CN110721317A - Carrier responding to pH value and reducing agent based on pseudorotaxane molecular structure and preparation method thereof - Google Patents
Carrier responding to pH value and reducing agent based on pseudorotaxane molecular structure and preparation method thereof Download PDFInfo
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- CN110721317A CN110721317A CN201911101368.6A CN201911101368A CN110721317A CN 110721317 A CN110721317 A CN 110721317A CN 201911101368 A CN201911101368 A CN 201911101368A CN 110721317 A CN110721317 A CN 110721317A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a carrier responding to pH and a reducing agent based on a pseudorotaxane molecular structure and a preparation method thereof, belonging to the field of material science. The carrier comprises hollow mesoporous inorganic oxide and pseudorotaxane molecules; the pseudorotaxane molecule comprises a chain molecule and a ring molecule with a hydrophobic cavity; one end of the chain molecule is a silane coupling agent, the other end of the chain molecule is a cysteine residue, and the silane coupling agent and the cysteine residue are connected through a disulfide bond; the silane coupling agent is connected with the hollow mesoporous inorganic oxide through a covalent bond; the ring-shaped molecules with hydrophobic cavities form a molecular barrier of the hollow mesoporous inorganic oxide; the cysteine residue can make the ring-shaped molecule with the hydrophobic cavity fall off under the acidic or alkaline condition, and the disulfide bond can be broken under the action of a reducing agent. The carrier disclosed by the invention can realize the release of the medicine in an acid-base environment and a reduction environment.
Description
Technical Field
The invention belongs to the field of material science, and particularly relates to a pH and reducing agent response carrier based on a pseudorotaxane molecular structure and a preparation method thereof.
Background
The nano drug-carrying system gradually becomes the most promising chemotherapeutic drug transportation platform, which benefits from the characteristics of targeted drug delivery in cancer treatment, not only greatly reduces the damage of chemotherapy to normal tissues, but also enhances the lethality of chemotherapeutic drugs to cancer tissues. The ideal drug delivery system for cancer therapy must have the most basic ability to respond in cancer cells, and also have the characteristics of being able to concentrate in the vicinity of cancer cells, penetrate cancer cells deeply, and be taken up by cancer cells effectively. In addition to its application in anticancer therapy, environmentally responsive drug delivery systems can also be used in metal corrosion resistant coatings. Since the hydrogen ions released by the metal during corrosion change the pH, it can also act as a stimulus for drug release.
The modification of silica-based nanopharmaceutical systems often comprises: transition metal/alkaline metal oxide particles are used as mesoporous molecular plugs, and the outer layer is coated with a polymer coat which can generate structural change along with environmental change, and a supermolecule valve with a pseudo-rotaxane structure. The first modification is often a pH one-sided response, and the second modification is also used in drug release process and faces the problem of high release baseline under neutral condition. The supermolecule of the pseudorotaxane structure is always a hot spot in an intelligent drug-carrying container, the supermolecule structure is mainly divided into two parts, namely an organic long chain and a macrocyclic molecule which can be sleeved on the long chain, and all researches are carried out around the two parts. For example, how to introduce specific chemical bonds or molecular structures to long-chain molecules, or to develop some derivatives of a larger variety of typical macrocyclic molecules to achieve more responsive functions.
Due to the design of the supramolecular pseudorotaxane structure, the process is often a multi-step synthesis and multi-step purification process, and more time may be needed for modifying the supramolecular pseudorotaxane structure to the surface of silicon oxide. There are also experimental studies of in-situ grafting of pseudorotaxane molecular structures directly on silicon oxide step by step, but surface mounting of long-chain parts only requires a day or even two days, and often occurs in flammable and explosive toluene reflux, or has a very complicated preliminary modification synthesis reaction and a long reaction time.
Disclosure of Invention
The invention solves the technical problems that the nano-carrier in the prior art can not realize multiple responses, the release base line is high under a neutral condition, and the nano-carrier is explosive and needs long time in the preparation process. The invention constructs a carrier responding to pH and a reducing agent based on a pseudorotaxane molecular structure, wherein the carrier comprises a hollow mesoporous inorganic oxide and pseudorotaxane molecules; the pseudorotaxane molecule comprises a chain molecule and a ring molecule with a hydrophobic cavity; one end of the chain molecule is a silane coupling agent, and the other end of the chain molecule is a cysteine residue; the silane coupling agent is connected with the hollow mesoporous inorganic oxide through a covalent bond; the ring-shaped molecules with the hydrophobic cavity form a molecular barrier of the hollow mesoporous inorganic oxide; the cysteine residue can make the cyclic molecule with the hydrophobic cavity shed under the acidic or alkaline condition, and the disulfide bond can be broken under the action of a reducing agent. When the pH value deviates from neutrality, the chain molecules carry charges and generate repulsion with the macrocyclic molecules to cause the shedding of the macrocyclic molecules, so that the medicine is smoothly diffused and released along the mesopores; the reducing agent can break the disulfide bond in the long chain to break down the structure of the pseudorotaxane so as to release the drug.
According to a first aspect of the present invention, there is provided a pH and reductant responsive support based on a pseudorotaxane molecular structure, the support comprising a hollow mesoporous inorganic oxide and a pseudorotaxane molecule; the pseudorotaxane molecule comprises a chain molecule and a ring molecule with a hydrophobic cavity; one end of the chain molecule is a silane coupling agent, the other end of the chain molecule is a cysteine residue, and the silane coupling agent and the cysteine residue are connected through a disulfide bond; the silane coupling agent is connected with the hollow mesoporous inorganic oxide through a covalent bond; the cysteine residue is positioned in the cavity of the cyclic molecule with the hydrophobic cavity and is connected with the cyclic molecule with the hydrophobic cavity through intermolecular force; the ring-shaped molecules with the hydrophobic cavity form a molecular barrier of the hollow mesoporous inorganic oxide;
the cysteine residue can make the cyclic molecule with the hydrophobic cavity shed under the acidic or alkaline condition, and the disulfide bond can be broken under the action of a reducing agent.
Preferably, the cyclic molecule with a hydrophobic cavity is gamma-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin or cucurbituril;
the silane coupling agent is mercaptopropyltrimethoxysilane, mercaptopropyltriethoxysilane, mercaptopropyltributoxysilane, mercaptopropyldimethoxysilane, mercaptoundecoxytrimethylsilane or mercaptoethyltriethoxysilane.
Preferably, the hollow mesoporous inorganic oxide is hollow mesoporous silica or hollow mesoporous zirconia; the hollow mesoporous inorganic oxide is loaded with drugs or corrosion inhibitors.
According to another aspect of the present invention, there is provided a method for preparing a pH and reductant responsive support based on the molecular structure of pseudorotaxane, comprising the steps of:
(1) dispersing a hollow mesoporous inorganic oxide material in an organic solvent with polarity less than that of benzene, and then adding a silane coupling agent with sulfydryl to modify the silane coupling agent with sulfydryl to the surface of the hollow mesoporous inorganic oxide;
(2) dispersing the intermediate product obtained in the step (1) in an acidic organic alcohol aqueous solution, adding 2, 2-dipyridyl disulfide, and carrying out disulfide bond exchange reaction on disulfide bonds of the 2, 2-dipyridyl disulfide and sulfydryl on a silane coupling agent;
(3) dispersing the intermediate product obtained in the step (2) in an acidic organic alcohol aqueous solution, adding cysteine, and performing a disulfide bond exchange reaction to obtain an intermediate product of the hollow mesoporous inorganic oxide with the surface modified with chain molecules;
(4) and (4) adding a cyclic molecule with a hydrophobic cavity into the intermediate product obtained in the step (3), and connecting the cysteine residue of the chain molecule with the cyclic molecule with the hydrophobic cavity through intermolecular force to form a pseudorotaxane molecule, so as to obtain the carrier with pH value and reducing agent response based on the pseudorotaxane molecule structure.
Preferably, before the cyclic molecule with a hydrophobic cavity is added in the step (4), a step of adding a drug or a corrosion inhibitor is further included, so that the drug or the corrosion inhibitor is loaded in the hollow mesoporous inorganic oxide; and then adding the cyclic molecules with the hydrophobic cavities, so that the cyclic molecules with the hydrophobic cavities form a molecular barrier of the hollow mesoporous inorganic oxide.
Preferably, the silane coupling agent with mercapto group of step (1) is mercaptopropyltrimethoxysilane, mercaptopropyltriethoxysilane, mercaptopropyltributoxysilane, mercaptopropyldimethoxysilane, mercaptoundecoxy trimethylsilane or mercaptoethyltriethoxysilane; the hollow mesoporous inorganic oxide is hollow mesoporous silicon oxide or hollow mesoporous zirconium oxide.
Preferably, the cyclic molecule having a hydrophobic cavity in step (4) is γ -cyclodextrin, α -cyclodextrin, β -cyclodextrin or cucurbituril.
Preferably, the reaction temperature for modifying the silane coupling agent with the mercapto group to the surface of the hollow mesoporous inorganic oxide in the step (1) is 80-110 ℃, the reaction time is 12-24 h, and the ratio of the amount of the silane coupling agent with the mercapto group to the amount of the hollow mesoporous inorganic oxide is 1: (2-9).
Preferably, in the step (2) and the step (3), the pH value of the acidic organic alcohol aqueous solution is in the range of 2-6; the reaction time in the step (2) is 2-8 h, and the reaction time in the step (3) is 0.25-2 h.
Preferably, the mass ratio of the drug or the corrosion inhibitor in the step (4) to the intermediate product of the hollow mesoporous inorganic oxide with the surface modified with the chain molecule is 40-50 mg/g; the medicament is rhodamine or gefitinib, and the corrosion inhibitor is rosin amine.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) the hollow mesoporous inorganic oxide and the pseudo-rotaxane structure are designed into two parts which are mutually connected, so that the variety of medicament storage can be improved, and multiple responses can be realized. The multiple-response type drug-carrying container based on the pseudo-rotaxane supermolecular structure provided by the invention has double responsiveness of pH and a reducing agent. The pseudo-rotaxane supramolecular structure modified on the surface of the silicon oxide is in a stable state in a solution with a neutral pH value, silicon oxide mesopores can be shielded by the supramolecular structure, a drug cannot come out, when the pH value deviates from the neutral pH value, macrocyclic molecules in the pseudo-rotaxane structure are separated, the silicon oxide mesopores are exposed, and the drug can be normally diffused out. The reducing agent GSH is used for realizing the complete disintegration of a pseudo-rotaxane structure by breaking a disulfide bond in the pseudo-rotaxane structure, thereby exposing silicon oxide mesopores to release a medicament.
(2) In the pseudo-rotaxane structure, because the long-chain molecules are in a neutral state under a neutral condition and hardly have repulsion with the internal hydrophobic macrocyclic molecules, the macrocyclic molecules can be stably arranged on the long-chain molecules and do not fall off, a barrier of the mesopores on the surface of the silicon oxide is formed, and the drug is difficult to release through the mesopores. Therefore, the amount released under neutral conditions is very low (the release baseline under neutral conditions is low).
(3) In the preparation process, the reaction solvent is not a flammable and explosive toxic reagent such as toluene, but a safer methanol aqueous solution; the supermolecular structural component is cysteine, and the natural raw material which belongs to one of the basic 20 amino acids of the human body ensures that the medicine-carrying material is safer to apply in biomedicine; in the step of modifying long-chain molecules to the surface of the oxide, a linker 2, 2-dithiodipyridine is introduced in the whole reaction, so that the reaction time of quasi-long-chain modification is shortened to 4.5 hours from 1-2 days.
Drawings
Fig. 1 is a schematic view showing a basic structure of a main body container according to the present invention.
FIG. 2 shows a high molecular polystyrene pellet template used in the process of preparing the main body container of the present invention.
FIG. 3 is a transmission electron microscope image of hollow silica spheres of the main container of the present invention.
FIG. 4 is a scanning electron microscope image of the air silica spheres of the main container of the present invention.
FIG. 5 is an x-ray diffraction pattern of hollow silica spheres of the main vessel of the present invention.
FIG. 6 is a graph showing the response release curves of the present invention in response to different pH conditions of the container.
FIG. 7 is a graph of the response release profile of the invention in response to a container under different reductant conditions.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention relates to a multiple response type (pH, reducing agent) carrier based on a pseudorotaxane structure, which comprises a pseudorotaxane supermolecule with a pH sensitive structure and a hollow mesoporous inorganic oxide with a drug storage function, wherein the structural schematic diagram of the pseudorotaxane supermolecule is shown in figure 1, and the pseudorotaxane molecule comprises a chain molecule and a ring molecule with a hydrophobic cavity; one end of the chain molecule is a silane coupling agent, the other end of the chain molecule is a cysteine residue, and the silane coupling agent and the cysteine residue are connected through a disulfide bond; the silane coupling agent is connected with the hollow mesoporous inorganic oxide through a covalent bond; the cysteine residue is positioned in the cavity of the cyclic molecule with the hydrophobic cavity and is connected with the cyclic molecule through intermolecular force; the ring-shaped molecules with the hydrophobic cavity form a molecular barrier of the hollow mesoporous inorganic oxide;
the cysteine residue can make the cyclic molecule with the hydrophobic cavity shed under the acidic or alkaline condition, and the disulfide bond can be broken under the action of a reducing agent.
The mercapto-containing silane coupling agent is mercaptopropyltrimethoxysilane (KH590), and similarly, mercaptopropyltriethoxysilane, mercaptopropyltributoxysilane, mercaptopropyldimethoxysilane, mercaptoundecoxyloxytrimethylsilane, mercaptoethyltriethoxysilane; thus in the structural schematic diagram of fig. 1R 1 is methoxy or ethoxy and R2 is a methylene carbon chain of varying length from 3 to 11. The mass ratio of the chain part to the cyclic molecule part of the quasi-rotaxane supermolecular structure part is 7-10.
The cyclic molecule with the hydrophobic cavity is gamma-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin or cucurbituril; the hollow mesoporous inorganic oxide is hollow mesoporous silicon oxide or hollow mesoporous zirconium oxide. FIG. 3 is a transmission electron microscope image of hollow silica spheres of the main vessel of the present invention, FIG. 4 is a scanning electron microscope image of air silica spheres of the main vessel of the present invention, and FIG. 5 is an x-ray diffraction pattern of hollow silica spheres of the main vessel of the present invention.
The hollow mesoporous oxide has an ordered mesoporous structure with surface hydroxyl and MCM-41 structural characteristics, and is prepared by using polystyrene spheres as a template, wherein the polystyrene sphere template is shown in figure 2, and similarly, the polyformaldehyde-melamine resin spheres can also be used as the template.
The invention aims to provide a simple-made environment-responsive (pH or reducing agent) hollow mesoporous inorganic oxide carrier, which is mainly characterized in that a long-chain structure is modified on the surface of a hollow mesoporous oxide, then macrocyclic molecules are sleeved on the surface of the hollow mesoporous oxide to form a pseudorotaxane structure, when the pH is deviated from neutral, the long-chain molecules carry charges and generate repulsion with the macrocyclic molecules to cause the macrocyclic molecules to fall off, and mesopores are not blocked by the macrocyclic molecules, so that a medicament is smoothly diffused and released along the mesopores. Acidic conditions, the amino group at the end of the long chain is protonated (to give a hydrogen ion), and the amino group is positively charged. Under alkaline conditions, the carboxyl group at the end of the long chain is deprotonated and takes a negative charge. Reducing agents such as Glutathione (GSH) can then break the disulfide bonds in the long chain, breaking down the pseudo-rotaxane structure and releasing the drug. The response material is in a molecular valve 'closed' state in a neutral environment; and under acidic conditions, to a molecular valve "open" state.
Example 1
The invention relates to a multiple response (pH, reducing agent) type drug-carrying container based on a pseudo-rotaxane supermolecular structure, which comprises the following steps:
(1) dispersing 200mg of hollow silicon oxide material in xylene, heating to 100 ℃, adding 72.72mg of coupling agent KH590 (mercaptopropyl trimethoxy silane), and carrying out surface modification reaction for 12 h;
(2) dispersing 150mg of the product obtained in the step (1) in a 15% methanol aqueous solution with the pH value of 4.5, adding 75mg of 2, 2-dithiodipyridine, and carrying out disulfide bond exchange reaction at room temperature for 4 h;
(3) dispersing 100mg of the product obtained in the step (2) in 15% methanol aqueous solution with pH 4.5, adding 100mg of cysteine for reaction, and performing disulfide bond exchange reaction for 0.25h at room temperature;
(4) and (3) dispersing the product obtained in the step (3) in a high-concentration rhodamine 6g drug aqueous solution, stirring and loading for 1d, adding alpha cyclodextrin, continuously stirring for 2d, and filtering and cleaning the residual drug on the surface to obtain the multi-response silicon oxide-based drug-carrying container.
Controlled release testing of drugs: in order to study the release effect of the drug-loaded response container under different pH conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple-response (pH and reducing agent) medicine carrying container material attached with 6g of rhodamine, placing the material in three buffer solutions with pH values of 3, 7 and 11, after a period of time interval, extracting and filtering insoluble substances by using a syringe and a filter head, testing the medicine concentration in the filtrate, and obtaining a relation curve chart 6 of the rhodamine 6g and the time.
In order to study the release effect of the drug-loaded response container under different reducing conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple-response (pH and reducing agent) drug-loaded container material attached with 6g of rhodamine, respectively placing the materials in neutral buffer solution containing 10mM reduced glutathione or not, after a period of time interval, using a syringe and a filter head to extract and filter insoluble substances, testing the drug concentration in the filtrate, and obtaining a graph 6 of the relationship between 6g of rhodamine and time, wherein the graph shows that the pH is 3 and 100% is released, the graph shows that the graph.
Figure 6 shows the effect of drug release from the container at different pH conditions, where there is essentially no release at neutral conditions, acidic conditions stimulate the maximum and fastest release, and basic conditions stimulate release as well, but slightly less so than acidic. Figure 7 shows the drug release profiles in different reducing environments. It can be seen that the drug release increased by 25% after addition of the reducing agent.
Example 2
The invention relates to a multiple response (pH, reducing agent) type drug-carrying container based on a pseudo-rotaxane supermolecular structure, which comprises the following steps:
(1) dispersing 200mg of hollow zirconia material in xylene, heating to 110 ℃, adding 30.3mg of mercaptopropyl tributoxysilane coupling agent, and carrying out surface modification reaction for 16 h;
(2) dispersing 150mg of the product obtained in the step (1) in a 15% methanol aqueous solution with the pH value of 3.5, adding 75mg of 2, 2-dithiodipyridine, and carrying out disulfide bond exchange reaction at room temperature for 2 h;
(3) dispersing 100mg of the product obtained in the step (2) in 15% methanol aqueous solution with the pH value of 3.5, adding 100mg of cysteine for reaction, and performing disulfide bond exchange reaction for 30min at room temperature;
(4) and (3) dispersing the product obtained in the step (3) in a high-concentration rhodamine 6g drug aqueous solution, stirring and loading for 1d, adding beta cyclodextrin, continuously stirring for 2d, and filtering and cleaning the residual drug on the surface to obtain the multi-response silicon oxide-based drug-carrying container.
Controlled release testing of drugs: in order to study the release effect of the drug-loaded response container under different pH conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple response (pH and reducing agent) drug-loaded container material attached with 6g of rhodamine, placing the material in three buffers of pH 3, 7 and 11, after a period of time, using a syringe and a filter head to extract and filter insoluble substances, and testing the drug concentration in the filtrate, wherein the drug concentration is 100% released when the pH is 3, 13% released when the pH is 7 and 65% released when the pH is 11.
In order to study the release effect of the drug-loaded response container under different reducing conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple-response (pH and reducing agent) drug-loaded container material attached with 6g of rhodamine, respectively placing the container material in neutral buffer solution containing 10mM reduced glutathione or not, after a period of time interval, extracting and filtering insoluble substances by using an injector and a filter head, testing the drug concentration in the filtrate, and finding that the release amount is improved by 20% after the reducing agent glutathione is added.
Example 3
The invention relates to a multiple response (pH, reducing agent) type drug-carrying container based on a pseudo-rotaxane supermolecular structure, which comprises the following steps:
(1) dispersing 200mg of hollow silicon oxide material in toluene, heating to 80 ℃, adding 150mg of mercaptopropyl dimethoxysilane, and carrying out surface modification reaction for 24 h;
(2) dispersing 150mg of the product obtained in the step (1) in a 15% methanol aqueous solution with the pH value of 5.5, adding 75mg of 2, 2-dithiodipyridine, and carrying out disulfide bond exchange reaction at room temperature for 6 h;
(3) dispersing 100mg of the product obtained in the step (2) in 15% methanol aqueous solution with pH of 5.5, adding 100mg of cysteine for reaction, and performing disulfide bond exchange reaction for 2 hours at room temperature;
(4) and (3) dispersing the product obtained in the step (3) in a high-concentration rhodamine 6g drug aqueous solution, stirring and loading for 1d, adding gamma cyclodextrin, continuously stirring for 2d, and filtering and cleaning the residual drug on the surface to obtain the multi-response silicon oxide-based drug-carrying container.
Controlled release testing of drugs: in order to study the release effect of the drug-loaded response container under different pH conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple response (pH and reducing agent) drug-loaded container material attached with 6g of rhodamine, placing the material in three buffers of pH 3, 7 and 11, after a period of time, using a syringe and a filter head to extract and filter insoluble substances, and testing the drug concentration in the filtrate, wherein the drug concentration is 100% released when the pH is 3, 14% released when the pH is 7 and 55% released when the pH is 11.
In order to study the release effect of the drug-loaded response container under different reducing conditions, the following test experiments were carried out: the change curve of the drug release amount with time is detected at 526nm (rhodamine characteristic peak) by an ultraviolet-visible light tester. Accurately weighing 3mg of multiple-response (pH and reducing agent) drug-loaded container material attached with 6g of rhodamine, respectively placing the container material in neutral buffer solution containing 10mM reduced glutathione or not, after a period of time interval, extracting and filtering insoluble substances by using an injector and a filter head, testing the drug concentration in the filtrate, and finding that the release amount is improved by 23% after the reducing agent glutathione is added.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A carrier based on pH and reducing agent response of a pseudorotaxane molecular structure is characterized in that the carrier comprises a hollow mesoporous inorganic oxide and a pseudorotaxane molecule; the pseudorotaxane molecule comprises a chain molecule and a ring molecule with a hydrophobic cavity; one end of the chain molecule is a silane coupling agent, the other end of the chain molecule is a cysteine residue, and the silane coupling agent and the cysteine residue are connected through a disulfide bond; the silane coupling agent is connected with the hollow mesoporous inorganic oxide through a covalent bond; the cysteine residue is positioned in the cavity of the cyclic molecule with the hydrophobic cavity and is connected with the cyclic molecule with the hydrophobic cavity through intermolecular force; the ring-shaped molecules with the hydrophobic cavity form a molecular barrier of the hollow mesoporous inorganic oxide;
the cysteine residue can make the cyclic molecule with the hydrophobic cavity shed under the acidic or alkaline condition, and the disulfide bond can be broken under the action of a reducing agent.
2. The pH and reductant responsive support based on a pseudorotaxane molecular structure of claim 1, wherein the cyclic molecule having a hydrophobic cavity is γ -cyclodextrin, α -cyclodextrin, β -cyclodextrin or cucurbituril;
the silane coupling agent is mercaptopropyltrimethoxysilane, mercaptopropyltriethoxysilane, mercaptopropyltributoxysilane, mercaptopropyldimethoxysilane, mercaptoundecoxytrimethylsilane or mercaptoethyltriethoxysilane.
3. The pH and reductant-responsive support based on a pseudorotaxane molecular structure according to claim 1, wherein the hollow mesoporous inorganic oxide is a hollow mesoporous silica or a hollow mesoporous zirconia; the hollow mesoporous inorganic oxide is loaded with drugs or corrosion inhibitors.
4. A method for preparing a pH and reductant-responsive support based on a pseudorotaxane molecular structure, comprising the steps of:
(1) dispersing a hollow mesoporous inorganic oxide material in an organic solvent with polarity less than that of benzene, and then adding a silane coupling agent with sulfydryl to modify the silane coupling agent with sulfydryl to the surface of the hollow mesoporous inorganic oxide;
(2) dispersing the intermediate product obtained in the step (1) in an acidic organic alcohol aqueous solution, adding 2, 2-dipyridyl disulfide, and carrying out disulfide bond exchange reaction on disulfide bonds of the 2, 2-dipyridyl disulfide and sulfydryl on a silane coupling agent;
(3) dispersing the intermediate product obtained in the step (2) in an acidic organic alcohol aqueous solution, adding cysteine, and performing a disulfide bond exchange reaction to obtain an intermediate product of the hollow mesoporous inorganic oxide with the surface modified with chain molecules;
(4) and (4) adding a cyclic molecule with a hydrophobic cavity into the intermediate product obtained in the step (3), and connecting the cysteine residue of the chain molecule with the cyclic molecule with the hydrophobic cavity through intermolecular force to form a pseudorotaxane molecule, so as to obtain the carrier with pH value and reducing agent response based on the pseudorotaxane molecule structure.
5. The method for preparing a pH and reductant-responsive support based on a pseudorotaxane molecular structure according to claim 4, wherein the method further comprises a step of adding a drug or a corrosion inhibitor before adding the cyclic molecule having a hydrophobic cavity in the step (4), such that the drug or the corrosion inhibitor is loaded in the hollow mesoporous inorganic oxide; and then adding the cyclic molecules with the hydrophobic cavities, so that the cyclic molecules with the hydrophobic cavities form a molecular barrier of the hollow mesoporous inorganic oxide.
6. The method for preparing a pH and reducing agent response carrier based on a pseudorotaxane molecular structure according to claim 4, wherein the silane coupling agent having a mercapto group in the step (1) is mercaptopropyltrimethoxysilane, mercaptopropyltriethoxysilane, mercaptopropyltributoxysilane, mercaptopropyldimethoxysilane, mercaptoundecoxytrimethylsilane, or mercaptoethyltriethoxysilane; the hollow mesoporous inorganic oxide is hollow mesoporous silicon oxide or hollow mesoporous zirconium oxide.
7. The method for preparing a pH and reductant-responsive carrier based on a pseudorotaxane molecular structure according to claim 4, wherein the cyclic molecule having a hydrophobic cavity in the step (4) is γ -cyclodextrin, α -cyclodextrin, β -cyclodextrin or cucurbituril.
8. The method for preparing a carrier based on the pH of the pseudorotaxane molecular structure and the response of a reducing agent according to claim 4, wherein the reaction temperature for modifying the silane coupling agent having a mercapto group to the surface of the hollow mesoporous inorganic oxide in the step (1) is 80 ℃ to 110 ℃, the reaction time is 12h to 24h, and the ratio of the amount of the silane coupling agent having a mercapto group to the amount of the hollow mesoporous inorganic oxide is 1: (2-9).
9. The method for producing a pH and reducing agent-responsive support based on a pseudorotaxane molecular structure according to claim 4, wherein in the step (2) and the step (3), the pH of the acidic aqueous organic alcohol solution is in the range of 2 to 6; the reaction time in the step (2) is 2-8 h, and the reaction time in the step (3) is 0.25-2 h.
10. The method for preparing a carrier based on the pH of the pseudorotaxane molecular structure and the response of a reducing agent according to claim 5, wherein the ratio of the mass of the drug or the corrosion inhibitor to the mass of the intermediate product of the hollow mesoporous inorganic oxide modified with the chain molecule on the surface thereof in the step (4) is 40-50 mg/g; the medicament is rhodamine or gefitinib, and the corrosion inhibitor is rosin amine.
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