CN113350293A - Hybrid single micelle nanoparticle for encapsulating functional molecules and preparation method thereof - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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Abstract
The invention belongs to the technical field of nano material preparation, and particularly relates to a hybrid single micelle nano particle for packaging functional molecules and a preparation method thereof. The preparation method comprises the following steps: the block polymer Pluronic F127 forms a single micelle in an aqueous solution, functional molecules are introduced, the single micelle is hybridized, and the single micelle nanoparticles are purified. The method has the advantages of mild synthesis conditions, simple process, strong universality and low cost; the prepared hybrid single micelle nano-particles have good dispersibility in aqueous solution and controllable size. Compared with the traditional micelle, the hybrid single micelle nanoparticle prepared by the invention has stronger structural stability and better protection on substances in the micelle, has good biocompatibility and universality, and has good application prospect in the fields of biological imaging, catalysis, treatment and the like.
Description
Technical Field
The invention belongs to the technical field of nano materials, and particularly relates to a hybrid single micelle nano particle for packaging functional molecules and a preparation method thereof.
Background
Due to the complexity of the in vivo environment and the biological safety and hydrophilicity and hydrophobicity of the materials themselves, many functional molecules such as imaging probes, hydrophobic drugs, enzymes, etc. cannot be delivered directly into the body. In order to achieve better biological imaging, catalysis, treatment and other effects, certain surface modification on functional molecules or providing a transportation carrier for the functional molecules is of great significance for biological application of the functional molecules.
Currently, a range of delivery vehicles have been developed for the delivery of various types of functional molecules, such as liposomes, silica nanoparticles, micelles, and the like. The nano-carriers effectively enhance the hydrophilicity of the surfaces of various functional molecules, improve the biological distribution of the functional molecules in vivo and effectively improve the bioavailability of the functional molecules. Micelles are of interest because of their excellent biocompatibility and versatility for loading various types of hydrophobic substances, but because the formation of micelles is mainly based on weak interactions between amphiphilic surfactants (usually hydrophilic and hydrophobic interactions), micelles tend to suffer from structural instability and insufficient protection of the encapsulated cargo under physiological conditions. For example, when micelles are diluted below the critical micelle concentration during use, the micelles will break down into free surfactant; biomolecules such as proteins and enzymes in the blood may also induce degradation of the micelles. Although some strategies have been proposed to solve the above-mentioned disadvantage of insufficient stability of micelles, such as introducing superhydrophilic zwitterionic polymer domains to lower the critical micelle concentration of micelles, or designing cyclic hydrophilic moieties to increase the stability of micelles, etc.[1, 2]However, the current solutions focus mainly on the design of amphiphilic surfactants, but since amphiphilic surfactants self-assemble mainly through weak interactionsSo that it is difficult to fundamentally solve the problems faced by micelles.
Therefore, in order to improve the structural and functional stability of micelles, enhancing the interaction between surfactants at the single micelle level, designing and synthesizing more stable micelle carriers remains a great challenge.
Disclosure of Invention
The invention aims to provide a hybrid single micelle nanoparticle for encapsulating functional molecules and a preparation method thereof.
The invention provides a preparation method of hybrid single micelle nanoparticles for encapsulating functional molecules, which comprises the following specific steps:
(1) stirring and dissolving a block polymer Pluronic F127 and inorganic salt in water at room temperature to form a single micelle solution;
(2) pre-dissolving functional molecules in mesitylene, and dropwise adding a functional molecule solution into the single micelle solution formed in the previous step to introduce the functional molecules;
(3) adding silane into the mixed solution to realize hybridization of the single micelle;
(4) and purifying the hybrid single micelle nanoparticles through dialysis to obtain monodisperse size-uniform hybrid single micelle nanoparticles encapsulating the functional molecules.
Preferably, the functional molecules mainly comprise organic fluorescent probes, complexes, hydrophobic drugs, quantum dots, up-conversion nanoparticles and the like; the specific amount of functional molecule added will depend on the specific circumstances.
Preferably, the inorganic salt is KCl or KF; the dosage is 0.075mmol-0.225 mmol.
Preferably, the silane is tetramethoxysilane.
Preferably, the dosage ratio of the Pluronic F127, the water, the mesitylene and the silane is (0.3-0.7 g): 15mL (300-.
Preferably, the block polymer Pluronic F127 forms single micelle in aqueous solution, introduces functional molecule, hybridizes with single micelle for three processes, each of which requires 2-3 hours of reaction time and is carried out under high speed stirring (> 700 rpm).
Preferably, the purification of the hybrid single micelle obtained after the reaction is finished needs dialysis with deionized water, and the molecular cut-off of the dialysis bag is 14000.
According to the invention, the particle size of the hybrid single micelle nano-particles can be well controlled by controlling the addition amount of the block copolymer and the addition amount of the silane.
The hybrid single micelle nano particles prepared by the preparation method disclosed by the invention are uniform in size, have the particle size of 17-35 nm, are good in dispersity, and can be used for packaging various functional molecules.
The preparation method of the hybrid single micelle nano-particle for encapsulating the functional molecules, provided by the invention, comprises the steps of stirring and mixing a block polymer Pluronic F127, water, mesitylene, inorganic salt and the functional molecules at room temperature; adding silane to realize hybridization of single micelle, dialyzing to realize purification of the hybridized single micelle nanoparticle to obtain the monodisperse and uniform-size hybridized single micelle nanoparticle for encapsulating functional molecules. According to the invention, a micelle is formed in an aqueous solution by using a block polymer Pluronic F127, mesitylene is used as a micelle solubilizer, so that functional molecules enter hydrophobic cores in the micelle, the interaction force between subsequent silane and a block copolymer skeleton is enhanced by introducing inorganic salt so as to complete hybridization of the micelle, and finally, redundant inorganic salt ions and byproducts generated by reaction are removed by dialysis. The whole reaction is carried out at room temperature and under a neutral condition, which is beneficial to the protection of functional molecules, the hybridization on the single micelle layer surface well ensures the monodispersity of the hybridized single micelle nanoparticles, the structural stability of the hybridized micelle is effectively improved, and the protection of internal functional molecules is further improved.
The invention can obtain monodisperse hybrid single micelle nano particles which can encapsulate different functional molecules under the conditions of room temperature and neutrality, and has the advantages of simple preparation and stable structural performance.
In addition, the particle size of the hybrid single micelle nanoparticle can be well controlled by controlling the addition amount of the block copolymer and the silane.
Drawings
FIG. 1 is a TEM image of the hybrid single-micelle nanoparticles obtained in example 1.
FIG. 2 is a TEM image of the indocyanine green (hereinafter referred to as ICG) encapsulated hybrid single-micelle nanoparticles (ICG @ H-micell) obtained in example 2.
FIG. 3 is a spectrum of the ICG hybrid single micelle nanoparticle encapsulated (ICG @ H-micell) obtained in example 2.
FIG. 4 is a study of the structural stability of the ICG hybrid single micelle nanoparticle encapsulated (ICG @ H-micell) obtained in example 2 under dialysis and dilution conditions.
FIG. 5 is a study of the structural stability of the ICG hybrid single micelle nanoparticle encapsulated (ICG @ H-micell) in the oxidative (hydrogen peroxide) and reductive (glutathione) substances obtained in example 2.
FIG. 6 is a study of the structural stability of the ICG hybrid single micelle nanoparticle encapsulated (ICG @ H-micell) obtained in example 2 in different pH environments.
FIG. 7 is a TEM image of the hybrid single-micelle nanoparticle obtained in example 3.
FIG. 8 is a TEM image of the hybrid single-micelle nanoparticles obtained in example 4.
Detailed Description
The invention provides a preparation method of hybrid single micelle nanoparticles for encapsulating functional molecules, which comprises the following specific steps:
stirring and dissolving a block polymer Pluronic F127 and inorganic salt in water at room temperature to form a single micelle solution;
functional molecules are introduced by dripping the functional molecules dissolved in mesitylene in advance into the single micelle solution formed in the previous step;
adding silane into the mixed solution to realize hybridization of the single micelle;
and purifying the hybridized single micelle nanoparticles by dialysis to obtain monodisperse size-uniform hybridized single micelle nanoparticles encapsulating functional molecules.
In the present invention, the inorganic salt is preferably KCl or KF in an amount of 0.075mmol to 0.225mmol, and the source of the inorganic salt is not particularly limited in the present invention.
In the present invention, the preferred ratio of the Pluronic F127, water and mesitylene is (0.3-0.7 g): 15mL of: (300-700. mu.L), the invention has no special requirements on the sources of Pluronic F127, water and mesitylene.
In the present invention, the stirring is preferably at a stirring speed >700 rpm.
In the present invention, the mixing method preferably adopts the following method: pluronic F127, water and inorganic salt are stirred at normal temperature until the solution is clear, and then mesitylene (or mesitylene containing functional molecules) is dropwise added into the solution, and stirring is continued for 2 hours at room temperature.
In the present invention, the silane is preferably tetramethoxysilane, and the amount is preferably 100-550. mu.L, and the source of the tetramethoxysilane is not particularly required in the present invention
In the invention, the hybrid micelle mode is preferably to add tetramethoxysilane dropwise into the mixed solution in the previous step, and the preferable reaction time is 2-3 hours.
In the present invention, the purification mode of the hybrid micelle is preferably dialysis, the preferred dialysis solvent is deionized water, the preferred molecular cut-off of the dialysis bag is 14000, the preferred dialysis frequency is about once dialysis solution replacement every 2 hours, and the preferred dialysis time is 24 hours.
In addition, the particle size of the finally obtained hybrid single micelle nano-particles can be well controlled by controlling the adding amount of the block copolymer Pluronic F127 and the adding amount of silane. Specifically, under the condition that other parameters are the same, the smaller the amount of the added block copolymer Pluronic F127 is, the larger the particle size of the obtained hybrid single micelle nano-particles is; with the same amount of the block copolymer Pluronic F127 and other parameters added, the smaller the amount of silane added, the smaller the particle size of the resulting hybrid single micelle nanoparticles.
The following examples are provided to illustrate the preparation method of the hybrid single micelle nanoparticle for encapsulating functional molecules according to the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
Weighing 0.5g of Pluronic F127 and 0.15mmol of KCl, dissolving in 15ml of water, stirring and clarifying, dropwise adding 500 mu L of mesitylene, continuing stirring for 2 hours, then dropwise adding tetramethoxysilane into the mixed solution, reacting for 2 hours, transferring the reaction solution into a dialysis bag with the molecular cut-off of 14000, dialyzing by taking deionized water as dialysate, and dialyzing for 24 hours to obtain the hybrid single micelle nano-particles. As can be seen from FIG. 1, the present invention successfully prepared hybrid single micelle nanoparticles having a particle size of about 25 nm.
Example 2
Weighing 0.5g of Pluronic F127 and 0.15mmol of KCl, dissolving in 15ml of water, stirring and clarifying, dropwise adding 500 mu L of mesitylene containing 0.1mg of ICG (ICG is taken as a functional molecule and belongs to an organic fluorescent probe), continuously stirring for 2 hours, then dropwise adding tetramethoxysilane into the mixed solution, totally 500 mu L, reacting for 2 hours, transferring the reaction solution into a dialysis bag with the molecular interception amount of 14000, dialyzing by taking deionized water as a dialysis solution, and dialyzing for 24 hours to obtain the hybridized single micelle nano-particles. As can be seen from FIG. 2, the present invention successfully prepared ICG-encapsulated hybrid single-micelle nanoparticles (ICG @ H-micell) having a particle size of about 25 nm. From the spectrum of FIG. 3, it can be seen that the ICG @ H-micell prepared by the present invention has similar and good optical properties to ICG, and from FIGS. 4 to 6, the ICG @ H-micell obtained by the present invention can maintain the structural stability and the optical stability well in the presence of dilution/dialysis, redox substances and in different pH environments.
Example 3
Weighing 0.3g of Pluronic F127 and 0.15mmol of KCl, dissolving in 15ml of water, stirring and clarifying, dropwise adding 500 mu L of mesitylene, continuing stirring for 2 hours, then dropwise adding tetramethoxysilane into the mixed solution, reacting for 2 hours, transferring the reaction solution into a dialysis bag with the molecular cut-off of 14000, dialyzing by taking deionized water as dialysate, and dialyzing for 24 hours to obtain the hybrid single micelle nano-particles. As can be seen from FIG. 1, the present invention successfully prepared hybrid single micelle nanoparticles having a particle size of about 35 nm.
From the results of examples 1 and 3, it can be seen that the particle size of the hybrid single micelle nanoparticle can be controlled by adjusting the addition amount of the block copolymer Pluronic F127.
Example 4
Weighing 0.5g of Pluronic F127 and 0.15mmol of KCl, dissolving in 15ml of water, stirring and clarifying, dropwise adding 300 mu L of mesitylene, continuing stirring for 2 hours, then dropwise adding tetramethoxysilane into the mixed solution, reacting for 2 hours, transferring the reaction solution into a dialysis bag with the molecular cut-off of 14000, dialyzing by taking deionized water as dialysate, and dialyzing for 24 hours to obtain the hybrid single micelle nano-particles. As can be seen from FIG. 8, the present invention successfully prepared hybrid single micelle nanoparticles having a particle size of about 17 nm.
From the results of examples 1 and 4, it can be seen that the particle size of the hybrid single micelle nanoparticles can be controlled by adjusting the amount of silane added.
The embodiments of the present invention show that the preparation method of the hybrid single micelle nanoparticle for encapsulating functional molecules is simple, the synthesis conditions are mild, and the energy consumption is low.
In addition, the particle size of the hybrid single micelle nanoparticles can be well controlled by controlling and adjusting the adding amount of Pluronic F127 and silane.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make modifications and changes without departing from the principle of the present invention, and these modifications and changes should be also considered as the protection scope of the present invention.
Reference documents:
1.Lu, Y.;Yue, Z.; Xie, J.; Wang, W.;Zhu, H.; Zhang, E.; Cao, Z., Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat Biomed Eng 2018,2 (5), 318-325.
2.Wang, Y.; Wu, Z.; Ma, Z.; Tu, X.;Zhao, S.; Wang, B.; Ma, L.; Wei, H., Promotion of micelle stability via a cyclic hydrophilic moiety. Polymer Chemistry 2018,9 (19), 2569-2573。
Claims (9)
1. a preparation method of hybrid single micelle nanoparticles for encapsulating functional molecules is characterized by comprising the following specific steps:
(1) stirring and dissolving a block polymer Pluronic F127 and inorganic salt in water at room temperature to form a single micelle solution;
(2) pre-dissolving functional molecules in mesitylene, and dropwise adding a functional molecule solution into the single micelle solution formed in the previous step to introduce the functional molecules;
(3) adding silane into the mixed solution to realize hybridization of the single micelle;
(4) and purifying the hybrid single micelle nanoparticles through dialysis to obtain monodisperse size-uniform hybrid single micelle nanoparticles encapsulating the functional molecules.
2. The method according to claim 1, wherein the functional molecule comprises an organic fluorescent probe, a complex, a hydrophobic drug, a quantum dot, and an upconversion nanoparticle, and the amount of the functional molecule is varied according to the type.
3. The method according to claim 1, wherein the inorganic salt is KCl or KF; the dosage is 0.075mmol-0.225 mmol.
4. The method according to claim 1, wherein the silane is tetramethoxysilane.
5. The method according to claim 1, wherein the Pluronic F127, water, mesitylene and silane are used in a ratio of (0.3-0.7 g): 15mL (300-.
6. The preparation method according to claim 1, wherein the block polymer Pluronic F127 forms single micelle in aqueous solution, introduces functional molecule, hybridizes single micelle, reaction time of each process is 2-3 hours, and the reaction is carried out under high speed stirring of more than 700 rpm.
7. The method of claim 1, wherein the dialysis bag has a molecular cut-off of 14000.
8. The preparation method of claim 1, wherein the particle size of the hybrid single micelle nanoparticle is controlled by controlling the addition amount of the block copolymer and the silane.
9. Hybrid single micelle nanoparticles for encapsulating functional molecules obtainable by the preparation process according to one of claims 1 to 7, having a uniform particle size of 17nm to 35 nm.
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Citations (6)
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