CN118203647A - Superparamagnetic nano drug targeting Alzheimer disease Abeta protein pathological region as well as preparation method and application thereof - Google Patents
Superparamagnetic nano drug targeting Alzheimer disease Abeta protein pathological region as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a superparamagnetic nano drug targeting an Alzheimer's disease Abeta protein pathological region, a preparation method and application thereof, wherein the structural formula of the superparamagnetic nano drug targeting the Alzheimer's disease Abeta protein pathological region is Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide; the compound polypeptide sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, a Sema3A inhibitory peptide and a neuroprotective peptide from N to C; the targeting Abeta protein has a positioning sequence as follows: FFXXK. According to the invention, by reducing introduction of the Sema3A inhibitory peptide and the neuroprotective peptide in the Alzheimer's disease Abeta protein deposition pathological area, the Abeta protein deposition spots in the hippocampal brain area can be effectively reduced, the repair of the neural network in the hippocampal brain area is facilitated, and the preparation method has great potential for treating Alzheimer's disease.
Description
Technical Field
The invention belongs to the technical field of targeting nanomaterials, and in particular relates to a superparamagnetic nano-drug targeting an Abeta protein pathological region of Alzheimer's disease as well as a preparation method and application thereof.
Background
Alzheimer's disease is a major neurodegenerative disease that is manifested clinically by progressive decline in memory and cognitive ability. At present, about five tens of millions of Alzheimer's patients worldwide bring about serious burden to families and society. However, no effective medicine exists in Alzheimer's disease until now, most of the traditional medicines, whether acting on Abeta protein deposition or Tau protein phosphorylation, are administered in a whole body, and lack targeting, have a plurality of side effects and have insignificant improvement of cognitive ability, so that research on a medicine for treating Alzheimer's disease, which has strong targeting and small side effects, is needed.
Disclosure of Invention
Aiming at the problem that medicines for treating Alzheimer's disease (medicines for Abeta protein deposition or Tau protein phosphorylation) in the prior art lack of targeting, the invention provides a superparamagnetic nano-medicine for targeting Abeta protein pathological areas of Alzheimer's disease, a preparation method and application thereof, and the superparamagnetic nano-medicine can specifically target Abeta protein deposition pathological areas under the action of guide peptide and membrane penetrating peptide, simultaneously has the functions of clearing Abeta protein deposition and reducing colloid scars, and has the function of repairing a neural network.
The invention is realized by the following technical scheme:
The structural formula of the superparamagnetic nano-drug targeting the Alzheimer's disease Abeta protein pathological region is Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide;
The compound polypeptide sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, a Sema3A inhibitory peptide and a neuroprotective peptide from N to C;
the positioning (Starg) sequence of the target Abeta protein is as follows: FFXXK, X is any hydrophobic amino acid.
Further, the membrane penetrating sequence (Sccp) is YGRKRRQRRRR; the Sema3A inhibitory peptide (Score) sequence is HAVEHGFMQTLLKVTLE; the neuroprotective peptide (Sopt) sequence is NAPSIPQ.
Further, the N end of the composite polypeptide is coupled with a FITC luminescent group.
The preparation method of the superparamagnetic nano drug targeting the Alzheimer disease Abeta protein pathological region comprises the following steps:
(1) Preparation of Fe 3O4 -HS-PEG 600-carboxyl terminal nanoparticle: adding oleic acid iron powder into a mixture composed of oleic acid and l-octadecene, preserving heat for 3-10 min at 90-120 ℃, then heating to 300-350 ℃ and preserving heat for 20-50 min, cooling, collecting and dispersing in heptane through a magnet, and washing to obtain a Fe 3O4 nano particle core; dissolving the Fe 3O4 nano particle core in PEG 600, and stirring for reaction to obtain Fe 3O4 -HS-PEG 600-carboxyl terminal nano particles;
(2) Composite polypeptide: synthesizing composite polypeptide by Fmoc solid-phase carrier synthesis method, wherein the composite polypeptide sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, a Sema3A inhibitory peptide and a neuroprotective peptide from N to C terminal;
(3) Preparation of Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide: mixing N-ethynyl-N, 4-dimethylbenzenesulfonamide and the composite polypeptide in the step (2), adding dichloromethane, stirring to react until the acid is consumed, removing the dichloromethane in vacuum after the reaction is finished, adding the Fe 3O4 -HS-PEG 600-carboxyl end nano particles prepared in the step (1), water and DMSO mixed solvent, stirring at room temperature to react until alpha-acyloxyamine is completely consumed, concentrating and purifying the reactant, and obtaining the superparamagnetic nano drug targeting the Alzheimer's disease A beta protein pathological area.
Further, the feed ratio of the iron oleate powder, the oleic acid and the l-octadecene in the step (1) is 2mmol:1mmol:10g; the ratio of the iron oleate powder to the PEG 600 is 4mmol to 5mL; stirring reaction time is 1-5 h.
Further, the molar ratio of the composite polypeptide to the Fe 3O4 -HS-PEG 600-carboxyl-terminal nanoparticle in step (3) was 1:1.
Further, the molar ratio of N-ethynyl-N, 4-dimethylbenzenesulfonamide to composite polypeptide in step (3) is 1:1.
Further, the volume ratio of water to DMSO in the mixed solvent of water and DMSO in the step (3) is 1:4-1:6.
The invention discloses application of a superparamagnetic nano drug targeting an Abeta protein pathological region of Alzheimer's disease in preparation of a drug for treating Alzheimer's disease; the templated peptide in Scpp enhances the ability of the nanoparticle to cross the cell membrane; the neuroprotective peptide is contained in the Sopt sequence to enhance the protective effect on neurons; starg polypeptide sequences that recognize the amyloid β region of alzheimer's disease; the Score polypeptide sequence specifically inhibits the effects of Sema 3A.
Advantageous effects
According to the invention, sulfhydryl polyethylene glycol carboxyl (SH-PEG 600-COOH) is grafted and is connected with Fe 3O4 through sulfhydryl, and SH-PEG600-COOH is connected with N-terminal amino of compound polypeptide through carboxyl to form an amide bond, so that the prepared superparamagnetic nano-drug (Fe 3O4-HS-PEG600-CO-NH2 -compound polypeptide) targeting the pathological region of Alzheimer's disease Abeta protein can realize the identification of space pathological regions, and the targeting polypeptide sequence can start the release of the compound polypeptide after being combined with the Abeta protein of the pathological region, thereby realizing the inhibition of Sema3A protein of the pathological region, realizing the space targeting and real-time traceability of the nano-particle, and being the innovation of the Alzheimer's disease drug for regulating and controlling diseases in vivo. The Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide particles have pathological targeting, achieve the regulation and control of the expression of the Sema3A in a pathological region, relieve the pathological process of the Alzheimer disease and have great potential for treating the Alzheimer disease.
Drawings
FIG. 1 shows a high performance liquid chromatogram and a mass spectrum of Fe 3O4-HS-PEG600-CO-NH2 -complex polypeptide, on: high performance liquid chromatogram, the following: a mass spectrogram;
FIG. 2 is a graph of Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide atomic force microscope and transmission microscope versus composite nanotopography detection, (a) atomic force microscope surface topography detection; (b) transmission electron microscope detection results; (c) composite nano-drug size statistics;
FIG. 3 is an EDS spectrum analysis chart of Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide and an element analysis table of Fe 3O4 core particles;
FIG. 4 is a graph showing the cell membrane penetration result of Fe 3O4-HS-PEG600-CO-NH2 -complex polypeptide;
FIG. 5 is a graph showing the effect of Fe 3O4-HS-PEG600-CO-NH2 -complex polypeptide on clearing Abeta deposition spots; (a) Immunofluorescence staining results of the Abeta deposition spots of the hippocampal tissues of the mice in the control group; (b) The administration group mice hippocampal tissue Abeta deposition spot immunofluorescence staining result; (c) Two groups of mice were subjected to a-beta deposition spot immunofluorescent staining, t-value test, p <0.001, n=5.
Detailed Description
Reference will now be made in detail to exemplary embodiments of the invention, which should not be construed as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. .
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Any equivalent or similar process and material changes and modifications can be made without departing from the spirit of the invention.
In the following examples: the targeting sequence of the A beta protein is as follows: FFXXK, X is valine, FFVVK; the membrane penetrating sequence is YGRKRRQRRRR; the Sema3A inhibitory peptide sequence is HAVEHGFMQTLLKVTLE; the neuroprotective peptide sequence was NAPVSIPQ.
Example 1
Preparation of Fe 3O4 -HS-PEG 600-carboxyl terminal nanoparticle:
(1) The ferric oxide nano-particles are prepared by adopting an oleic acid method: firstly, mixing 80 ml ethanol, 60 ml deionized water and 140 ml heptane to prepare a mixed solvent, adding 120 mmol sodium oleate and 40 mmol ferric chloride hexahydrate into the mixed solvent, and dissolving 4h in an inert atmosphere at 70 ℃; separating a heptane layer containing ferric oleate, washing with deionized water, and evaporating the washed solution by using heptane to obtain ferric oleate powder;
(2) Adding 40 mmol dried oleic acid iron powder into a mixture of 20 mmol oleic acid and 200 g l-octadecene, preserving heat at 100 ℃ for 5min, heating the mixed solution to 320 ℃, preserving heat at 320 ℃ for 30min, suspending the mixed solution in air, cooling to 25 ℃, collecting by a magnet, dispersing in heptane, and washing with ethanol for 3 times to obtain a Fe 3O4 nanoparticle core;
(3) The Fe 3O4 nano particle core is dissolved in 50 mL sulfhydryl polyethylene glycol carboxyl (PEG, MW 600), stirred at room temperature for reaction 2h, washed with ethanol and PBS for three times respectively for purification, and Fe 3O4 -HS-PEG 600-carboxyl terminal nano particle is obtained; prior to further modification, the Fe 3O4 nanoparticle cores were stored in sodium citrate buffer at pH 6.0 at a temperature of 4 ℃ and a concentration of about 4 mg Fe/mL.
Example 2
The preparation of the N-terminal FITC modified composite polypeptide adopts Fmoc solid-phase carrier synthesis method to synthesize the composite polypeptide, and specifically comprises the following steps:
(1) 1 g Fmoc-lys (Dde) -Wang resin as insoluble solid support, swelling overnight with 30: 30 ml dichloromethane;
(2) 30 ml (30% PIPE in dimethylformamide) was added to the resin and reacted for 20 minutes to remove the Fmoc protected amino moiety;
(3) After 6 alternating washes with 30 ml dimethylformamide and dichloromethane (this step is repeated before each step), 8 resin volumes of DSC and 16 resin volumes of DIEA are added to the resin and reacted with the exposed amino groups 90 min to give an NHS structural intermediate;
(4) Adding 8 times of amino acid with no alpha amino protection (side chain protected) and 16 times of DIEA into resin, reacting with NHS 24 h to form stable peptide bond structure, and repeating peptide bond synthesis;
(5) Finally adding Fmoc-Ahx (aminocaproic acid) -OH with the resin amount being 8 times, HOBT with the resin amount being 8 times and DIC with the resin amount being 8 times into the resin, and reacting 2h to obtain final-length polypeptide, so as to obtain composite polypeptide which sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, sema3A inhibitory peptide and neuroprotective peptide from N to C terminal;
(6) Adding FITC-NHS with the resin amount of 8 times and succinyl iodoacetate with the resin amount of 8 times into resin, reacting with the amino group of Ahx in DMF solution, and purifying to obtain the N-terminal FITC-modified composite polypeptide.
Example 2
Preparation of Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide:
(1) The Fe 3O4 -HS-PEG 600-carboxyl terminal nanoparticle was linked to the polypeptide using Ynamide mild coupling method: a 5ml flask was charged with 0.24 mM N-ethynyl-N, 4-dimethylbenzenesulfonamide and 0.24 mM of the N-terminal FITC-modified composite polypeptide prepared in example 2, then 1ml of methylene chloride was added to the flask, stirred at room temperature in air until the acid was completely consumed, and after the reaction was completed, methylene chloride was removed in vacuo;
(2) After removing methylene dichloride in vacuum, adding a mixed solvent of 0.24 mM of Fe 3O4 -HS-PEG 600-carboxyl terminal nano particles prepared in example 1 and 1ml H 2 O/DMSO (1:5) into a flask, stirring at room temperature until the alpha-acyloxyamine is completely consumed, and finishing the reaction;
(3) 1ml of 20% 4-methylpiperidine (dissolved in dimethylformamide) was added to the above reaction product, shaken well for 12min, centrifuged at 8000 rpm for 8: 8 min, and the supernatant was discarded; 1ml of dimethylformamide was then added, shaken for 3min, centrifuged at 8000 rpm for 8 min and the supernatant discarded; adding 1ml of dichloromethane, shaking the system for 3min, centrifuging at 8000 rpm for 5-10 min, and discarding the supernatant; vacuum drying to remove dichloromethane 1.5 h to obtain Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide; 200 μl of purified water was added with oleic acid (1:1) to dissolve the product.
Property and application detection
1. Quality, molecular weight and solubility detection of superparamagnetic nano-drugs targeting the pathological region of the Alzheimer's disease Abeta protein:
Determining the mass of Fe 3O4-HS-PEG600-CO-NH2 -compound polypeptide by adopting a reversed-phase high performance liquid chromatography; ultraviolet absorbance spectra were detected at 220 nm using a C18 reverse phase chromatography column (5 μm, 250 x 4.6 mm); the flow rate was 1 mL/min, the mobile phase was 70% solvent A (0.05% TFA+2% acetonitrile) and 30% solvent B (0.05% TFA+90% acetonitrile), 16: 16 min followed by 54% solvent A and 46% solvent, respectively.
2. Mass analysis is carried out by a mass spectrometry high performance liquid chromatography system, and chromatographic separation peaks are submitted to matrix assisted laser desorption ionization time of flight (MALDI-TOF) analysis; mass spectrometry using MALDI-TOF AutoFlex III (Bruker Daltonics) mass spectrometer, peptide calibration standard II (Bruker Daltonics), α -cyano-4-hydroxycinnamic acid as matrix, flexControl software to control mass to charge ratio in positive/reflection mode; the high performance liquid chromatogram and the mass spectrum of the polypeptide prepared in example 3 are shown in fig. 1, and as can be seen from fig. 1, the molecular weight of the polypeptide is 5439 Da, the result of the polypeptide accords with theoretical value 5439.36 Da, the purity is 99.4%, and the yield is 78.4%.
3. Characterizing Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide by adopting a transmission electron microscope (TEM, JEM-1011 TEM, 100 kV) and an atomic force microscope (AFM, FSM-precision), detecting the appearance of the Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide, and carrying out statistical analysis on the size of the Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide, wherein the result is shown in figure 2, (a) detecting the surface appearance of the atomic force microscope; (b) transmission electron microscope detection results; (c) composite nano-drug size statistics; as can be seen from fig. 2, the composite nano-particles are approximately spherical overall, the composite nano-drug particles are relatively uniform, and the size is between 30.1±5.22 nm. The transmission electron microscope result shows that the polypeptide on the surface of the composite nano-particle forms regular distribution characteristics, which indicates that in water: the composite nano structure in the oil mixed system has better stability.
4. The energy spectrum of the composite nano-drug and the empty metal particles are subjected to qualitative analysis (EDS) by a transmission microscope (TEM, JEM-1011 TEM, 100 kV), and the core particle elements of Fe 3O4 are subjected to qualitative analysis, and the result is shown in figure 3. As can be seen from figure 3, the energy spectrum of the composite nano-drug shows that the iron content is smaller than that of the empty metal particles, the sulfur content of the composite nano-drug (containing sulfur amino acid) is obviously higher than that of the empty metal particles, and the successful synthesis of the composite nano-drug is verified.
In vitro membrane penetration test:
(1) 2X 10 6 Neuro2A cells were plated in 24 mm dishes and grown 24 h in 37℃humid environment with 5% CO 2;
(2) Washing the cells with PBS, adding 100 μg of Fe 3O4-HS-PEG600-CO-NH2 -complex polypeptide to the cell culture medium, and incubating at 37℃for 8 h;
(3) After incubation, cells were washed three times with PBS and fixed with 4% paraformaldehyde for 15 min, the cells were rinsed three more times with PBS, the cell membranes were labeled with DiL dye, and the nuclei were stained with DAPI dye. Olympus-3000 confocal fluorescence microscopy was performed, and 405 nm, 488 nm and 561nm lasers were selected for excitation and image acquisition, and as shown in FIG. 4, the result is that the compound nano-drug was distributed in the cytoplasm after having penetrated the cell membrane and being distributed in the cell when 40 min is shown in FIG. 4.
Test of therapeutic Effect
The experimental object: AD mice 10 months old;
(1) Fe 3O4-HS-PEG600-CO-NH2 -complex polypeptide was continuously administered by nasal instillation for 7 days (2.5 μl each nostril instillation, 2.34 μΜ), and 20mL of 0.01M phosphate buffered saline (PBS, ph=7.4) was infused with pentobarbital sodium (50 mg/kg) after deep anesthesia to the dosing group and the control group (non-dosing littermate AD mice) 2 months after dosing, followed by 100mL of 4% paraformaldehyde 0.1M phosphate buffer (PB, ph=7.4) in vivo infusion;
(2) Brain tissue was removed, fixed in the same fixative solution at 3 h, then cryopreserved at 4 ℃ in 0.1M PBS containing 30% sucrose at 24h, then embedded with OCT and frozen sagittal sections (20 μm);
(3) Sections were rinsed three times with PBS, then blocked (0.1% Triton X-100 and 2% donkey serum) 40 min, incubated with aβ 42 and GFAP primary antibody respectively (overnight at 4 ℃), washed with 0.1M PBS, incubated with secondary antibody (overnight at 4 ℃), nuclear counterstained with DAPI staining solution, rinsed with 0.1M PBS, blocked with anti-fluorescence quencher blocking tablets, and staining results observed as shown in fig. 5, wherein (a) control mice hippocampal tissue aβ deposition spot immunofluorescence staining results; (b) The administration group mice hippocampal tissue Abeta deposition spot immunofluorescence staining result; (c) Two groups of mice hippocampal tissue aβ deposition spot immunofluorescence staining results, t-value test, <0.001 with p, n=5; as can be seen from fig. 5, the immunostaining results of aβ deposition spots in AD pathological areas show that the aβ deposition spots in hippocampal brain areas of mice treated with the drug are significantly less than those of mice in the same-age drug-free treatment group, and the diameter of the deposition spots is also significantly reduced, which indicates that the composite nano-drug has significant effects in removing aβ deposition spots.
Claims (9)
1. The superparamagnetic nano-drug targeting the pathological region of the Alzheimer's disease Abeta protein is characterized in that the structural formula of the superparamagnetic nano-drug targeting the pathological region of the Alzheimer's disease Abeta protein is Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide;
The compound polypeptide sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, a Sema3A inhibitory peptide and a neuroprotective peptide from N to C;
the targeting Abeta protein has a positioning sequence as follows: FFXXK, X is any hydrophobic amino acid.
2. The superparamagnetic nano-drug targeting an aβ protein pathology region of alzheimer's disease according to claim 1, wherein the transmembrane sequence is YGRKKRRQRRR; the Sema3A inhibitory peptide sequence is HAVEHGFMQTLLKVTLE; the neuroprotective peptide sequence is NAPSIPQ.
3. The superparamagnetic nano-drug targeting an Abeta protein pathological region of Alzheimer's disease according to claim 1, wherein the N-terminal of the composite polypeptide is coupled with a FITC luminescent group.
4. A method for preparing a superparamagnetic nano-drug targeting an aβ protein pathological zone of alzheimer's disease according to any one of claims 1-3, comprising the steps of:
(1) Preparation of Fe 3O4 -HS-PEG 600-carboxyl terminal nanoparticle: adding oleic acid iron powder into a mixture composed of oleic acid and l-octadecene, preserving heat for 3-10 min at 90-120 ℃, then heating to 300-350 ℃ and preserving heat for 20-50 min, cooling, collecting and dispersing in heptane through a magnet, and washing to obtain a Fe 3O4 nano particle core; dissolving the Fe 3O4 nano particle core in PEG 600, and stirring for reaction to obtain Fe 3O4 -HS-PEG 600-carboxyl terminal nano particles;
(2) Composite polypeptide: synthesizing composite polypeptide by Fmoc solid-phase carrier synthesis method, wherein the composite polypeptide sequentially comprises a targeting Abeta protein positioning sequence, a membrane penetrating sequence, a Sema3A inhibitory peptide and a neuroprotective peptide from N to C end, and adopts FITC labeling at the N end;
(3) Preparation of Fe 3O4-HS-PEG600-CO-NH2 -composite polypeptide: mixing N-ethynyl-N, 4-dimethylbenzenesulfonamide and the composite polypeptide in the step (2), adding dichloromethane, stirring to react until the acid is consumed, removing the dichloromethane in vacuum after the reaction is finished, adding the Fe 3O4 -HS-PEG 600-carboxyl end nano particles prepared in the step (1), water and DMSO mixed solvent, stirring at room temperature to react until alpha-acyloxyamine is completely consumed, concentrating and purifying the reactant, and obtaining the superparamagnetic nano drug targeting the Alzheimer's disease A beta protein pathological area.
5. The method for preparing the superparamagnetic nano-drug targeting the pathological region of the Abeta protein of the Alzheimer's disease according to claim 4, wherein the feeding ratio of the iron oleate powder, the oleic acid and the l-octadecene in the step (1) is 2mmol:1mmol:10g; the ratio of the iron oleate powder to the PEG 600 is 4mmol to 5mL; stirring reaction time is 1-5 h.
6. The method of claim 4, wherein the molar ratio of the compound polypeptide to the Fe 3O4 -HS-PEG 600-carboxyl-terminal nanoparticle in the step (3) is 1:1.
7. The method for preparing a superparamagnetic nano-drug targeting an Abeta protein pathological region of Alzheimer's disease according to claim 4, wherein the molar ratio of N-ethynyl-N, 4-dimethylbenzenesulfonamide to composite polypeptide in the step (3) is 1:1.
8. The preparation method of the superparamagnetic nano drug targeting the pathological area of the Abeta protein of the Alzheimer disease, which is disclosed in claim 4, is characterized in that the volume ratio of water to DMSO in the mixed solvent of water and DMSO in the step (3) is 1:4-1:6.
9. Use of a superparamagnetic nano-drug targeting an aβ protein pathological zone of alzheimer's disease according to any of claims 1-3 in the preparation of a drug for treating alzheimer's disease.
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