esters, thereby synthesizing unimolecular micelles in situ.

[0011] It is further defined that the electrostatic interaction between BTEAB and SDS anchors BTEAB on the surface of mixed micelles, promoting the formation of ester bonds between BTEAB and DM. At this time, the pK a =8.37. When pH≤8.0, the ester bond breaks to obtain a sparingly soluble salt of BTEAB and SDS. When pH≥8.8, it becomes a unimolecular micelle solution, realizing the pH-responsive unimolecular micelle synthesis.

[0012] It is further defined that the unimolecular micelle is a pH-responsive soft nanocarrier.

[0013] The present invention has the following advantages and beneficial effects: the particle size of the unimolecular micelles prepared in situ from small molecule surfactant micelles is less than 10 nm, the molecular weight is limited by the micelle aggregation number, and it is not easy to precipitate in an aqueous solvent. The aromatic borate is used for covalent bonding, and the conversion of unimolecular micelles responsive to pH stimulation to supramolecular micelles can be achieved, thereby constructing a more valuable soft nanocarrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the phase diagram of a dilute ternary BTEAB / SDS / DM solution. The single-component angle corresponds to a concentration of 10 mM. L, S+L, and C represent the liquid phase, solid-liquid two-phase region, and flocculated-liquid two-phase region, respectively. S+L represents the phase region at pH 8.0, and C represents the phase region at pH 8.8. The dots with varying shades of color represent the region centered around the ternary BTEAB / SDS / DM composition of 0.25 / 0.5 / 0.25.

[0015] Figure 2 The absorbance of BTEAB at 266 nm in a BTEAB / SDS / DM ternary mixed solution changes with the pH value of the solution and its first-order derivative curve. The measurement temperature is 25°C.

[0016] Figure 3 The molar ratio of residual BTEAB in a 1:2:1 BTEAB / SDS / DM ternary system between pH 8.0 (S+L two-phase) and pH 8.8 (single-phase). BTEAB concentration was measured by UV absorbance, and digital images show the precipitate formation process. The experimental temperature was 25°C.

[0017] Figure 4 Intrinsic fluorescence spectra of BTEAB in aqueous solution (solid line), SDS aqueous solution (dotted line) and SDS / DM aqueous solution (short dash line), respectively, the solutions contain 100 mM phosphate, pH ≥ 8.8. DETAILED DESCRIPTION

[0018] The above contents of the present invention are further described in detail below through examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention.

[0019] Example

[0020] SDS is an anionic surfactant. BTEAB is anchored on the micelle surface through electrostatic attraction between the positive charge of quaternary ammonium salt and the negative charge of SDS micelle. That is, BTEAB, as the counterion of SDS, exists in a dynamic balance between free ions and electrostatically bound ions in the solution. DM is a polyhydroxy nonionic surfactant that undergoes an esterification reaction with the boric acid of BTEAB to form boric acid diol ester, especially at pH>pK a The binding constant is large when (BTEAB) ± 1. The structural formula of the unimolecular micelle indicates that the diol hydroxyl groups of the borate ester bond originate from the same DM molecule. Due to the thermal motion restriction of the mixed micelle on the DM and BTEAB molecules, the two alcohol hydroxyl groups of the borate ester may originate from the same DM head group or from two adjacent DM head groups, forming an ester-linked network structure and obtaining in situ dynamic covalent ester-bonded unimolecular micelles.

[0021] Based on the design of the ternary BTEAB / SDS / DM system, SDS is the limiting molecule that anchors BTEAB on the micelle surface. However, in the BTEAB / SDS mixed system without DM, BTEAB is only the counterion of the micelle, and charge neutralization causes phase separation in a wide composition range. DM is a hydroxyl donor molecule for dynamic covalent ester bonds, but its weak affinity is insufficient to resist the thermal motion of BTEAB and cannot form unimolecular micelles with DM. Figure 1 This is a quasi-ternary phase diagram for a dilute BTEAB / SDS / DM solution. The single-component angle corresponds to a concentration of 10 mM. The gradient dots represent the ternary BTEAB / SDS / DM composition centered at 0.25 / 0.5 / 0.25. Near this composition, the S+L phase coexists at pH 8.0, while a unimolecular micelle solution forms at pH 8.8. The formation of unimolecular micelles is the result of the synergistic action of the three components.

[0022] Based on the weak acid properties of BTEAB, the pH function was obtained and the pK of BTEAB / SDS / DM was measured experimentally. a is 8.37, such as Figure 2 As shown in Figure 2, if the solution pH is << 8.37, BTEAB in the ternary system is a cationic species; if the pH is >> 8.59, BTEAB is a zwitterionic species. This indicates that the ternary BTEAB / SDS / DM aggregate is pH-responsive around pH 8.37.

[0023] Based on the weak acid properties of BTEAB, a pH-responsive function was obtained. A solution with a BTEAB / SDS / DM concentration ratio of 1:2:1 and a pH ≥ 8.8 was prepared. For example, when the BTEAB concentration was 5 mM and the pH was adjusted to 8.0 with concentrated hydrochloric acid, a white precipitate appeared. The BTEAB concentration in the supernatant after centrifugation was measured, and the amount remaining in the liquid phase was expressed as a molar ratio relative to the original BTEAB. The molar ratios for the three cycles were all 0.67. The two-phase system with a pH of 8.0 was then adjusted to pH 8.8 with concentrated NaOH solution, and the system returned to a single-phase solution. The results are as follows: Figure 3 As shown. The precipitate phase is a complex salt of BTEAB and SDS. At this time, BTEAB has sp 2 The hybrid boron atoms have a relatively low concentration in the solution and are difficult to form closed covalent bonds with the mixed surfactants, resulting in the dissociation of the unimolecular micelles.

[0024] Based on the intrinsic fluorescence properties of BTEAB, the formation of unimolecular micelles was demonstrated. The intrinsic fluorescence of BTEAB in three systems, BTEAB / SDS and BTEAB / SDS / DM, was measured at pH ≥ 8.8. Figure 4 As shown. Under alkaline conditions, the fluorescence of BTEAB is very weak and has no obvious analytical chemical value; after adding SDS with equal charge ratio, the fluorescence is enhanced to a certain extent, reflecting the anchoring effect of SDS micelles on BTEAB; when DM is added in an equal molar amount to BTEAB, the fluorescence intensity is significantly enhanced, which can clearly characterize the formation of covalent borate ester bond between BTEAB and DM. Combined with our ITC measurement, 11 B NMR and 1 Analysis of H NMR measurements further confirmed the formation of dynamic covalent boronate-linked unimolecular micelles.

[0025] The unimolecular micelles prepared from small molecule surfactant micelles in the present invention have a particle size of less than 10 nm, a molecular weight determined by the micelle aggregation number, and are not easily aggregated in aqueous solvents. Aromatic borate esters are used for covalent linkage to achieve the conversion of pH-stimulated unimolecular micelles into supramolecular micelles, thereby constructing more valuable soft nanocarriers.

[0026] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for in situ synthesis of unimolecular micelles via pH-responsive dynamic covalent borate bonds promoted by electrostatic interaction, characterized in that The specific process is as follows: the original supramolecular micelle is a mixed micelle of sodium dodecyl sulfate (SDS) surfactant and dodecyl maltodextrin (DM) surfactant. The biphenylboronic acid linker molecule (BTEAB) is anchored on the surface of the mixed micelle through electrostatic interaction with SDS, promoting the formation of dynamic covalent single-molecule micelles between BTEAB and DM. The pK of borate ester in the single-molecule micelle is a =8.37, across pK a The narrow pH range has pH response function, pH ≤ 8.0 to obtain SL two-phase system, pH ≥ 8.8 to obtain unimolecular micelle solution, the structural formula of the unimolecular micelle is:

2. The method for in situ synthesis of unimolecular micelles using electrostatically promoted pH-responsive dynamic covalent borate bonds according to claim 1, characterized in that: The molar ratio of the sodium lauryl sulfate surfactant to the lauryl maltodextrin surfactant in the mixed micelles is 2:1, and the surface of the mixed micelles is rich in negative charges and hydroxyl groups.

3. The method for in situ synthesis of unimolecular micelles by electrostatically promoted pH-responsive dynamic covalent borate ester bonds according to claim 1, characterized in that The synthetic route of the biphenylboronic acid linker molecule is:

4. The method for in situ synthesis of unimolecular micelles using electrostatically promoted pH-responsive dynamic covalent borate bonds according to claim 1, characterized in that: The interaction between BTEAB and SDS / DM mixed micelles is the electrostatic interaction between the two quaternary ammonium cations of BTEAB and the sulfate anions of SDS in the mixed micelles, which anchors the BTEAB ions on the surface of the mixed micelles. The two boric acid head groups of BTEAB react with the polyhydroxyl groups of DM to form pH-responsive dynamically covalently bonded borate esters, thereby synthesizing unimolecular micelles in situ.

5. The method for in situ synthesis of unimolecular micelles using electrostatically promoted pH-responsive dynamic covalent borate bonds according to claim 1, characterized in that: The electrostatic interaction between BTEAB and SDS anchors BTEAB on the surface of mixed micelles, promoting the formation of ester bonds between BTEAB and DM. At this time, the pK a =8.

37. When pH≤8.0, the ester bond breaks to obtain a sparingly soluble salt of BTEAB and SDS. When pH≥8.8, it becomes a unimolecular micelle solution, realizing the pH-responsive unimolecular micelle synthesis.

6. The method for in situ synthesis of unimolecular micelles using electrostatically promoted pH-responsive dynamic covalent borate bonds according to claim 1, characterized in that: The unimolecular micelle is a pH-responsive soft nanocarrier.

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