CN108125926B - Preparation method and application of magnetic nanoparticles spanning blood-eye barrier - Google Patents
Preparation method and application of magnetic nanoparticles spanning blood-eye barrier Download PDFInfo
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Abstract
The invention discloses a preparation method and application of magnetic nanoparticles spanning blood-eye barriers, which comprises the following steps: taking purified bacterial magnetosomes BMs, and combining amino terminals of the bacterial magnetosomes BMs with sulfydryl of cysteine in TAT polypeptide by using N-succinimide 3- (2-pyridine dithio) propionate as a cross-linking agent to obtain magnetic nanoparticles capable of crossing blood eye barriers, wherein the magnetic nanoparticles are TAT-BMs composite carriers. The magnetic nano-particles can cross the blood-eye barrier, and the application potential of the magnetic nano-material in the treatment of eye diseases is expanded.
Description
Technical Field
The invention relates to a magnetic nanoparticle, in particular to a preparation method and application of a magnetic nanoparticle spanning blood-eye barriers.
Background
Bacterial Magnetosomes (BMs) are biosynthetic magnetic nanoparticles with unique nanostructures, surface-covered biological membranes with structures similar to cell membranes, and stable size and morphology. BMs have a wide range of potential applications in the biomedical field, such as magnetic resonance imaging, drug delivery, and magnetic hyperthermia. Unlike chemically synthesized magnetic nanoparticles, BMs are synthesized intracellularly by magnetotactic bacteria, and the main component is Fe3O4Or Fe3S4The size is 30-120 nm.
The eye is a very delicate organ of the human body, and the whole organ forms an almost closed space under the protection of the blood-eye barrier. However, the blood-ocular barrier also prevents most drugs from entering the eye. At present, there are no reports and applications related to the crossing of blood-eye barriers by BMs, so that the application of nano-materials constructed based on BMs in the treatment of eye diseases is limited, and research and improvement on the reports are needed.
Disclosure of Invention
The first purpose of the invention is to provide a preparation method of magnetic nanoparticles crossing the blood-eye barrier.
It is a second object of the present invention to provide a magnetic nanoparticle that crosses the blood-eye barrier.
The third purpose of the invention is to provide the application of the magnetic nano-particles crossing the blood-eye barrier in an ophthalmic drug carrier.
In order to achieve the first purpose of the invention, the technical scheme of the invention comprises the following steps:
taking purified bacterial magnetosomes BMs, and combining amino terminals of the bacterial magnetosomes BMs with sulfydryl of cysteine in TAT polypeptide by using N-succinimide 3- (2-pyridine dithio) propionate as a cross-linking agent to obtain magnetic nanoparticles capable of crossing blood eye barriers, wherein the magnetic nanoparticles are TAT-BMs composite carriers.
The method is further provided with the steps that bacteria magnetosome BMs and N-succinimide 3- (2-pyridine dithio) propionate are uniformly mixed at room temperature to activate the bacteria magnetosome BMs, a mixed system of the activated bacteria magnetosome BMs and N-succinimide 3- (2-pyridine dithio) propionate and TAT polypeptide are uniformly mixed at 0-4 ℃ overnight, and the mixture is repeatedly subjected to magnetic adsorption and cleaning to obtain the purified TAT-BMs composite carrier.
A further setup is that purified bacterial magnetosomes BMs are obtained by:
the method for separating and purifying the bacterial magnetosome BMs from the Gerfiella magnetospirillum MSR-1 comprises the following steps: collecting MSR-1 strain in logarithmic growth phase, suspending the strain in PBS buffer solution, collecting crude bacteria magnetosome BMs by ultrasonic disruption and magnetic recovery, and continuously purifying the crude bacteria magnetosome BMs by ultrasonic cleaning and magnetic recovery until the supernatant can not detect protein and DNA residue to obtain purified bacteria magnetosome BMs.
Further set is the mass ratio of TAT polypeptide to purified bacterial magnetosomes BMs: 1:2-1:10.
It was further set that the optimal mass ratio of TAT polypeptide to purified bacterial magnetosomes BMs was 1: 5.
The second invention of the invention provides a magnetic nanoparticle capable of crossing the blood eye barrier, which is a TAT-BMs composite carrier, prepared by the preparation method.
The third object of the invention is to provide the application of the magnetic nanoparticles crossing the blood-eye barrier in preparing the ocular drug crossing the blood-eye barrier, wherein the magnetic nanoparticles crossing the blood-eye barrier are used as carriers of the ocular drug crossing the blood-eye barrier, thereby helping the ocular drug to cross the blood-eye barrier.
The magnetic nano-particle has the beneficial effects that the magnetic nano-particle with the function of crossing the blood-eye barrier is provided, the corresponding preparation method is provided, the application potential of the magnetic nano-material in the treatment of eye diseases is expanded, and meanwhile, the application of the magnetic nano-particle as a carrier for crossing the blood-eye barrier when eye drugs are used for eye treatment is also provided. The specific effect is shown in the test example.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 is a UV-Vis spectrum of a TAT-BMs supernatant;
FIG. 2TEM micrograph of BMs (FIG. 2 a) and TAT-BMs (FIG. 2 b);
FIG. 3 is a graph of BMs or TAT-BMs crossing the function of the in vitro blood-eye barrier (BRB) (FIG. 3a. model for in vitro BRB construction; FIG. 3b. optical microscopy of in vitro BRB, in which cells are stained with calcein to give a green, dense layer; FIG. 3c, FIG. 3d. optical microscopy of underlying ARPE-19 cells, in which FIG. 3c is an image of cells stimulated by BMs and FIG. 3d is an image of cells stimulated by TAT-BMs);
FIG. 4 drug loading rates for BMs-DOX and TAT-BMs;
FIG. 5TEM observation of BMs-DOX (FIG. 5 a) and TAT-BMs-DOX (FIG. 5 b);
FIG. 6 ultraviolet-visible (UV-Vis) (FIG. 6 a) and Fourier Infrared (FTIR) (FIG. 6 b) spectra of BMs-DOX and TAT-BMs-DOX;
FIG. 7 survival of OCM-1 cells in the underlayer of BRB under stimulation by free DOX, BMs-DOX or TAT-BMs-DOX;
FIG. 8 is a preparation scheme of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
In this embodiment, the TAT polypeptide is NH2-CGRKKRRQRRRK-COOH, SPDP is N-succinimidyl 3- (2-pyridyldithio) propionate, BMs means bacteriaMagnetosomes, TAT-BMs, refer to magnetic nanoparticles that can cross the blood-eye barrier.
Examples
(1) Firstly, separating and purifying bacterial magnetosomes BMs from the Gerfiella schroederi MSR-1. The specific method comprises the following steps: MSR-1 strains were collected in the logarithmic growth phase and resuspended in PBS buffer. Crude BMs were collected by sonication and magnetic recovery. And continuously purifying the crude BMs by ultrasonic cleaning and magnetic recovery until the supernatant can not detect protein and DNA residues, thereby obtaining the purified BMs.
(2) The amino terminal of BMs is combined with the sulfhydryl of cysteine in TAT polypeptide (NH 2-CGRKKRRQRRRK-COOH) by using SPDP (N-succinimide 3- (2-pyridine dithio) propionate) crosslinking agent to obtain the TAT-BMs carrier capable of crossing the blood eye barrier. The specific method comprises the following steps: and uniformly mixing BMs and SPDP for 2h at room temperature, uniformly mixing the activated BMs-SPDP and TAT polypeptide at 4 ℃ overnight, and repeatedly carrying out magnetic adsorption and washing on the mixture to obtain purified TAT-BMs. The invention respectively sets different mass ratios of TAT and BMs: 1:2, 1:5 and 1:10, wherein the optimal mass ratio of the effect is 1: 5.
Test examples
In vitro testing of TAT-BMs function across the blood-eye barrier: firstly, a six-hole Transwells cell culture plate is used for constructing an in-vitro blood-eye barrier model (BRB), the specific method is that retinal pigment epithelial cells (ARPE-19) are planted on the upper layer of the Transwells culture plate and cultured for 72 hours, and the inventor sets three planting densities of 5 ten thousand per hole, 10 ten thousand per hole and 20 ten thousand per hole, wherein the best effect is achieved by 10 ten thousand per hole. After BRB preparation, ARPE-19 cells are planted at the lower layer of the Transwells culture plate, 20 ten thousand per well, and the cells are cultured in an adherent way overnight.
TAT-BMs with certain concentration are added into the culture medium of the upper culture plate, a high-strength magnet (1T) is placed at the bottom layer of the Transwells culture plate, after the material is stimulated for 6 hours, the cells at the bottom layer are fixed and stained by Prussian blue, and the function of the TAT-BMs penetrating through BRB is observed by a microscope.
And characterizing the TAT-BMs vector by using methods such as ultraviolet visible spectrum (UV-Vis), Zeta potential, Transmission Electron Microscope (TEM) and the like. As shown in FIG. 1, a peak of pyridine-2-thione (P2T), a byproduct of the SPDP crosslinking reaction, appears at 343nm in the UV-Vis spectrum of the supernatant solution of TAT-BMs, thereby illustrating covalent bonding of TAT and BMs by the crosslinking action of SPDP. Based on the molar extinction coefficient of P2T, we calculated the linkage efficiency of TAT to be 8.4%. The potential of TAT-BMs is-27.87 +/-2.72 as found by Zeta potential detection, and the dispersion is relatively good. We further observed TAT-BMs by using a TEM electron microscope, as shown in FIG. 2, the morphology of the TAT-BMs is not obviously changed compared with the BMs, the diameter size is 30-40nm, and the dispersity is good.
Detection of TAT-BMs function across the in vitro blood-eye barrier: first, an in vitro BRB was constructed using a 6-well Transwells cell culture plate, and as shown in FIG. 3a, ARPE-19 cells were grown in 10W/well on the upper layer of the Transwells plate, and after 72 hours of culture, the cells grew into a dense film-like structure (FIG. 3 b), and at this time, ARPE-19 cells were grown in 20W/well on the lower layer of the Transwells plate, and cultured until they were adherent. Adding BMs or TAT-BMs with certain concentration into the upper solution of the Transwells culture plate, placing a magnet on the bottom layer of the culture plate for stimulation, and after culturing for 6h, carrying out Prussian blue staining on ARPE-19 cells on the bottom layer. Little material was observed in the cells co-cultured with BMs in the lower layer (FIG. 3 c), but the cells co-cultured with TAT-BMs phagocytosed a large amount of TAT-BMs material in the lower layer (FIG. 3 d). Furthermore, as shown in FIG. 3c, the panel at the bottom left of d, BMs material was almost entirely concentrated in the upper layer of the Transwells plate, while TAT-BMs material was almost entirely passed through the BRB barrier and into the lower layer of the broth. Thus, TAT-BMs have the function of penetrating BRB in vitro.
Examples of drug carriers
The magnetic nanoparticles spanning the blood-eye barrier of the invention serve as a carrier for ocular drugs spanning the blood-eye barrier, thereby helping the ocular drugs to cross the blood-eye barrier.
Application example of TAT-BMs as Doxorubicin (DOX) drug carrier for killing and treating choroidal melanoma cells (OCM-1)
(1) Preparing TAT-BMs-DOX vector:
according to the detection result of the Zeta potential, BMs and TAT-BMs both carry negative potential, so that BMs or TAT-BMs and DOX drugs are uniformly mixed overnight at room temperature by utilizing the effect of electrostatic combination, the mass ratio of the materials to the drugs is set to be 0.5:1,1:1 and 1:2, wherein the ratio of 1:1 can reach the highest drug loading ratio, the drug loading ratio of BMs-DOX is 98%, and the drug loading ratio of TAT-BMs is 93% (figure 4). In addition, when morphology of BMs-DOX and TAT-BMs-DOX is observed by using TEM, compared with BMs, morphology of two carriers after drug loading is not obviously changed, and the two carriers are both similar to spheres and have diameters of 30-50nm (figure 5). Further using ultraviolet visible spectrum (UV-Vis) and Fourier infrared spectrum (FTIR) to characterize BMs-DOX and TAT-BMs-DOX, as shown in FIG. 6a, both drug-loaded systems have characteristic absorption peak of DOX at 482nm, and UV-Vis spectrum of TAT-BMs-DOX also has typical TAT polypeptide special absorption peak (280 nm); as shown in FIG. 6b, the FTIR spectra of BMs-DOX and TAT-BMs-DOX also have typical DOX structures.
(2) Detecting the efficiency of TAT-BMs-DOX in killing tumor cells across the blood-eye barrier:
firstly, a 6-hole Transwells culture plate is utilized to construct an in-vitro blood eye barrier model, human choroid melanoma cells (OCM-1) are planted in a lower layer culture plate, BMs-DOX or TAT-BMs-DOX with different concentrations are respectively added into upper layer culture holes after the cells are attached to the wall, and after the cells are cultured for 6 hours, the survival rate of the lower layer OCM-1 cells is detected by utilizing a CCK-8 method. As shown in FIG. 7, free DOX hardly penetrated the BRB barrier and entered the lower culture plate, and TAT-BMs-DOX showed 5, 6 and 8 times higher lethality to the lower tumor cells than corresponding concentrations of DOX (10, 50, 100. mu.g/mL), respectively. And the killing power of TAT-BMs-DOX on the lower layer cells is respectively increased by 2.5, 3 and 3.2 times compared with the corresponding concentration of BMs-DOX (DOX carrying concentration of 10, 50 and 100 mu g/mL). Thus, it was demonstrated that TAT-BMs can be used as drug carriers across the blood-ocular barrier for the treatment of ocular diseases.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (5)
1. A preparation method of magnetic nanoparticles crossing blood-eye barriers is characterized by comprising the following steps:
taking purified bacterial magnetosomes BMs, and combining amino ends of the bacterial magnetosomes BMs with sulfydryl of cysteine in TAT polypeptide by using N-succinimide 3- (2-pyridine dithio) propionate as a cross-linking agent to obtain magnetic nanoparticles capable of crossing blood eye barriers, wherein the magnetic nanoparticles are TAT-BMs composite carriers;
uniformly mixing the bacterial magnetosome BMs and N-succinimide 3- (2-pyridine dithio) propionate at room temperature to activate the bacterial magnetosome BMs, uniformly mixing an activated bacterial magnetosome BMs and N-succinimide 3- (2-pyridine dithio) propionate mixed system with TAT polypeptide at 0-4 ℃ overnight, and repeatedly carrying out magnetic adsorption and cleaning on the mixture to obtain a purified TAT-BMs composite carrier;
mass ratio of TAT polypeptide to purified bacterial magnetosomes BMs: 1:2-1:10.
2. The method of claim 1, wherein: purified bacterial magnetosome BMs were obtained by:
the method for separating and purifying the bacterial magnetosome BMs from the Gerfiella magnetospirillum MSR-1 comprises the following steps: collecting MSR-1 strain in logarithmic growth phase, suspending the strain in PBS buffer solution, collecting crude bacteria magnetosome BMs by ultrasonic disruption and magnetic recovery, and continuously purifying the crude bacteria magnetosome BMs by ultrasonic cleaning and magnetic recovery until the supernatant can not detect protein and DNA residue to obtain purified bacteria magnetosome BMs.
3. The method of claim 1, wherein: the mass ratio of TAT polypeptide to purified bacterial magnetosomes BMs is 1: 5.
4. A magnetic nanoparticle capable of crossing blood eye barriers prepared by the preparation method according to any one of claims 1 to 3, wherein the magnetic nanoparticle is TAT-BMs complex vector.
5. Use of the magnetic nanoparticle for crossing the blood-eye barrier according to claim 4 as a carrier for an ocular drug that crosses the blood-eye barrier to assist the ocular drug in crossing the blood-eye barrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101077418A (en) * | 2007-02-08 | 2007-11-28 | 中国农业大学 | Bacteria nano magnetosome loaded with primary amino medicine and preparation method thereof |
| CN104624176A (en) * | 2015-02-12 | 2015-05-20 | 江南大学 | Bacterial magnetic particle (BMP)-agglutinin complex and preparation method and application thereof |
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| US20020012698A1 (en) * | 1999-09-01 | 2002-01-31 | Edmund Bauerlein | Magnetosomes, method for making and using |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101077418A (en) * | 2007-02-08 | 2007-11-28 | 中国农业大学 | Bacteria nano magnetosome loaded with primary amino medicine and preparation method thereof |
| CN104624176A (en) * | 2015-02-12 | 2015-05-20 | 江南大学 | Bacterial magnetic particle (BMP)-agglutinin complex and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Cytotoxicity and genotoxicity of bacterial magnetosomes against human retinal pigment epithelium cells;Lei Qi et al.;《Scientific Reports》;20160601;第6卷;第1-8页 * |
| 复合功能基因投递系统的构建和体外研究;韩磊;《中国博士学位论文全文数据库 基础科学辑》;20090815(第08期);A006-18 * |
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