CN110693836A - Lipopeptide self-assembly ultra-small nano vesicle and preparation method thereof - Google Patents
Lipopeptide self-assembly ultra-small nano vesicle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a super-small nano vesicle formed by self-assembly of lipopeptide micromolecules in an aqueous solution and a preparation method thereof, wherein the diameter of the lipopeptide self-assembled super-small nano vesicle is 10-20 nm. The hydrophobic tail end of the lipopeptide is an alkyl chain of saturated fatty acid, and the chain length is C12-C16; the hydrophilic head group is a linear short peptide consisting of 2-4 histidine H, and the C-terminal alpha carboxylic acid of the terminal histidine is not blocked or is blocked by amidation. The lipopeptide self-assembly ultra-small nano vesicle provided by the invention has the advantages of simple preparation process, easy regulation and control, good stability and monodispersity of the ultra-small nano vesicle, and wide application prospect in the aspects of drug loading, delivery, slow release, gene transfer and the like.
Description
Technical Field
The invention belongs to the field of supramolecular chemistry and nano material engineering, and particularly relates to a small molecule lipopeptide self-assembly ultra-small nano vesicle and a preparation technical method thereof.
Background
Natural vesicles are widely found in bacteria, archaea, plants and animals. These vesicles are compartments formed by layers of lipid molecules that separate their contents, which may be liquid or gaseous, from the cytoplasm or extracellular environment. They may be involved in regulation of buoyancy and optimization of photosynthesis (gas vesicles), intercellular signaling and mass exchange (exosomes), intracellular digestion (lysosomes), trafficking and secretion (vesicles produced by the golgi network), and the like.
The classification can be made according to various factors such as the function, position, and nature of the contents of the vesicle. According to the function of the vesicle, the vesicle can be classified into a transport vesicle, a digestion vesicle, a protection vesicle, a secretion vesicle, an osmotic regulation vesicle and the like, and the vesicles in different cells have different functions, but the vesicles in the same cell can also have different functions. They may also be classified as intracellular vesicles or extracellular vesicles, depending on where the vesicles are found. While the contents of most vesicles are liquids, there are also some microorganisms that use gas vesicles to optimize photosynthesis and regulate buoyancy.
The bionic artificial vesicle has a unique biological membrane structure and has advantages in drug delivery, slow release, gene transfer and the like. Phospholipid vesicles (liposomes) are a class of artificial vesicles which are reported in scientific research and application, and vesicle suspensions with different phospholipid compositions and different sizes are prepared by an extrusion method or an ultrasonic method. Generally, those with a diameter of less than 20nm are called ultra-small vesicles, those with a diameter of 20-100nm are called small vesicles, those with a diameter of 0.1-1 μm are called large vesicles, and those with a diameter of 1-50 μm are called large vesicles. According to the physicochemical characteristics of the drug, the drug molecules can be wrapped in the water environment in the vesicle and can also be inserted into the lipid bilayer of the vesicle. The vesicle surface is easily modified with targeting ligands and polymers. The patent CN 2014102177307 discloses a homopolymer nano vesicle and a preparation method and application thereof, the homopolymer nano vesicle comprises a homopolymer vesicle formed by self-assembling a homopolymer and nano silver deposited on the homopolymer vesicle, the homopolymer is formed by polymerizing 4,4' -diaminodiphenyl ether and pyromellitic dianhydride in a molar ratio of 1:0.2-4, and the molar ratio of the nano silver to carboxyl in the homopolymer is (1-20: 1); the particle size of the prepared homopolymer vesicle is 100-600 nm. Patent CN 2014105642809 discloses a method for preparing γ -polyglutamic acid organic phase nano vesicles, which comprises adding precipitant ethanol dropwise into dimethyl sulfoxide solution of tridecafluoroctanol modified γ -polyglutamic acid graft copolymer to promote self-assembly of the graft copolymer to form nano vesicles, wherein the method requires the use of catalyst 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and the like, and the particle size of the formed nano vesicles is between 150-300 nm.
The application of phospholipid vesicles (liposomes) in biological nanotechnology is greatly expanded by the wide integration of functional molecules such as polymers, oligonucleotides, polypeptides, proteins, chelators, developers, small molecule drugs and the like. More and more researchers are assembling nanostructured materials or monomeric molecules into large vesicular supramolecular structures. The supermolecular assembly material with larger size has enhanced permeability and retention effect, and is easier to aggregate at tumor tissues, thereby obtaining better imaging diagnosis and disease treatment effects. However, the large size of vesicles (greater than 50nm in diameter) has disadvantages in that they can accumulate in tumor tissues, but have poor ability to penetrate target organs and tissues, and are difficult to penetrate deep into tumor cells. The nano-scale ultra-small vesicles can penetrate deeper tissues and cells, so that the photoacoustic imaging and the photothermal therapy of the material have three-dimensional performance and better treatment effect. The liposome ultra-small vesicles with the diameter less than 50nm have poor colloidal stability and are difficult to process, and loose and disordered accumulation of lipid molecules in a double-layer membrane is easily caused, so that payload leakage, inter-particle fusion and lipid membrane aggregation are promoted. Although there have been some strategies to improve the colloidal stability of ultrasmall vesicles, the results are not satisfactory: in biological media, the long-term stability of the colloid remains low and the payload still leaks significantly. Therefore, the preparation and application of the effective and stable ultra-small nano vesicle are of great significance.
The vesicle formed by self-assembly of the amphiphilic micromolecule can simulate the structure and the function of a natural lipid membrane. Lipopeptide molecules have an amphiphilic structure, the hydrophilic head group of the lipopeptide molecule consists of an amino acid sequence, the hydrophobic tail part of the lipopeptide molecule consists of one or more lipid chains, and the lipopeptide molecule can be self-assembled in an aqueous solution to form supermolecule nano structures with protein-like structures and functions, such as micelles, vesicles, fibers and the like. The invention self-assembles the ultra-small nano vesicle through the small molecular lipopeptide, has the advantages of simple preparation process, good stability of the ultra-small vesicle and the like, and provides a new thought for preparing effective and simple biological vesicles through small molecular self-assembly in aqueous solution. The basic property of the nano vesicle formed by self-assembling the small molecular lipopeptide is similar to that of a cell membrane phospholipid layer, the biocompatibility is good, the nano vesicle not only can stably load and transport drugs, but also can be fused into a phospholipid bilayer of a cell membrane, can be used for designing and applying a vesicle physiology and intelligent response drug delivery system, and has important significance for revealing the basic intermolecular interaction in the life process.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing ultra-small nano vesicles with excellent colloidal stability by adopting self-assembly of lipopeptide surfactant micromolecules with good biocompatibility.
The technical scheme adopted by the invention is as follows:
a super-small nano-vesicle formed by lipopeptide self-assembly and its preparation method, lipopeptide powder is dissolved in water, pH value is adjusted to 2-3 under stirring condition, and the super-small nano-vesicle is prepared. And (3) adjusting the pH value of the lipopeptide solution which forms micelles in the solution with the pH value of 2-3 to about 6.0 under the stirring condition to obtain the ultra-small nano vesicles.
The method specifically comprises the following steps: an ultra-small nano vesicle is prepared by self-assembling lipopeptide micromolecules in an aqueous solution, wherein the diameter of the vesicle is 10-20 nm.
Preferably, the hydrophobic tail end of the lipopeptide is an alkyl chain of saturated fatty acid, the chain length is C12-C16, and the hydrophilic head group is a linear short peptide consisting of 2-4 histidine H.
The lipopeptide is selected from head-tail structure C12HH-COOH、C14HH-CONH2And C16HHH-CONH2One or more of the lipopeptides of (a).
A lipopeptide self-assembly ultra-small nano vesicle is disclosed, wherein the molecular formula of the lipopeptide is as follows:
wherein the short peptide terminal histidine may be blocked (amidated) without blocking the C-terminus.
The invention also claims a preparation method of the ultra-small nano-vesicle, the lipopeptide powder is dissolved by adding water and reinforced acid, the pH value is adjusted to 2-3 under the stirring condition, and the ultra-small nano-vesicle is prepared by self-assembly; or dissolving lipopeptide powder in water and reinforced acid to form lipopeptide micelles in a solution with the pH value of 2-3, adjusting the pH value to about 6.0 under the stirring condition, and self-assembling to prepare the ultra-small nano vesicles. The strong acid is an acid commonly used in the art, such as hydrochloric acid, sulfuric acid, nitric acid, and the like.
The ultra-small nano vesicles prepared by the method have no obvious change within 6 months.
The invention also claims the application of the ultra-small nano-vesicle, which is used for drug loading, delivery, slow release and gene delivery.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the ultra-small nano-vesicle prepared by the method is realized by self-assembly of rationally designed amphiphilic lipopeptide micromolecules in an aqueous solution, extrusion or ultrasonic crushing by an extruder is not needed, a catalyst is not needed, and the method has the characteristics of simple preparation process, good repeatability and the like;
the diameter of the prepared ultra-small nano vesicle is 10-20nm, the colloidal stability in the solution can be kept better, and the monodispersity in the aggregation and precipitation can be kept better.
The ultra-small nano-vesicle prepared by the method has pH responsiveness, the dispersion and coagulation of the ultra-small nano-vesicle in an aqueous solution can be regulated and controlled by adjusting the pH value, and the ultra-small nano-vesicle can keep better monodispersity in the solution and the precipitate.
Drawings
FIG. 1 is a molecular structure of several exemplary lipopeptides of the present invention.
FIG. 2 shows the results of DLS analysis and TEM analysis of the lipopeptide solution obtained in example 1 to detect the micelle structure.
FIG. 3 shows the results of DLS analysis and TEM analysis of the lipopeptide solution obtained in example 2 to detect the structure of ultra-small nanovesicles.
FIG. 4 shows the results of DLS analysis and TEM analysis of the lipopeptide solution obtained in example 3 to detect the structure of ultra-small nanovesicles.
FIG. 5 shows TEM analysis of aggregation and precipitation of lipopeptide assemblies obtained by pH control in example 4, and the ultra-small nano vesicles still maintain good monodispersity.
FIG. 6 shows TEM analysis of aggregation and precipitation of lipopeptide assemblies obtained by pH control in example 5, and the ultra-small nano vesicles still maintain good monodispersity.
FIG. 7 shows TEM analysis of aggregation and precipitation of lipopeptide assemblies obtained by pH control in example 6, and the ultra-small nano vesicles still maintain good monodispersity.
Detailed Description
The present invention is further described with reference to the following specific examples, which are provided for illustration only and are not to be construed as limiting the invention, and the scope of the present invention is defined by the appended claims, and insubstantial changes and substitutions made by those skilled in the art based on the disclosure of the present invention are included in the scope of the present invention.
Example 1
Weighing C12HH-COOH lipopeptide powder, adding water and strong acid, stirring to dissolve, preparing 20-100mmol/L solution, and regulating pH to 2-3, C12The HH-COOH lipopeptide forms an average particle size of 5nm in solutionLeft and right micelles (fig. 2), and lipopeptide micelles detected no significant change within 6 months of investigation, with long-term stability.
Example 2
Weighing C12HH-CONH2Dissolving lipopeptide powder in water and strong acid under stirring to obtain 20-100mmol/L solution, and regulating pH to 2-3, C12HH-CONH2Lipopeptides form ultra-small nanocapsules with a diameter of 10-20nm in solution (fig. 3), and no significant change was detected in the lipopeptide vesicles within 6 months of investigation, with long-term colloidal stability.
Example 3
Weighing C12HHH-CONH2Dissolving lipopeptide powder in water and strong acid under stirring to obtain 20-100mmol/L solution, and regulating pH to 2-3, C12HHH-CONH2Lipopeptides formed ultra-small nanovesicles in solution with diameters of 10-20nm (fig. 4), and the lipopeptide vesicles did not detect significant changes within 6 months of investigation, with long-term colloidal stability.
Example 4
Weighing C12HH-COOH lipopeptide powder is added with water and reinforced acid to stir and regulate the pH value of the solution to 2-3, 2-100mmol/L solution is prepared, and then the pH value is regulated to about 6.0 under the stirring condition, so that the aggregation and precipitation of the ultra-small nano vesicles (shown in figure 5) with good monodispersity and the diameter of 10-20nm can be obtained, and the lipopeptide vesicles have no obvious change within 6 months of investigation and have long-term stability.
Example 5
Weighing C12HH-CONH2Lipopeptide powder, water and reinforced acid are added to stir and regulate the pH value of the solution to 2-3, 2-100mmol/L solution is prepared, the pH value is regulated to about 6.0 under the stirring condition, the aggregation and precipitation of the ultra-small nano vesicles (shown in figure 6) with good monodispersity and the diameter of 10-20nm can be obtained, and the lipopeptide vesicles have long-term stability and no obvious change within 6 months of investigation.
Example 6
Weighing C12HHH-CONH2Adding water and strong acid into lipopeptide powder, stirring to regulate pH value of solution to 2-3, and preparing into lipopeptide powder of 2-100mmol/LThe solution is stirred and the pH value is adjusted to about 6.0, so that the aggregation and precipitation of the ultra-small nano vesicles (figure 7) with good monodispersity and the diameter of 10-20nm can be obtained, and the lipopeptide vesicles have long-term stability and no obvious change within 6 months.
Example 4 is based on example 1 and the pH is adjusted to prepare the ultra-small nano-vesicles. The embodiment 1 has the advantages of forming micelles, facilitating the micelle dispersion of the hydrophobic drug in the solution, and realizing the high-efficiency drug loading of the ultra-small nano-vesicles by combining with the embodiment 4.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (10)
1. An ultra-small nanovesicle, comprising: the ultra-small nano vesicle is prepared by self-assembling lipopeptide micromolecules in an aqueous solution, and the diameter of the vesicle is 10-20 nm.
2. The ultra-small nanovesicles of claim 1, wherein: the hydrophobic tail end of the lipopeptide is an alkyl chain of saturated fatty acid, and the chain length is C12-C16; the hydrophilic head group is a linear short peptide consisting of 2-4 histidine H.
3. The ultra-small nanovesicles of claim 2, wherein: short peptides as hydrophilic head groups, whose terminal histidine C-terminal alpha carboxylic acid is blocked by amidation.
4. The ultra-small nanovesicles of claim 2, wherein: the short peptide as the hydrophilic head group has a terminal histidine without a C-terminal alpha carboxylic acid block.
5. The ultra-small nanovesicles of claim 1, wherein: the lipopeptide is selected from C as head-tail structure12HH-COOH、C14HH-CONH2And C16HHH-CONH2One or more of the lipopeptides of (a).
6. The ultra-small nanovesicles of claim 1, wherein: the lipopeptide has the molecular formula
7. The method for preparing ultra-small nanovesicles according to any one of claims 1 to 6, wherein: adding water and reinforced acid into lipopeptide powder for dissolving, adjusting the pH value to 2-3 under the stirring condition, and carrying out self-assembly to obtain the ultra-small nano vesicle.
8. The method for preparing ultra-small nanovesicles according to any one of claims 1 to 6, wherein: adding water and reinforced acid into lipopeptide powder to dissolve, forming lipopeptide micelles in a solution with a pH value of 2-3, adjusting the pH value to about 6.0 under the stirring condition, and carrying out self-assembly to obtain the ultra-small nano vesicles.
9. The method for preparing ultra-small nanovesicles according to claim 7 or 8, wherein: the prepared ultra-small nano vesicles have no obvious change within 6 months.
10. Use of ultra-small nanovesicles according to any one of claims 1-9, wherein: for drug loading, delivery and sustained release, and gene delivery.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111888460A (en) * | 2020-07-27 | 2020-11-06 | 燕山大学 | Preparation method of nano drug-loaded micelle with daptomycin-entrapped small-molecule hydrophobic drug |
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| CN104587446A (en) * | 2014-12-19 | 2015-05-06 | 华东理工大学 | Temperature-sensitive lipopeptid, lipidosome containing lipopeptid and application of temperature-sensitive lipopeptid and lipidosome |
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| WO2002009647A2 (en) * | 2000-07-28 | 2002-02-07 | Emory University | Biological component comprising artificial membrane |
| CN102614152A (en) * | 2012-01-13 | 2012-08-01 | 河南大学 | Method for preparing vesicle medicinal nanoparticles |
| CN104587446A (en) * | 2014-12-19 | 2015-05-06 | 华东理工大学 | Temperature-sensitive lipopeptid, lipidosome containing lipopeptid and application of temperature-sensitive lipopeptid and lipidosome |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111888460A (en) * | 2020-07-27 | 2020-11-06 | 燕山大学 | Preparation method of nano drug-loaded micelle with daptomycin-entrapped small-molecule hydrophobic drug |
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