CN113081965B - Sensitivity and H based on ROS 2 S-responsive multifunctional liposome and preparation method and application thereof - Google Patents
Sensitivity and H based on ROS 2 S-responsive multifunctional liposome and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a method for sensitivity and H based on ROS 2 The multifunctional liposome with S response and the preparation method and the application thereof, the multifunctional liposome comprises: introduction of ROS reactive groups and H by chemical bonds 2 PFC carrier, phospholipids and cholesterol of S donor; meanwhile, entrapping hydroxyl safflower yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2 to 4:1; the molar ratio of the phospholipid to the PFC carrier is 4-8: 1. the PFC carrier of the invention introduces ROS reaction group and H 2 S donor, liposomes prepared using PFC vectors are ROS sensitive and H 2 And S response function. The liposome also entraps a strong water-soluble drug hydroxyl carthamin yellow A to prolong the slow release time of the HSYA, improve the cell penetration capability of the HSYA and treat renal ischemia-reperfusion injury in various 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 ROS 2 S-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: (1) inhibiting renal ischemia reperfusion-induced renal tubular epithelial cell apoptosis; (2) tubular-interstitial inflammatory response; (3) promote the proliferation and repair of renal tubular epithelial cells. ROS are a series of substances with superoxide function, such as H, produced at inflammatory sites 2 O 2 、O 2 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. H 2 S donors have been used to treat kidney disease, H 2 S donor can slowly release H 2 S, 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 ROS 2 An S-responsive multifunctional liposome, its preparation method and application, entrapping hydroxysafflor yellow A (HSYA) for improving body dysfunction caused by acute renal injury.
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 ROS 2 An S-responsive multifunctional liposome comprising: introduction of ROS reactive groups and H by chemical bonds 2 PFC carrier, phospholipids and cholesterol of S donor; meanwhile, entrapping hydroxyl safflower yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2-4: 1; the mol 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 H 2 The S donor is allyl cysteine.
Further, reacting the reactant of the ferrocenecarboxylic acid and the allylcysteine with 1, 2-dimyristoyl-sn-triorganyl-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 into 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-propanetriyl-3-phosphatidylethanolamine; dropwise adding the 1, 2-dimyristoyl-sn-propanetriyl-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 C 2 H 5 In OH, drying by rotary evaporation at 40-50 ℃ to obtain a uniform liposome membrane; the liposome membrane is treated with 0.1-0.3M NaHCO 3 Hydrolyzing the solution at 45-55 ℃ for 2h, 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 CHCl 3 (ii) a The concentration is 0.1-0.5 mol/1.
Further, CHCl is used in the steps (1) and (2) 3 Extracting for 1-3 times, and alternately using H 2 And O and 10% citric acid aqueous solution.
Further, the pore diameter of the microporous filter membrane in the step (3) is 220-800 nm.
Further, the mol 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, the mass ratio of the phospholipid to the hydroxysafflor yellow A in the step (3) is 2-4: 1
Further, the mass fraction of mannitol in the step (3) is 2-10%.
The invention also provides the method based on ROS sensitivity and H 2 The 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 H 2 S-responsive multifunctional liposomes can reduce intracellular H 2 O 2 Concentration of and increase of intracellular H 2 The concentration of S.
Compared with the prior art, the invention has the advantages and beneficial effects that: the invention selects the material with ROS sensitivity and H 2 The S-responsive multifunctional liposome is also coated with a strong water-soluble drug Hydroxy Safflower Yellow A (HSYA) 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.
(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 capability 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 H 2 S donor allylcysteine to release H in vivo 2 S, 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 carrier 1 H-NMR chart;
FIG. 3 is a graph of the infrared absorption spectrum of a PFC carrier of the novel nano-carrier material;
FIG. 4 shows electron microscope, particle size and zeta potential maps 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 the cytotoxicity of mesangial cells at different 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 H 2 S concentration determination graph;
FIG. 11 shows Raw264.7 intracellular H 2 O 2 Concentration measurement graph.
Detailed Description
The following embodiments better illustrate the present disclosure. 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) Accurately weighing 229mg of ferrocenecarboxylic acid, 764mg of EDC and 661mg of NHS, dissolving in 5ml of DMSO, and carrying out catalytic reaction for 3h at room temperature to obtain a first solution. Precision allyl cysteine 629mg, dissolved in 30ml DMSO. And dropwise adding an allyl cysteine solution into the first solution, and reacting for 12 hours.
After the reaction is completed, the reaction solution is added,the reaction solution was diluted with 0.5-fold amount of CHCl 3 Extracted 3 times with 100ml H 2 O extraction and washing for 2 times, 10% citric acid aqueous solution 100ml extraction and washing for 1 time, 100ml H 2 O extraction and washing are carried out for 2 times, and saturated NaCl solution extraction and washing are carried out for 1 time. Taking CHCl 3 Layer, adding a certain amount of anhydrous Na 2 SO 4 And standing for 4 hours, 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 CHCl 3 And catalyzing for 3 hours at room temperature to obtain a second solution. 84mg of (1, 2-dimyristoyl-sn-propanetriyl-3-phosphatidylethanolamine) was precisely weighed and dissolved in 1ml of CHCl 3 And 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 solution 2 And (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 in a mass ratio of 3: 1, wherein the weight ratio of the soybean lecithin: PFC carrier is about 4-8: 1 (mol/mol)), and is dissolved in C 2 H 5 In OH, drying by rotary evaporation at 40-50 ℃ to obtain a uniform liposome membrane. Liposome membranes were treated with 0.2M NaHCO 3 The solution is hydrolyzed for 2 hours at the temperature of 45-55 ℃ and is subjected to ultrasonic treatment for 30min. 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 solution 3 . HSYA (soybean lecithin: HSYA = 3: 1, mass ratio) was added to the dialyzed liposome solution, and incubated at 37 ℃ for 30min. And (3) dialyzing the incubated liposome solution in a MW =2000 dialysis bag 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, 1 H-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 combination 1 The novel vector was examined by H-NMR and FT-IR. FIG. 2 shows that 7.70ppm is NH-CH 2 -PO 3 NH proton absorption peaks of (4.83 ppm) and (4.68 ppm) are C of ferrocenecarboxylic acid 5 H 5 Proton absorption peak, 3.58ppm is CO-NH-CH 2 NH proton absorption Peak of-2.87 ppm is S-CH 2 Proton absorption peak of-OH-PO at 1.56ppm 3 the-OH proton absorption peak of (1). FIG. 3 shows, 3364.16cm -1 The peak of stretching vibration of N-H, 2920.61cm -1 Is C-N stretching vibration peak, 1762cm -1 And 1731cm -1 C = O peak of stretching vibration, 1635cm -1 Peak of stretching vibration of C = C, 1427cm -1 And 1377cm -1 Is 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, with a particle size of about 218nm, a zeta potential of-17.48 mV, with good dispersibility and good stability, by particle size, zeta potential, and TEM images.
2. HSYA liposome in vitro release experiment
HSYA liposomes were placed in dialysis bags and placed in 20mL pH7.4PBS release media 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.
The results of in vitro release experiments are shown in fig. 5, and after HSYA is coated into liposome, the HSYA can be slowly released, thereby playing a role of slow release. The PFC liposome preparation is proved to be capable of prolonging the retention time of the medicament in vivo and reducing the metabolism of the medicament by the body.
2. Cytological study of HSYA liposomes
(1) Cytotoxicity study. Inoculating mesangial cells and Raw264.7 macrophages in a 96-well plate, at 37 deg.C, 5% 2 And culturing under saturated moisture. And HSYA liposome with different concentrations is added, and CCK8 experiments are carried out after 12h and 24h, so as to verify the cytotoxicity of the 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 24h. The novel nanoliposome is proved to have good cell safety.
(2) Cellular uptake studies. Mesangial cells and Raw264.7 macrophages were inoculated into 96-well plates, apoptosis of cell nuclei was observed by fluorescent staining of coumarin 6 (Cou 6) and DAPI (4', 6-diamidino-2-phenylindole), and uptake of HSYA liposomes at different concentrations by the two cells was examined at different time points to verify whether concentration-dependent and time-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 H 2 O 2 And H 2 And (4) measuring the concentration of S. Raw264.7 macrophages were seeded into 6-well plates and stimulated with LPS (1. Mu.g/mL) as H 2 O 2 And H 2 S detection kit instruction for detection, and calculating each group of supernatant H 2 O 2 And H 2 S level.
Raw264.7 intracellular H 2 O 2 And H 2 The results of the S concentration measurement experiments are shown in FIGS. 10 and 11, and show that the novel HSYA liposome can reduce intracellular H 2 O 2 Concentration of and increase of intracellular H 2 The S concentration has the function of reducing inflammation and simultaneously ensuring H 2 S has the functions of 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 (7)
1. Sensitivity and H based on ROS 2 The S-responsive multifunctional liposome is characterized in that: the multifunctional liposome comprises: introduction of ROS reactive group and H through chemical bond 2 PFC carrier, phospholipids and cholesterol of S donor; meanwhile, entrapping hydroxyl safflower yellow A; the mass ratio of the phospholipid to the hydroxysafflor yellow A is 2 to 4:1; the molar ratio of the phospholipid to the PFC carrier is 4 to 8:1; the ROS reactive group is ferrocenecarboxylic acid; said H 2 The S donor is allyl cysteine; reacting the reactant of the ferrocenecarboxylic acid and the allyl cysteine with 1, 2-dimyristoyl-sn-trioctyl-3-phosphatidylethanolamine to prepare the PFC carrier;
the structure of the PFC carrier is shown as formula 1:
formula 1.
2. The ROS-sensitivity and H-based sensor of claim 1 2 The S-responsive multifunctional liposome is characterized in that: the mass ratio of the phospholipid to the cholesterol is 2 to 4:1.
3. the ROS-sensitivity and H-based compound of claim 1 2 The preparation method of the S-responsive multifunctional liposome is characterized by comprising the following steps: the preparation method 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 C 2 H 5 In OH, drying by rotary evaporation at 40 to 50 ℃ to obtain a uniform liposome membrane; the liposome membrane is coated with 0.1 to 0.3M NaHCO 3 Hydrating the solution at 45 to 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.
4. The ROS-sensitivity and H-based sensor of claim 3 2 The 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.
5. The ROS-sensitivity and H-based sensor of claim 3 2 The 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 CHCl 3 。
6. The ROS-sensitivity and H-based composition of claim 3 2 The 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 to 10%.
7. The ROS-sensitivity and H-based composition of any of claims 1-2 2 The application of the S-responsive multifunctional liposome in preparing medicaments for reducing inflammation, promoting tubular cell regeneration and reducing apoptosis of kidney parts.
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