CN113081965A - Sensitivity and H based on ROS2S-responsive multifunctional liposome and preparation method and application thereof - Google Patents
Sensitivity and H based on ROS2S-responsive multifunctional liposome and preparation method and application thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
Abstract
The invention provides a method for sensitivity and H based on ROS2The multifunctional liposome with S response, the preparation method and the application thereof, wherein the multifunctional liposome comprises: introduction of ROS reactive groups and H by chemical bonds2PFC carrier, phospholipids and cholesterol of S donor; simultaneously entrapping hydroxyl carthamin yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2-4: 1; the molar ratio of the phospholipid to the PFC carrier is 4-8: 1. PF of the inventionC carrier introduces ROS reaction group and H2S donor, liposomes prepared using PFC vectors are ROS sensitive and H2And S response function. The liposome also entraps the hydroxyl carthamin yellow A which is a strong water-soluble drug, so as to prolong the slow release time of the HSYA, improve the cell penetration capability of the HSYA and treat renal ischemia reperfusion injury in multiple aspects.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for detecting sensitivity and H based on ROS2S-responsive multifunctional liposome and a preparation method and application thereof.
Background
Renal ischemia reperfusion injury is one of the major causes of acute renal injury, characterized by tubular epithelial cell death and loss of renal function. The effective measures for preventing or treating ischemic acute kidney injury mainly comprise the following steps: firstly, inhibiting renal tubular epithelial cell apoptosis induced by renal ischemia reperfusion; ② tubular-interstitial inflammatory reaction; and promoting the proliferation and repair of renal tubular epithelial cells. ROS are a series of substances with superoxide function, such as H, produced at inflammatory sites2O2、O2 2-And the like. After renal ischemia reperfusion injury occurs, ROS are produced by the inflammatory cascade, leading to more severe renal tissue injury, where neutrophil and macrophage infiltration and inflammatory factor production play an important role in the early stages of renal ischemia reperfusion injury. H2S donors have been used to treat kidney disease, H2S donor can slowly release H2S, helps to reduce inflammation, reduce ROS, reduce the formation of cellular inflammatory factors, lower blood pressure, promote vascular remodeling, promote tubular cell regeneration, and reduce apoptosis and autophagy at the kidney site. No chemical medicine can obviously improve the body dysfunction caused by acute kidney injury of a patient.
Disclosure of Invention
The invention aims to provide a method for detecting sensitivity and H based on ROS2The S-responsive multifunctional liposome, as well as a preparation method and an application thereof, entraps hydroxysafflor yellow A (HSYA) for improving the body dysfunction caused by acute kidney injury of patients.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a method for sensitivity and H based on ROS2S responseThe multifunctional liposome of (1), comprising: introduction of ROS reactive groups and H by chemical bonds2PFC carrier, phospholipids and cholesterol of S donor; simultaneously entrapping hydroxyl carthamin yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2-4: 1; the molar ratio of the phospholipid to the PFC carrier is 4-8: 1.
Furthermore, the mass ratio of the phospholipid to the cholesterol is 2-4: 1.
Further, the ROS reactive group is ferrocenecarboxylic acid; said H2The S donor is allyl cysteine.
Further, reacting the reactant of the ferrocenecarboxylic acid and the allyl cysteine with 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine to prepare the PFC carrier.
Further, the structure of the PFC carrier is shown in formula 1:
the invention also provides a preparation method of the multifunctional liposome, which comprises the following steps:
(1) dissolving ferrocenecarboxylic acid, EDC and NHS, and carrying out catalytic reaction to obtain a first solution; preparing an allyl cysteine solution; dropwise adding the allyl cysteine solution to the first solution; after the reaction is finished, extracting after extraction; obtaining FC;
(2) dissolving EDC, NHS and the FC obtained in the step (1) to obtain a second solution; preparing a solution of 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine; dropwise adding the 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine solution into the second solution; extracting after the light-resistant reaction is finished, and extracting after extraction; obtaining a PFC carrier;
(3) dissolving the phospholipid and cholesterol, the PFC carrier obtained in the step (2) in C2H5In OH, rotationally evaporating at 40-50 ℃ to dryness to obtain a uniform liposome membrane; the liposome membrane is treated with 0.1-0.3M NaHCO3Solutions ofHydrating for 2 hours at the temperature of 45-55 ℃, carrying out ultrasonic treatment for 20-40 min, filtering by using a microporous filter membrane, and dialyzing to obtain a liposome solution; and adding hydroxysafflor yellow A into the liposome solution for incubation, dialyzing the incubated solution, and adding mannitol serving as a freeze-drying protective agent for freeze-drying to obtain the multifunctional liposome.
Further, the solvent of the first solution and the allyl cysteine solution in the step (1) is DMSO.
Further, the concentration of the ferrocenecarboxylic acid in the first solution is 0.1-1.0 mol/l; the concentration of the allyl cysteine solution is 0.1-1 mol/l.
Further, the solvent of the second solution and the solution of 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine in the step (2) is CHCl3(ii) a The concentration is 0.1 to 0.5 mol/1.
Further, CHCl is used in the steps (1) and (2)3Extracting for 1-3 times, and alternately using H2And O and 10% citric acid aqueous solution.
Further, the aperture of the microporous filter membrane in the step (3) is 220-800 nm.
Further, the molar ratio of the phospholipid to the PFC carrier in the step (3) is 4-8: 1.
Further, the mass ratio of the phospholipid to the cholesterol in the step (3) is 2-4: 1.
Further, in the step (3), the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2-4: 1
Further, the mass fraction of mannitol in the step (3) is 2-10%.
The invention also provides the sensitivity and H based on ROS2The application of the S-responsive multifunctional liposome in preparing medicines for reducing inflammation, promoting the regeneration of tubular cells and reducing the apoptosis of kidney parts.
Further, the method is based on ROS sensitivity and H2S-responsive multifunctional liposomes can reduce intracellular H2O2Concentration of and increase of intracellular H2The concentration of S.
Compared with the prior art, the method has the advantages that,the invention has the advantages and beneficial effects that: the invention selects the material with ROS sensitivity and H2The S-responsive multifunctional liposome is also coated with a strong water-soluble drug Hydroxy Safflor Yellow A (HSYA) to prolong the slow release time of the HSYA, improve the cell penetration capacity of the HSYA and treat renal ischemia-reperfusion injury in multiple aspects.
(1) The liposome is prepared to entrap the strong water-soluble drug HSYA, delay the drug release time, reduce the metabolism of the organism to the drug and simultaneously enhance the cell transmembrane capacity of the drug.
(2) And the ROS reaction group ferrocenecarboxylic acid is introduced, so that ROS can be consumed, and the damage of ROS to the kidney is reduced.
(3) Introduction of H2S donor allylcysteine to release H in vivo2S, can relieve inflammation, reduce ROS, reduce the formation of inflammatory factors, promote the regeneration of renal tubular cells and reduce the apoptosis of kidney parts.
Drawings
Fig. 1 is a scheme of synthesis of novel nanocarrier materials PFC carriers;
FIG. 2 is a novel nano carrier material PFC carrier1H-NMR chart;
FIG. 3 is a graph of the infrared absorption spectrum of a PFC carrier of the novel nano-carrier material;
FIG. 4 is an electron microscope, particle size, zeta potential map of HSYA liposomes;
FIG. 5 is an in vitro release profile of the novel nano-formulation;
FIG. 6 is a graph of Raw264.7 cytotoxicity at different times;
FIG. 7 is a graph of renal membranous cell cytotoxicity at various times;
FIG. 8 is a concentration-dependent, time-dependent uptake plot for Raw264.7 cells;
FIG. 9 is a concentration-dependent, time-dependent uptake plot of mesangial cells;
FIG. 10 shows Raw264.7 intracellular H2S concentration determination graph;
FIG. 11 shows Raw264.7 intracellular H2O2Concentration measurement graph.
Detailed Description
The following embodiments better illustrate the present invention. However, the present invention is not limited to the following examples.
Example 1: synthesis of HSYA liposomes
1. Synthesis of multifunctional carrier PFC
The structural formula of the PFC carrier is formula 1:
the synthetic route is shown in figure 1; the method comprises the following specific steps:
(1) ferrocene formic acid 229mg, EDC 764mg and NHS 661mg were weighed out accurately, dissolved in 5ml DMSO and catalytically reacted for 3h at room temperature to obtain a first solution. Precision allyl cysteine 629mg, dissolved in 30ml DMSO. The allyl cysteine solution was added dropwise to the first solution, and reacted for 12 hours.
After completion of the reaction, the reaction solution was treated with 0.5-fold amount of CHCl3Extracted 3 times with 100ml H2O extraction and washing for 2 times, 10% citric acid aqueous solution 100ml extraction and washing for 1 time, 100ml H2O extraction and washing are carried out for 2 times, and saturated NaCl solution extraction and washing are carried out for 1 time. Taking CHCl3Layer, adding a certain amount of anhydrous Na2SO4Standing for 4h, centrifuging, taking supernatant, and performing rotary evaporation to extract a product to obtain a reaction product FC.
(2) EDC 56mg, NHS 34mg and FC 50mg were weighed out accurately and dissolved in 2ml CHCl3And catalyzing for 3 hours at room temperature to obtain a second solution. 84mg of (1, 2-dimyristoyl-sn-propanetriyl-3-phosphatidylethanolamine) is precisely weighed and dissolved in 1ml of CHCl3And dropwise adding the 1, 2-dimyristoyl-sn-propanetriyl-3-phosphatidylethanolamine solution into the second solution, and reacting for 24 hours at room temperature in a dark place.
After completion of the reaction, 10ml of H was added to the solution2And (3) fully oscillating, and then extracting and rotationally evaporating the solution in the same extraction sequence in the step (1) to obtain a reaction product PFC carrier.
2. Synthesis of hydroxysafflor yellow A (HSYA) liposomes
(3) Precisely weighing soybean lecithin and cholesterol at a mass ratio of 3: 1Lecithin: PFC carrier is about 4-8: 1(mol/mol)), and is dissolved in C2H5And (4) in OH, rotationally evaporating at 40-50 ℃ to dryness to obtain a uniform liposome membrane. Liposome membranes were treated with 0.2M NaHCO3Hydrating the solution at 45-55 ℃ for 2h, and carrying out ultrasonic treatment for 30 min. And (3) passing the liposome solution through 800nm, 450nm and 220nm microporous filter membranes for 5 times to obtain homogeneous liposome solution. The liposome solution was dialyzed in dialysis bag for 48h to remove NaHCO from the solution3. HSYA (soybean lecithin: HSYA: 3: 1, mass ratio) was added to the dialyzed liposome solution, and incubated at 37 ℃ for 30 min. And (3) putting the incubated liposome solution into a MW 2000 dialysis bag for dialysis for 48h, and adding 5% mannitol serving as a freeze-drying protective agent for freeze-drying to obtain the HSYA liposome.
Example 2: structure of PFC novel carrier
By FT-IR,1H-NMR characterizes the structure of PFC to verify the success of the synthesis of the novel multifunctional material.
Synthesizing PFC novel carrier by means of chemical bond combination1The novel vector was examined by H-NMR and FT-IR. FIG. 2 shows that 7.70ppm is NH-CH2-PO3NH proton absorption peaks of (4.83 ppm) and (4.68 ppm) are C of ferrocenecarboxylic acid5H5Proton absorption peak, 3.58ppm is CO-NH-CH2NH proton absorption Peak of-2.87 ppm is S-CH2Proton absorption peak of-1.56 ppm OH-PO3-OH proton absorption peak of (a). FIG. 3 shows, 3364.16cm-1Is the stretching vibration peak of N-H, 2920.61cm-1Is C-N stretching vibration peak, 1762cm-1And 1731cm-1Is C ═ O stretching vibration peak, 1635cm-1Is the stretching vibration peak of C ═ C, 1427cm-1And 1377cm-1Is a characteristic peak of the five-membered ring of ferrocenecarboxylic acid. Thus, the synthesis of the PFC carrier was verified.
Example 3: performance Studies of HSYA liposomes
1. The particle size and zeta potential of the HSYA liposome were characterized by a particle size analyzer, and the morphology of the liposome was characterized by a Transmission Electron Microscope (TEM).
FIG. 4 shows the particle size, zeta potential, and electron microscope images of HSYA liposomes, showing that the particles are spherical, uniform in size, about 218nm in size, zeta potential of-17.48 mV, good in dispersibility and good in stability, by particle size, zeta potential, and TEM image.
2. HSYA liposome in vitro release experiment
HSYA liposomes were placed in dialysis bags and placed in 20mL pH7.4PBS release medium in a shaker at 37 ℃ and 120rpm for in vitro drug release. The release medium of each sample was replaced at fixed time points with an equal amount of fresh medium, 0.5mL each time. The resulting sample was filtered through a 0.22 μm microfiltration membrane. The cumulative release amount is then calculated.
In vitro release experiment results are shown in fig. 5, after HSYA is coated into liposome, the HSYA can be slowly released, and the sustained release effect is achieved. The PFC liposome preparation is proved to be capable of prolonging the retention time of the drug in the body and reducing the metabolism of the drug by the body.
2. Cytological study of HSYA liposomes
(1) Cytotoxicity study. The mesangial cells and Raw264.7 macrophages were seeded in 96-well plates at 37 ℃ with 5% CO2And culturing under saturated moisture. And adding HSYA liposome with different concentrations, and performing CCK8 experiment after 12h and 24h to verify cytotoxicity of HSYA liposome to two cells.
The results of cytotoxicity tests are shown in fig. 6 and 7, and the cell survival rate of the HSYA liposome is high after the HSYA liposome is co-cultured with two cells for 12h and 24 h. The novel nanoliposome is proved to have good cell safety.
(2) Cellular uptake studies. Mesangial cells and Raw264.7 macrophages are inoculated in a 96-well plate, the apoptosis of cell nuclei is observed by fluorescent staining of coumarin 6(Cou 6) and DAPI (4', 6-diamidino-2-phenylindole), and the uptake of HSYA liposomes at different concentrations by the two cells is examined at different time points to verify whether the concentration and the time are dependent. The results of the cell uptake experiments are shown in FIGS. 8 and 9,
the results show that the HSYA liposome can smoothly enter two cells and show good concentration dependence and time dependence. The novel liposome is proved to have good biocompatibility.
(3) Dividing into control group, HSYA group, blank liposome group, and HSYA liposome group, and performing Raw264.7 intracellular H2O2And H2And (4) measuring the concentration of S. Raw264.7 macrophages were seeded into 6-well plates and stimulated with LPS (1. mu.g/mL) as H2O2And H2S detection kit instruction for detection, and calculating supernatant H of each group2O2And H2S level.
Raw264.7 intracellular H2O2And H2The results of the S concentration measurement experiments are shown in FIGS. 10 and 11, and show that the novel HSYA liposome can reduce intracellular H2O2Concentration of and increase of intracellular H2The S concentration plays a role in reducing inflammation and simultaneously enables H to be also added2S plays a role in promoting the regeneration of renal tubular cells and reducing the apoptosis of the kidney.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (10)
1. Sensitivity and H based on ROS2An S-responsive multifunctional liposome characterized by: the multifunctional liposome comprises: introduction of ROS reactive groups and H by chemical bonds2PFC carrier, phospholipids and cholesterol of S donor; simultaneously entrapping hydroxyl carthamin yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2-4: 1; the molar ratio of the phospholipid to the PFC carrier is 4-8: 1.
2. The ROS-sensitivity and H-based sensor of claim 12An S-responsive multifunctional liposome characterized by: the phospholipid and cholesterolThe mass ratio of (A) to (B) is 2-4: 1.
3. The ROS-sensitivity and H-based sensor of claim 12An S-responsive multifunctional liposome characterized by: the ROS reactive group is ferrocenecarboxylic acid; said H2The S donor is allyl cysteine.
4. The ROS-sensitivity and H-based composition of claim 32An S-responsive multifunctional liposome characterized by: and reacting the reactant of the ferrocenecarboxylic acid and the allyl cysteine with 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine to prepare the PFC carrier.
5. The ROS-sensitivity and H-based composition of claim 42An S-responsive multifunctional liposome characterized by: the structure of the PFC carrier is shown as formula 1:
6. the ROS-sensitive and H-based compound of claim 12A method for preparing an S-responsive multifunctional liposome, the method comprising the steps of:
(1) dissolving ferrocenecarboxylic acid, EDC and NHS, and carrying out catalytic reaction to obtain a first solution; preparing an allyl cysteine solution; dropwise adding the allyl cysteine solution to the first solution; after the reaction is finished, extracting after extraction; obtaining FC;
(2) dissolving EDC, NHS and the FC obtained in the step (1) to obtain a second solution; preparing a 1, 2-dimyristoyl-sn-trioctyl 030 phosphatidylethanolamine solution; dropwise adding the 1, 2-dimyristoyl-sn-trioctyl 03-phosphatidylethanolamine solution into the second solution; extracting after the light-resistant reaction is finished, and extracting after extraction; obtaining a PFC carrier;
(3) mixing phospholipid and cholesterol, the PFC carrier obtained in the step (2)Soluble in C2H5In OH, rotationally evaporating at 40-50 ℃ to dryness to obtain a uniform liposome membrane; the liposome membrane is treated with 0.1-0.3M NaHCO3Hydrating the solution at 45-55 ℃, performing ultrasonic treatment, filtering by using a microporous filter membrane, and performing dialysis to obtain a liposome solution; and adding hydroxysafflor yellow A into the liposome solution for incubation, dialyzing the incubated solution, and adding mannitol serving as a freeze-drying protective agent for freeze-drying to obtain the multifunctional liposome.
7. The ROS-sensitivity and H-based composition of claim 62The preparation method of the S-responsive multifunctional liposome is characterized by comprising the following steps: and (2) in the step (1), the solvents of the first solution and the allyl cysteine solution are DMSO.
8. The ROS-sensitivity and H-based composition of claim 62The preparation method of the S-responsive multifunctional liposome is characterized by comprising the following steps: the solvent of the second solution and the 1, 2-dimyristoyl-sn-propanetriyl-3-phosphatidylethanolamine solution in the step (2) is CHCl3。
9. The ROS-sensitivity and H-based composition of claim 62The preparation method of the S-responsive multifunctional liposome is characterized by comprising the following steps: in the step (3), the mass fraction of mannitol is 2-10%.
10. The method of any of claims 1-5 based on ROS sensitivity and H2The application of the S-responsive multifunctional liposome in preparing the medicines for reducing inflammation, promoting the regeneration of tubular cells and reducing the apoptosis of kidney parts.
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