CN107320738B - Trimanganese tetroxide-lactalbumin nanospheres and preparation and application thereof - Google Patents
Trimanganese tetroxide-lactalbumin nanospheres and preparation and application thereof Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
- A61K49/1869—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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Abstract
The invention belongs to the field of nano material preparation and biomedicine, and particularly relates to manganic manganous oxide-lactalbumin (Mn)3O4-LA) nanospheres and preparation and application thereof. The Mn is3O4LA nanospheres are hydrophobic Mn modified with oleic acid3O4The nano-particles and α -LA subjected to enzymatic hydrolysis and DTT treatment are self-assembled through hydrophobic effect, the average size of the nano-particles is 120-140 nm, the surface of the nano-particles is negatively charged, and the nano-particles are good in dispersibility in a water phase3O4The LA nanosphere not only has the function of nuclear magnetic imaging, but also can load hydrophobic and/or hydrophilic drug molecules, and can be used for preparing diagnostic and therapeutic agents integrating nuclear magnetic imaging diagnosis and drug delivery.
Description
Technical Field
The invention belongs to the field of nano material preparation and biomedicine, and particularly relates to manganic manganous oxide-lactalbumin nanospheres as well as preparation and application thereof.
Background
The manganese-based nuclear magnetic resonance imaging contrast agent is a T1 and T2-weighted MRI imaging contrast agent, is a common contrast agent in medical treatment, and has the characteristics of low toxicity, good biological affinity, in-vivo stability and the like. The small-sized trimanganese tetroxide nanoparticles also have the advantages of good vascular permeability, complete degradation, high relaxation efficiency and the like. Therefore, the development is based on Mn3O4The nuclear magnetic diagnostic agent of the nano-particles has important research significance for promoting the clinical application of the nano-particles. However, the small size of Mn is currently3O4The nano particles are mostly synthesized by adopting a solvothermal method, and the surfaces of the nano particles are modified by oleic acid or oleylamine, so that the nano particles have hydrophobicity and are not beneficial to the application of the nano particles in organisms.
α -lactalbumin (α -LA for short) is a globular protein with a compact structure consisting of 123 amino acids, wherein about 26% of secondary structures of the globular protein are α -helices, 14% of the globular protein are β -folds, and other 60% of the globular protein are disordered structures, the lactalbumin after enzymolysis has significant amphiphilic peptide chains which can be used as amphiphilic monomers to aggregate to form micelles, so the LA micelles can be used as drug carriers to load hydrophobic drug molecules, on the other hand, the α -lactalbumin chains have four disulfide bonds, free sulfydryl can be obtained by cutting the disulfide bonds by a reducing agent, and new disulfide bonds can be formed by crosslinking after the LA micelles are formed, so that the stability of the micelles as the drug carriers can be improved.
The invention utilizes the amphipathy of LA peptide chain and the characteristic of forming micelle, and the Mn for hydrophobicity3O4Nano particles are assembled and phase-inverted to develop Mn with the functions of nuclear magnetic imaging and drug carrier3O4-LA self-assembled nanospheres.
Disclosure of Invention
The invention aims to provide manganous-manganic oxide-lactalbumin nanospheres as well as a preparation method and application thereof. The nanosphere has the functions of nuclear magnetic imaging and drug carrier, has dual stimulation response and release characteristics to low pH and high GSH, and can be used for preparing diagnostic and therapeutic agent integrating nuclear magnetic imaging diagnosis and drug delivery.
In order to achieve the purpose, the invention adopts the following technical scheme:
a trimanganese tetroxide-lactalbumin nanosphere is prepared by subjecting α -LA to enzyme hydrolysis and DTT treatment, and mixing with hydrophobic Mn3O4The nano particles are self-assembled by hydrophobic acting force; the average size of the water-soluble polymer is 120-140 nm, the surface of the water-soluble polymer is negatively charged, and the water-soluble polymer is good in dispersibility in a water phase.
The preparation method of the nanosphere comprises the following steps:
1) α -LA is dissolved in Tris-HCl, an amphipathic polypeptide chain solution is obtained by hydrolysis of proteolytic enzyme, and Dithiothreitol (DTT) is added for treatment, so that disulfide bonds on a peptide chain are cut to form naked sulfydryl, and thus treatment liquid is obtained;
2) adding hydrophobic Mn3O4Dispersing the nano particles in Tetrahydrofuran (THF) solution, adding the dispersion into the treatment solution obtained in the step 1) for reaction for 12 hours, centrifuging and washing the product to obtain Mn3O4-LA composite particles;
3) the obtained Mn3O4Introducing oxygen to the-LA composite particles for 30min to re-crosslink disulfide bonds, and centrifuging to obtain self-assembled Mn3O4-LA nanospheres.
Wherein α -LA and hydrophobic Mn are used3O4The mass ratio of the nano particles is 1: 1-5: 1; the hydrophobic Mn3O4The surface of the nano-particles is modified by oleic acid, and the particle size of the nano-particles is less than 10 nm.
The volume ratio of the treatment liquid to the dispersion liquid in the step 2) is 5: 1-10: 1.
The nanosphere can be dissociated under the dual stimulation of low pH (pH is less than or equal to 5.0) and high concentration GSH (GSH is more than or equal to 10 mM) to release Mn2+The (nuclear magnetic imaging agent) and the drug molecule are suitable for preparing the diagnostic and therapeutic agent integrating nuclear magnetic imaging diagnosis and drug delivery.
The drug molecules are hydrophobic drugs, and comprise photosensitizer chlorin e6 (Ce 6), indocyanine green (ICG), camptothecin, cisplatin, curcumin and the like; and/or is a hydrophilic drug, such as Doxorubicin (DOX).
Compared with the prior art, the invention has the remarkable advantages that:
(1) mn synthesized by the invention3O4the-LA nano-sphere particles are uniform in size, the preparation method is simple, and the conditions are mild and controllable; the derivative can be dissociated under the dual stimulation of low pH and high concentration GSH, not only can be used as a nuclear magnetic imaging agent, but also can be loaded with hydrophobic drugs and/or hydrophilic drugs, and is a multifunctional diagnostic therapeutic agent;
(2) mn obtained by the invention3O4The loading rate of the LA nanospheres to hydrophobic drugs and hydrophilic drugs is high, for example, the loading rate to a photosensitizer Ce6 can reach 75%, and the loading rate to hydrophilic drugs DOX can reach 42%.1 percent, thereby effectively reducing the dosage of the drug carrier in the treatment process and achieving the purpose of reducing side effects;
(3) mn obtained by the invention3O4-LA nanospheres are biocompatible and Mn3O4Both the nanoparticles and the LA are easy to degrade in cells and are degradable drug carriers.
Drawings
FIG. 1 shows Mn in different concentrations3O4-results of biocompatibility tests of LA nanospheres.
FIG. 2 shows Mn3O4In vitro magnetic resonance imaging contrast of LA nanospheres under different conditions.
FIG. 3 shows Mn3O4Transmission electron microscopy of Ce6-LA nanospheres.
FIG. 4 shows Mn at different times3O4Graph of particle size change of-Ce 6-LA nanospheres in PBS and culture medium.
FIG. 5 is a diagram of the variation of the singlet oxygen generation rate in vitro for different nanospheres.
FIG. 6 shows Mn3O4The release rate curve of Ce6-LA nanosphere Ce6 under different conditions.
FIG. 7 shows Mn3O4Release rate profiles of DOX from Ce6-LA-DOX nanospheres under different conditions.
FIG. 8 shows the cytotoxicity test results of nanospheres before and after illumination under different conditions, wherein Laser (+) represents the illuminated group and Laser (-) represents the non-illuminated group.
Detailed Description
Preparation of manganous-manganic oxide-lactalbumin nanospheres:
1) hydrophobic Mn3O4And (3) synthesis of nanoparticles:
dissolving 0.75 mg of potassium oleate in a mixed solution of 2.5 mL of ethanol, 5mL of toluene and 0.5mL of oleic acid, and carrying out ultrasonic treatment for 15 min; 0.1004g of Mn (NO)3·4H2Dissolving O in 5mL of water; mixing the two, placing in a reaction kettle, reacting at 150 deg.C for 18h, standing, collecting oil phase, precipitating with ethanol as precipitant, centrifuging to obtain hydrophobic Mn3O4A nanoparticle;
2) α -enzymatic hydrolysis of lactalbumin:
dissolving α -lactalbumin 6 mg in 75mM Tris-HCl 200 μ L, pH =7.5, adding proteolytic enzyme 12 μ L and 0.3U/mL, sucking the solution with a 1mL syringe, filtering once in a 0.22 μm polyethersulfone needle filter, heating in a water bath at 50 ℃ for 20min, centrifuging, taking the supernatant, freeze-drying, and re-dispersing the obtained product in 75mM Tris-HCl with pH =7.5 to obtain an amphipathic polypeptide chain solution of α -lactalbumin;
3) DTT treatment:
taking 52 mu L of 1mg/mL Dithiothreitol (DTT), adding the Dithiothreitol (DTT) into the amphiphilic polypeptide chain solution of α -lactalbumin obtained in the step 2), stirring for 10min at 1000rpm, and cutting off disulfide bonds on the peptide chains to form naked sulfydryl, thereby obtaining a treatment solution;
4）Mn3O4-preparation of LA composite particles:
subjecting the hydrophobic Mn obtained in the step 1)3O4Dispersing the nano particles in 5mL of THF solution, adding the dispersion into the treatment solution obtained in the step 3) according to the volume ratio of 1:5 for reaction for 12 hours, centrifuging and washing the product to obtain Mn3O4-LA composite particles;
5）Mn3O4-preparation of LA nanospheres:
the obtained Mn3O4Introducing oxygen to the-LA composite particles for 30min to re-crosslink disulfide bonds to obtain Mn3O4-LA nanospheres.
Mn3O4-biological affinity of LA nanospheres:
the digested HeLa cell suspension was diluted with the culture medium and seeded into a 96-well plate at a density of 100. mu.L/well, and the number of cells per well was controlled to about 105And (4) respectively. Placing 96-well plate at 37 deg.C and 5% CO2After 24 hours of incubation in the incubator, the culture medium was removed and Mn was added in different concentrations3O4-solution of LA nanospheres, each set provided with 4 replicate wells. After further incubation for 4h, the solution was removed, washed twice with PBS buffer (pH = 7.4), and addedAdding 100 μ L culture solution, culturing for 20 hr, adding 10 μ L MTT with concentration of 5mg/mL into each well, incubating for 4 hr, removing culture solution carefully, adding 150 μ L DMSO, culturing at 37 deg.C for 15min, shaking, measuring absorbance at 490 nm with enzyme labeling instrument, and calculating cell survival rate to evaluate Mn3O4-LA nanospheres biological affinity, results are shown in FIG. 7.
As can be seen from FIG. 1, in Mn3O4The cell survival rate is above 80% in the range of-LA nanosphere concentration of 5-100 mug/mL, which indicates that Mn is contained3O4The LA nanospheres have excellent biocompatibility.
Mn3O4In vitro magnetic resonance imaging of LA nanospheres:
1) firstly, 1mL of Mn and 0.287 mg/mL of Mn are taken3O4Adding the nanoparticle solution into a dialysis bag, adding 49 mL of 2wt% nitric acid solution, digesting for 24h to completely dissociate the nanoparticle solution, taking a certain amount of the nanoparticle solution, diluting the nanoparticle solution according to the requirement, and carrying out ICP-MS (inductively coupled plasma-mass spectrometry) determination. Calculating 1mL of Mn according to ICP-MS test results3O4The nano-particle solution contains Mn2+68.94 μ g;
2) taking 0.228 mL, 0.25mg/mL Mn3O4LA solution added to 1mL of PBS solution (corresponding to Mn contained) at pH =7.4, pH =5.0, pH =7.4+10mM GSH and pH =5.0+10mM GSH2+Concentration of 0.25 mM), soaking for 24h, centrifuging, and taking a certain amount of supernatant to respectively prepare 5 different Mn2+Solutions of concentration (0.01, 0.05, 0.1, 0.2, 0.25 mM) were then each 0.5mL for MRI detection.
FIG. 2 shows Mn3O4In vitro magnetic resonance imaging contrast of LA nanospheres under different conditions. Among them, as can be seen from fig. 2 (a): under the conditions of pH =5.0 and pH =5.0+10mM GSH, as the concentration of the dissociated manganese ions is increased, the brightness of the image is gradually lightened; whereas under the pH =7.4 condition, there was substantially no change in the brightness of the image, indicating Mn in the pH =7.4 buffer3O4Less amount of LA nanosphere manganese ion dissociation; on the other hand, under the condition of pH =7.4+10mM GSH, the imaging brightness gradually becomes brighter, which indicates that GSH has reduction effect and can reduce GSHMore Mn2+And restored, and thus the image brightness gradually becomes brighter. Further, as can be seen from fig. 2 (B): r1 at pH =5.0, pH =5.0+10mM GSH and pH =7.4+10mM GSH were 8.02 mM each-1·S-1、12.9 mM-1·S-1And 7.67 mM-1·S-1R1=2.98mM each at pH =7.4-1·S-1This indicates that Mn is present in the presence of GSH in the presence of acid3O4the-LA nanospheres are deconstructed and release more Mn2+So that the MRI imaging effect is enhanced. Thus, it was confirmed that Mn3O4LA nanospheres enable T1-weighted MRI imaging triggered by dual stimulation responses to pH and GSH.
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
1) Hydrophobic Mn3O4And (3) synthesis of nanoparticles:
dissolving 0.75 mg of potassium oleate in a mixed solution of 2.5 mL of ethanol, 5mL of toluene and 0.5mL of oleic acid, and carrying out ultrasonic treatment for 15 min; 0.1004g of Mn (NO)3·4H2Dissolving O in 5mL of water; mixing the two, placing in a reaction kettle, reacting at 150 deg.C for 18h, standing, collecting oil phase, precipitating with ethanol as precipitant, centrifuging to obtain hydrophobic Mn3O4A nanoparticle;
2) α -enzymatic hydrolysis of lactalbumin:
dissolving α -lactalbumin 6 mg in 75mM Tris-HCl 200 mu L, pH =7.5, adding proteolytic enzyme 12 mu L and 0.3U/mL, sucking the solution by using a 1mL syringe, filtering the solution once in a 0.22 mu m polyethersulfone needle filter, heating the solution in a water bath at 50 ℃ for 20min, centrifuging the solution, taking the supernatant, freeze-drying the supernatant, and dispersing the product in 75mM Tris-HCl with the pH =7.5 to obtain an amphipathic polypeptide chain solution of α -lactalbumin;
3) DTT treatment:
taking 52 mu L of 1mg/mL DTT, adding the DTT into the 0.5mg/mL α -lactalbumin amphipathic polypeptide chain solution obtained in the step 2), stirring at 1000rpm for 10min, and cutting off disulfide bonds on the peptide chain to form naked sulfydryl, thereby obtaining a treatment solution;
4）Mn3O4self-assembly of Ce6-LA nanospheres:
hydrophobic Mn prepared in the step 1)3O4Dispersed in 4mL THF; 3mg of chlorin e6 (Ce 6) was dissolved in 1ml of THF; then adding the two mixed solutions into the treatment solution prepared in the step 3), reacting for 12h, centrifuging and washing the product, introducing oxygen into the obtained composite particles for treating for 30min, and centrifuging to obtain Mn3O4-Ce6-LA nanospheres; the loading rate of Ce6 was 75% as measured by fluorescence data;
5）Mn3O4-synthesis of Ce6-LA-DOX nanospheres:
mn prepared in the step 4)3O4Re-dispersing the-Ce 6-LA nanospheres in water, adding adriamycin (DOX) according to the mass ratio of 10:1, stirring at room temperature for 12h, centrifuging, and washing with water to obtain Mn3O4-Ce6-LA-DOX nanospheres; the adsorption rate of DOX was 42.1% as measured by fluorescence data.
6）Mn3O4-synthesis of Ce6-LA-DOX-RGD nanospheres:
mn prepared in the step 5)3 O 450 μ g of-Ce 6-LA-DOX nanospheres were redispersed in water, reacted with 6.35 μ g of NHS for 1h with 5.5 μ g EDC, and then Mn was added3O4Adding RGD into the-Ce 6-LA-DOX nanosphere and RGD at the mass ratio of 2:1, reacting for 12h, and centrifuging to obtain Mn3O4-Ce6-LA-DOX-RGD nanospheres.
And (3) performance detection:
1. mn prepared in the step 4)3O4the-Ce 6-LA nanospheres were dispersed in water and then dropped on a copper mesh, and TEM scanning was performed after air drying, and the results are shown in FIG. 3.
As can be seen from FIG. 3, the obtained Mn3O4The particles of Ce6-LA are spherical and consist of Mn with an average size of 7nm3O4The nano particles are formed by self-assembly, the size is uniform, the dispersity is good, and the average particle size is about 180 +/-10 nm;
2. respectively taking the products of step 4)Mn obtained3O4the-Ce 6-LA nanospheres were added to PBS (pH = 7.4) buffer solution and cell culture solution to prepare a solution with a concentration of 1mg/mL, mixed well, and sampled at different times to determine the change of particle size, and the results are shown in fig. 4.
As can be seen from FIG. 4, Mn3O4The particle size of the-Ce 6-LA nanospheres hardly changed in either PBS buffer or cell culture, indicating that Mn was present3O4the-Ce 6-LA nanospheres are relatively stable over time.
3. Mn prepared in the step 4)3O4-Ce6-LA nanosphere is dispersed in water to prepare solution with concentration of 0.08 mg/mL (containing 10 μ M Ce 6), then the solution is uniformly mixed with 50 μ M DPBF, water is added to make total volume of 1mL, the total volume is 631nm, and power is 100mW/cm2The ultraviolet absorption value of the singlet oxygen trapping agent DPBF at 410nm is measured at different time points; separately, different particles (free Ce6 molecules, uncrosslinked Mn) containing 10. mu.M Ce6 were taken3O4-Ce6-LA nanospheres, cross-linked Mn3O4-Ce6-LA-DOX nanospheres) after DPBF was added and irradiated with the same light, the test results are shown in fig. 5 (wherein, I/I is used)0I is the ultraviolet absorption value of the initial singlet oxygen trapping agent DPBF at 410nm, I0Ultraviolet absorption value of the singlet oxygen trapping agent DPBF at 410nm at different time points).
As can be seen from FIG. 5, crosslinked Mn3O4Ce6-LA has a slightly lower singlet oxygen generation than the free Ce6 molecule, because the particles are more stable after crosslinking, Ce6 is released slowly and therefore the singlet oxygen generation is slightly lower in the same irradiation time.
4. Mn prepared in the step 4)3O4Ce6-LA nanospheres were dispersed into different solutions (pH =7.4, pH =7.4+10 mgsh, pH =5.0+10mM GSH), stored at 37 ℃ protected from light, and centrifuged at different time points for sampling. The peak emission at 630nm was measured using a fluorimeter at 404nm excitation and the release under different conditions was analyzed computationally according to a standard curve of Ce6, the test results of which are shown in fig. 6.
As can be seen from fig. 6, in the buffer with pH =7.4, the release rate of Ce6 was only 17.2%, indicating Mn after oxygen cross-linking3O4The Ce6-LA nanospheres are very stable; under the condition of pH =7.4+10mM GSH, the release rate of Ce6 reaches 70.2%, which shows that high GSH can effectively dissociate Mn3O4-Ce6-LA nanospheres, thereby releasing Ce 6. On the other hand, in the buffer solution of pH =5.0, the release rate of Ce6 was 62.1%, indicating that acidity can also induce Mn3O4The Ce6-LA nanosphere structure is dissociated; whereas, under the condition of pH =5.0+10mM GSH, the release rate of Ce6 increased to 83.9%, indicating that Mn, a double stimulus of low pH and high GSH, was present3O4the-Ce 6-LA nanosphere structure dissociates rapidly, releasing more Ce 6.
5. Mn prepared in the step 5)3O4Ce6-LA-DOX nanospheres were dispersed into different solutions (pH =7.4, pH =7.4+10mM GSH, pH =5.0+10mM GSH), stored at 37 ℃ protected from light, sampled at different time points and centrifuged. The emission peak at 596nm was determined by excitation at 488nm using a fluorimeter and the release under different conditions was analyzed by calculation according to a standard curve for DOX, the test results of which are shown in fig. 7.
As can be seen from fig. 7, in the buffer with pH =7.4, the release rate of DOX was only 19.8%, indicating that most of DOX was distributed in Mn3O4-Ce6-LA-DOX within the pores of the nanospheres; under the condition that the pH =7.4+10mM GSH, the release rate of DOX reaches 63.4%, which shows that high GSH can effectively dissociate Mn3O4-Ce6-LA-DOX nanospheres, thereby releasing DOX. On the other hand, in the buffer solution of pH =5.0, the release rate of DOX was 58.2%, indicating that acidity can also induce Mn3O4The Ce6-LA-DOX nanosphere structure is dissociated; whereas at pH =5.0+10mM GSH, the rate of DOX release increased to 85.3%, indicating a dual stimulation by low pH and high GSH, Mn3O4The structure of the-Ce 6-LA-DOX nanosphere dissociates rapidly, thereby releasing more DOX.
6. The digested HeLa cell suspension was diluted with the culture medium and seeded into a 96-well plate at a density of 100. mu.L/well, and the number of cells per well was controlled to about 105And 4 multiple holes are arranged in each group as a repeating group. Placing 96-well plate at 37 deg.C and 5% CO2After culturing for 24 hours in the incubator of (1), the culture solution in the wells was removed, and a solution containing: control, 2: free Ce6, 3: mn3O4-Ce6-LA，4：Mn3O4-Ce6-LA-DOX，5：Mn3O4Solutions of-Ce 6-LA-DOX-RGD (Mn in the above groups)3O4The concentrations of LA and Ce6 are 67 mug/mL, 5 mug/mL and 3.0 mug/mL respectively, after the continuous culture for 4 hours, the solution is removed, PBS buffer solution is used for washing twice, 100 mug culture solution is added for continuous culture for 20 hours, 10 mug MTT with the concentration of 5mg/mL is respectively added into each hole, the continuous incubation for 4 hours is continued, the culture solution is carefully removed, 150 mug DMSO is added, the culture is cultured for 15 minutes at 37 ℃, after the uniform oscillation, the absorption value at 490 nm is measured on a microplate reader, and a corresponding illumination group (the wavelength is 631nm and 100 mW/cm) is additionally arranged (the wavelength is 100mW/cm2Irradiation for 10 min), cell viability was calculated, and the treatment effect of each group was evaluated, and the results are shown in fig. 8.
As can be seen from FIG. 8, the cell death rate was higher in the light group than in the corresponding light-free group, indicating that singlet oxygen generated by light has some effect on the cell death rate. Wherein, the illumination group Mn3O4The inhibition rate of Ce6-LA-DOX-RGD on cancer cells reaches 90% within 24h, which indicates that the drug carrier can be effectively used for treating tumors.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (5)
1. A trimanganese tetroxide-lactalbumin nanosphere with dual response is characterized in that the nanosphere is prepared by carrying out enzyme hydrolysis and DTT treatment on α -LA, and then mixing with hydrophobic Mn3O4The nano particles are self-assembled by hydrophobic acting force; the average size of the water-soluble polymer is 120-140 nm, the surface of the water-soluble polymer is negatively charged, and the water-soluble polymer is good in dispersibility in a water phase;
the nanosphere can be dissociated to release Mn under the dual stimulation of low pH value and high-concentration GSH2+And pharmaceutical molecules, suitable for the preparation ofThe diagnostic and therapeutic agent integrates nuclear magnetic imaging diagnosis and drug delivery.
2. Trimanganese tetroxide-lactalbumin nanospheres according to claim 1, wherein: the preparation method comprises the following steps:
1) dissolving α -LA in Tris-HCl, performing enzyme hydrolysis to obtain an amphiphilic polypeptide chain solution, and then adding DTT for treatment to obtain a treatment solution;
2) adding hydrophobic Mn3O4Dispersing the nano particles in a THF solution, adding the dispersion into the treatment liquid obtained in the step 1), reacting for 12 hours, centrifuging and washing the product to obtain Mn3O4-LA composite particles;
3) the obtained Mn3O4Introducing oxygen into the-LA composite particles for 30min, and centrifuging to obtain self-assembled Mn3O4-LA nanospheres.
3. The trimanganese tetroxide-lactalbumin nanospheres of claim 2, wherein α -LA and hydrophobic Mn are used3O4The mass ratio of the nano particles is 1: 1-5: 1; wherein, hydrophobic Mn3O4The size of the nanoparticles is less than 10 nm.
4. Trimanganese tetroxide-lactalbumin nanospheres according to claim 2, wherein: the volume ratio of the treatment liquid to the dispersion liquid in the step 2) is 5: 1-10: 1.
5. Trimanganese tetroxide-lactalbumin nanospheres according to claim 1, wherein: the drug molecule is at least one of a hydrophobic drug or a hydrophilic drug.
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