CN114344464B - Self-oxygen-carrying mitochondria targeted photodynamic therapy nano platform, preparation method and application - Google Patents
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Abstract
The invention belongs to the technical field of photodynamic therapy, and discloses a self-oxygen-carrying mitochondrial targeting photodynamic therapy nano platform, a preparation method and application. The preparation method comprises the steps of regulating and controlling the growth structure of the organic silicon oxide by a two-step silicon source adding method to obtain eccentric organic silicon oxide and obtaining eccentric mesoporous organic silicon oxide by a hydrothermal etching method, carrying out functional modification on the surface of the organic silicon oxide to obtain mitochondrial targeting and photosensitizer, and loading perfluorocarbon with low boiling point and self oxygen carrying characteristics in a cavity. The prepared photodynamic therapy nano platform has a large internal cavity and a mesoporous pore canal, can efficiently load oxygen-carrying perfluorocarbon molecules to target mitochondria, and has high singlet oxygen generation characteristic and cancer cell killing characteristic after being irradiated by laser with specific wavelength. The preparation method is simple and easy to obtain, and the obtained product has high yield and great application potential in the fields of tumor photodynamic therapy and the like.
Description
Technical Field
The invention belongs to the technical field of photodynamic therapy, and particularly relates to a photodynamic nano platform with self-oxygen carrying property and mitochondrial targeting property, and a preparation method and application thereof.
Background
Photodynamic therapy is the use of photosensitizers to convert oxygen into cytotoxic reactive oxygen species under irradiation with laser light of appropriate wavelength to kill tumor cells. Compared with the traditional tumor treatment mode, the photodynamic therapy has the advantages of small traumatism, good repeatability, high spatial selectivity, less side effect and the like. Oxygen is one of three major factors of photodynamic therapy and is closely related to therapeutic effects. The ubiquitous hypoxia and oxygen consumption of photodynamic therapy of solid tumors often form a vicious circle, which is detrimental to adequate treatment of tumors. And effectively increasing the oxygen supply to the tumor part can improve the photodynamic therapy effect. In recent years, photodynamic therapy based on nano materials is receiving more and more attention, and the nano materials can not only increase the water solubility and cellular uptake of the photosensitizers, but also realize the combination of photodynamic therapy with oxygen supply, tumor targeting and the like by utilizing various properties of nano particles or coupling other functional molecules.
Mesoporous organic silicon oxide is a mesoporous material with uniformly doped organic and inorganic components in a structure, has regular and ordered mesopores, uniform and adjustable morphology and size, larger specific surface area and surface characteristics easy to modify, and can efficiently load and deliver drugs, genes, imaging molecules and the like to form a multifunctional whole. In addition, the mesoporous organic silicon oxide also has good biological safety and biodegradability, and lays a foundation for the application of the mesoporous organic silicon oxide in the field of biological medicine. However, because the organic silicon oxide nano-particles have single action as nano-drug carriers, the effect of treating tumors is difficult to achieve, and the characteristics of the functional molecules with self-oxygen carrying property, the mitochondrial targeting and the photodynamic therapy are combined, the mesoporous organic silicon oxide nano-material is widely researched in biomedical applications, but more new applications are still to be explored.
Disclosure of Invention
The invention aims to provide a preparation method for an eccentric hollow mesoporous organic silicon oxide nano delivery oxygen platform and loaded with Carboxyl Triphenylphosphine (CTPP) and photosensitizer Ce 6. The nano platform realizes a large amount of aggregation of mitochondrial parts, enhances the yield of singlet oxygen in cells, and further improves the killing efficiency in Ce6 cells. Based on the basic characteristics of mesoporous organic silicon oxide and photodynamic therapy, the invention provides a preparation method for the eccentric hollow mesoporous organic silicon oxide nano delivery platform and loading self-carried oxygen molecules, modifying carboxyl triphenylphosphine and photosensitizer Ce6, which improves the oxygen content in tumor and targets mitochondria at the same time, thereby further enhancing the photodynamic therapy effect.
The invention is realized by the following technical scheme:
in a first aspect, the invention provides a self-oxygen-carrying mitochondrial targeting photodynamic therapy nano-platform comprising eccentric hollow mesoporous organic silicon oxide, mitochondrial targeting molecules and photosensitizers modified on the surface of the eccentric hollow mesoporous organic silicon oxide, and self-oxygen-carrying perfluorocarbon molecules loaded in an eccentric cavity of the eccentric hollow mesoporous organic silicon oxide. Wherein, eccentric hollow structure helps the gaseous vaporization in the cavity to produce the bubble and promotes granule motion, realizes the motion effect of motor.
Further, the eccentric hollow mesoporous organic silicon oxide has an eccentric cavity size of 150-300nm.
Further, the eccentric hollow mesoporous organic silicon oxide has an ultrathin mesoporous shell layer on the surface of the eccentric cavity.
Further, the eccentric hollow mesoporous organic silicon oxide has uniform mesoporous channels.
Further, the mitochondrial targeting molecule is Carboxytriphenylphosphine (CTPP).
Further, the photosensitizer is chlorin e6 (Ce 6).
Further, the oxygen-carrying perfluorocarbon molecule is tetradecane.
In a second aspect, the invention provides a method for preparing a self-carrying oxygen mitochondria-targeted photodynamic therapy nano-platform, comprising the following steps: the method comprises the steps of synthesizing mesoporous inorganic silicon oxide with adjustable size by using an inorganic silicon source, coating the mesoporous inorganic silicon oxide by using an organic silicon source, removing the inorganic silicon oxide by adopting a hydrothermal method to form eccentric hollow mesoporous organic silicon oxide, jointly modifying mitochondria targeting molecules and photosensitizers by amination on the surface of the eccentric hollow mesoporous organic silicon oxide, and loading self-oxygen-carrying perfluorocarbon molecules in an eccentric cavity of the eccentric hollow mesoporous organic silicon oxide to obtain the self-oxygen-carrying mitochondria targeting photodynamic therapy nano platform.
Further, in the process of synthesizing the eccentric hollow mesoporous organic silicon oxide, the eccentric hollow mesoporous organic silicon oxide is obtained under the conditions that an organic silicon source is heterogeneously grown on the surface of the mesoporous inorganic silicon oxide, and the ratio of ammonia water to the organic silicon source is 1:100-25 at 35 ℃ and 500 rpm.
Further, the inorganic silicon source is TEOS, the organic silicon source is BTSE, and the volume ratio of the inorganic silicon source to the organic silicon source is 1:0.05-0.5.
Further, in the process of synthesizing the eccentric hollow mesoporous organic silicon oxide, inorganic silicon oxide is removed by a hydrothermal method under the water bath of 80 ℃ for 12 hours to form the eccentric hollow mesoporous organic silicon oxide.
Further, under the vacuum condition, the eccentric hollow mesoporous organic silicon oxide modified by the mitochondrial targeting molecule and the photosensitizer is uniformly mixed with the self-oxygen-carrying perfluorocarbon molecule, and the self-oxygen-carrying mitochondrial targeting photodynamic therapy nano platform is obtained by ultrasonic treatment in ice bath.
Specifically, the preparation method of the self-oxygen-carrying mitochondrial targeting photodynamic therapy nano platform comprises the following steps:
(1) Synthesis of inorganic silica nanoparticles (MSNs): 170 Adding ml of cetyl trimethyl ammonium bromide (CTAB, 6 mM) into a mixed solution of 75 ml ethanol and 0.1 ml ammonia water, adding 0.2 ml tetraethyl orthosilicate (TEOS) under stirring at 35 ℃ and 500rpm, adjusting the temperature to 60 ℃, reacting for 24-48 h, centrifuging, and washing with absolute ethanol for 3 times to obtain inorganic silicon oxide nano particles;
(2) Synthesizing eccentric hollow mesoporous organic silicon oxide (JMONs): centrifuging inorganic silicon oxide nano particles 3.5 and mg in a centrifuge tube, dispersing in a mixed solution of 0.5 ml ethanol, 8.5 ml deionized water, 0.015 g CTAB and 0.2-0.7 ml ammonia water, stirring for 30 minutes at the speed of 500rpm at 35 ℃, adding 0.01~0.1 ml ml 1,2-bis (triethoxysilyl) ethane (BTSE), continuing to react for 3 hours, centrifuging, washing with ethanol for three times, washing with water once, placing a sample in a water bath at 80 ℃ for 12 hours, centrifuging, and washing with ethanol for two times; placing the mixture into a mixed solution of 200 ml ethanol and 0.4 ml concentrated hydrochloric acid, reacting at 60 ℃ and a rotating speed of 1100 rpm for 3 times, wherein the reaction time is 3 hours, 12 hours and 3 hours respectively, washing the final product with ethanol for three times, and dissolving the final product in 30 ml ethanol to obtain the eccentric hollow mesoporous organic silicon oxide nano particles;
(3) Modification of Ce6 and CTPP: first, 1ml carboxytriphenylphosphine CTPP (20 mg/ml), 1ml photosensitizer Ce6 (20 mg/ml) were mixed with 0.5 ml bis [3- (triethoxysilyl) propyl ] tetrasulfide EDC (20 mg/ml in N, N-Dimethylformamide (DMF)) and 0.5 ml N-hydroxysuccinimide NHS (20 mg/ml in DMF), respectively. The mixture was shaken at room temperature for 3 hours to activate the carboxyl groups. Then 1ml of nanoparticles were dispersed into the carboxy activated CTPP solution. After 12h of reaction, the mixture is centrifugally washed for 3 times and then is dispersed into the carboxyl activated Ce6, and after 12h of reaction and 3 times of centrifugal washing, the stable JMONs-Ce6& CTPP with the surface function modified is obtained.
(4) Synthesizing self-oxygen-carrying eccentric hollow mesoporous organic silicon oxide nano particles (JMONS-Ce 6& CTPP@PFC): centrifuging 1mg of the JMONs-Ce6& CTPP with the surface modified at the rotating speed of 10000rpm, washing with water for 2 times, vacuumizing, rapidly adding 0.1 ml of PFC solution, and performing ultrasonic treatment in an ice bath for 2 minutes to obtain the JMONs-Ce6& CTPP@PFC.
In a third aspect, the invention also provides application of the self-oxygen-carrying mitochondrial targeting photodynamic therapy nano platform in preparation of antitumor drugs.
The beneficial effects are that:
1. the photodynamic therapy nano platform provided by the invention has a large internal cavity and mesoporous pore canal, can be used for loading perfluorocarbon with high efficiency and has high-efficiency release characteristic, and is beneficial to mass transportation of oxygen;
2. the eccentric hollow mesoporous organic silicon oxide nano particles are prepared by a simple hydrothermal method, and the process has low equipment requirement, low cost and environmental friendliness; the preparation method provided by the invention is simple and easy to obtain, and the obtained product has high yield and great application potential in the fields of tumor photodynamic therapy and the like;
3. the material with the oxygen-carrying property has simpler tumor oxygenation design and implementation mode, and has obvious singlet oxygen generation compared with a blank experiment;
4. the eccentric hollow mesoporous organosilicon nano-particles combine the mitochondrial targeting function, and improve the mitochondrial targeting capability, the intracellular singlet oxygen production efficiency and the photodynamic treatment effect.
Drawings
FIG. 1 is a schematic diagram of the working principle of a self-oxygen-carrying mitochondrial targeting photodynamic therapy nanoplatform in an embodiment of the invention;
FIG. 2 is a structural formula of photosensitizer Ce6 and Carboxytriphenylphosphine (CTPP);
FIG. 3 is a graph showing the Transmission Electron Microscope (TEM), scanning Electron Microscope (SEM) and hydration kinetics size characterization of the inorganic silica nanoparticles produced in example 1 of the present invention;
FIG. 4 is a Transmission Electron Microscope (TEM), scanning Electron Microscope (SEM), water and kinetic dimensions, element distribution, fourier infrared spectrum, nitrogen adsorption and desorption curve image of the eccentric hollow mesoporous organic silica nanoparticles prepared in example 1 of the present invention;
FIG. 5 is an image of the ultraviolet visible absorption spectrum, hydration kinetics dimensions, surface potential and element distribution of the eccentric hollow mesoporous organic silica nanoparticles modified Ce6 and CTPP produced in example 1 of the present invention;
FIG. 6 is a graph showing the cell compatibility of the surface-modified eccentric hollow mesoporous organic silica nanoparticles prepared in example 1 of the present invention;
FIG. 7 is a graph showing the comparison of the generation of intracellular and extracellular singlet oxygen in example 1 of the present invention, wherein the eccentric hollow mesoporous organic silica nanoparticles are prepared and loaded with perfluorocarbon and surface-modified, and the presence or absence of laser irradiation;
FIG. 8 is a comparative graph of targeted photodynamic therapy of the eccentric hollow mesoporous organic silica nanoparticle prepared and loaded with perfluorocarbon and surface-modified in example 1 of the present invention.
Detailed Description
The invention is further described below in connection with specific embodiments. The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention.
Referring to fig. 1 and 2, a preparation method of the eccentric hollow mesoporous organic silicon oxide nanoparticle delivery platform and loaded with perfluorocarbon, CTPP and photosensitizer Ce6 is specifically described.
Example 1:
1. synthesis of inorganic silica nanoparticles (MSNs):
firstly, preparing hexadecyl trimethyl ammonium bromide (CTAB) into a 6 mM aqueous solution, adding 170 ml into 75 ml ethanol, adding 0.1 ml ammonia water after bubbles disappear, stirring for 5 minutes at 35 ℃ and 500rpm, then slowly and dropwise adding 0.2 ml tetraethyl orthosilicate (TEOS), adjusting the temperature of a water bath kettle to 60 ℃, reacting for 24-48 hours, centrifuging, washing a sample with absolute ethyl alcohol for 3 times, and obtaining inorganic silicon oxide nano particles.
2. Synthesis of eccentric hollow mesoporous organic silicon oxides (JMONs)
The first step: taking inorganic silicon oxide nano particles 3.5 mg prepared in the previous step, centrifuging at 10000rpm, dispersing in 0.5 ml ethanol, 8.5 ml deionized water, 0.015 g CTAB and 0.2-0.7 ml ammonia water mixed solution, uniformly stirring for 30 minutes at 35 ℃ and 500rpm, slowly dripping 0.04ml 1, 2-bis (triethoxysilyl) ethane (BTSE), continuously stirring and reacting for 3 hours, centrifuging, washing the product with ethanol for three times, and washing with deionized water once;
and a second step of: dissolving the product obtained in the first step in 35 ml deionized water in a 50 ml centrifuge tube, standing in a water bath at 80 ℃ for 12 hours, centrifuging, washing with ethanol twice,
and a third step of: placing the product obtained in the second step into a mixed solution of 200 ml ethanol and 0.4 ml concentrated hydrochloric acid, reacting at 60 ℃ and a rotating speed of 1100 rpm, repeating for 3 times, wherein the reaction time is 3 hours, 12 hours and 3 hours respectively, washing the final product with ethanol for three times, and dissolving the final product in 30 ml ethanol to obtain the eccentric hollow mesoporous organic silicon oxide nano particles;
3. modification of Ce6 and CTPP
First, 1ml carboxytriphenylphosphine CTPP (20 mg/ml), 1ml photosensitizer Ce6 (20 mg/ml) were mixed with 0.5 ml bis [3- (triethoxysilyl) propyl ] tetrasulfide EDC (20 mg/ml in N, N-Dimethylformamide (DMF)) and 0.5 ml N-hydroxysuccinimide NHS (20 mg/ml in DMF), respectively. The mixture was shaken on a shaker at room temperature for 3 hours to activate the carboxyl groups. Then 1ml of the nanoparticle was dispersed into CTPP solution after carboxyl activation. After 12h of reaction, the mixture is centrifugally washed for 3 times and then is dispersed into Ce6 activated by carboxyl, and after 12h of reaction and 3 times of centrifugal washing, the stable JMONs-Ce6& CTPP with modified surface function is obtained.
4. Synthesis of self-oxygen-carrying eccentric hollow mesoporous organic silicon oxide nanoparticle (JMONS-Ce 6& CTPP@PFC)
Centrifuging 1mg of JMONS-Ce6& CTPP prepared in the previous step at a rotating speed of 10000rpm, washing with deionized water for 2 times, rapidly adding 0.1 ml of PFC solution after vacuumizing, performing ultrasonic treatment for 2 minutes in ice bath (lower than 4 ℃) to obtain JMONS-Ce6& CTPP@PFC, and dispersing in PBS for standby.
3 a-d, the prepared MSNs nanoparticles were observed using a Transmission Electron Microscope (TEM) and a Scanning Electron Microscope (SEM). The nano particles have good dispersibility and uniform size, and the particle size is about 200 and nm.
4 a-l are Transmission Electron Microscope (TEM), scanning Electron Microscope (SEM), water and kinetic dimensions, element distribution, fourier infrared spectrum, nitrogen adsorption and desorption curve images of the eccentric hollow mesoporous organic silicon oxide nano particles. As can be seen from the figure, the nano particles have good dispersibility, uniform size, about 320 a nm a particle size, uniform distribution of carbon, oxygen and silicon elements in the structure, occurrence of infrared characteristic peaks of organic components, existence of uniform mesoporous channels on the surface and 2.3 a nm a size.
Fig. 5 a-f are ultraviolet-visible absorption spectra, hydration kinetic dimensions, surface potential and element distribution images of eccentric hollow mesoporous organic silicon oxide nanoparticles modified with Ce6 and CTPP. The appearance of Ce6 characteristic peaks of the JMONS-Ce6& CTPP material in the ultraviolet-visible absorption spectrum shows that the Ce6 characteristic peaks on the eccentric hollow organic silicon oxide are successfully modified, the hydration kinetic size and potential change images reflect the size change and the surface potential condition of particles in the process of each stage, and the element distribution images show that phosphorus elements are uniformly distributed on the eccentric hollow organic silicon oxide.
Fig. 6 shows a biocompatibility test of JMONs-Ce6& CTPP, and a experiment is carried out by selecting mouse breast cancer cells (4T 1 cells), wherein the concentration is 0-200 mug/l, and the activity of 24 h cells and even 48h cells is more than 80% through co-incubation, so that the nanoparticles have good biocompatibility.
Fig. 7 a-b show that the JMONs-Ce6& CTPP nanoparticle loaded with PFC has more obvious extracellular and internal singlet oxygen generation after 660 nm excitation light source is applied, and the singlet oxygen generation rate of the JMONs-Ce6& ctpp@pfc experimental group is 3.5 times or more than that of the control group.
FIG. 8 is a graph of photodynamic effects of JMONS-Ce6& CTPP@PFC, with increasing concentrations of the different experimental groups, cell activity of the four experimental groups gradually decreases, and when the material concentration reaches 200 mug/ml, compared with a control group loaded with PFC, without an excitation light source or free Ce6, JMONS-Ce6& CTPP@PFC has greater cancer cell killing efficiency, and the cell survival rate is 2/5 and less than 40% of that of the free Ce6 control group.
The photodynamic therapy nano platform provided by the invention has a large internal cavity and a mesoporous pore canal, can efficiently load oxygen-carrying perfluorocarbon molecules to target mitochondria, and has high singlet oxygen generation characteristic and cancer cell killing characteristic after being irradiated by laser with specific wavelength. The preparation method comprises the steps of regulating and controlling the growth structure of the organic silicon oxide by a two-step silicon source adding method to obtain eccentric organic silicon oxide and obtaining eccentric mesoporous organic silicon oxide by a hydrothermal etching method, carrying out functional modification on the surface of the organic silicon oxide to obtain mitochondrial targeting molecule Triphenylphosphine (TPP) and photosensitizer chlorin e6 (Ce 6), and loading tetradecane liquid with low boiling point and self oxygen carrying characteristics into a cavity. The eccentric hollow oxygen-carrying mesoporous organic silicon oxide nano particles combine the mitochondrial targeting function, and improve the mitochondrial targeting capability, the singlet oxygen generation capability and the photodynamic treatment effect. The preparation method provided by the invention is simple and easy to obtain, and the obtained product has high yield and great application potential in the fields of tumor photodynamic therapy and the like.
The present invention has been disclosed in the preferred embodiments, but the invention is not limited thereto, and the technical solutions obtained by adopting equivalent substitution or equivalent transformation fall within the protection scope of the present invention.
Claims (8)
1. The self-oxygen-carrying mitochondrial targeting photodynamic therapy nano platform is characterized by comprising eccentric hollow mesoporous organic silicon oxide, mitochondrial targeting molecules and photosensitizers which are modified on the surface of the eccentric hollow mesoporous organic silicon oxide, and self-oxygen-carrying perfluorocarbon molecules loaded in an eccentric cavity of the eccentric hollow mesoporous organic silicon oxide;
the preparation method comprises the following steps: synthesizing mesoporous inorganic silicon oxide with adjustable size by using an inorganic silicon source, coating the mesoporous inorganic silicon oxide by using an organic silicon source, removing the inorganic silicon oxide by adopting a hydrothermal method to form eccentric hollow mesoporous organic silicon oxide, jointly modifying mitochondria targeting molecules and photosensitizers by amination of the surface of the eccentric hollow mesoporous organic silicon oxide, and loading self-oxygen-carrying perfluorocarbon molecules in an eccentric cavity of the eccentric hollow mesoporous organic silicon oxide to obtain a self-oxygen-carrying mitochondria targeting photodynamic therapy nano platform;
and uniformly mixing the modified mitochondria targeting molecule and the photosensitizer with the eccentric hollow mesoporous organic silicon oxide and the self-oxygen-carrying perfluorocarbon molecule under vacuum condition, and performing ultrasonic treatment under ice bath to obtain the self-oxygen-carrying mitochondria targeting photodynamic therapy nano platform.
2. The self-contained oxygen mitochondrial targeting photodynamic therapy nanoplatform of claim 1 wherein the eccentric hollow mesoporous organo-silica has an eccentric cavity size of 150-300nm.
3. The self-oxygen-carrying mitochondrial targeting photodynamic therapy nano-platform according to claim 1, wherein the eccentric hollow mesoporous organic silicon oxide has an ultrathin mesoporous shell on the surface of an eccentric cavity.
4. The self-contained oxygen mitochondrial targeting photodynamic therapy nanoplatform of claim 1 wherein the eccentric hollow mesoporous organic silica has uniform mesoporous channels.
5. The self-oxygen-carrying mitochondrial targeting photodynamic therapy nano-platform according to claim 1, wherein in the process of synthesizing the eccentric hollow mesoporous organic silicon oxide, an organic silicon source is heterogeneously grown on the surface of the mesoporous inorganic silicon oxide, and the eccentric hollow mesoporous organic silicon oxide is obtained under the conditions that the temperature is 35 ℃, the rpm is 500, and the ratio of ammonia water to the organic silicon source is 1:100-25.
6. The self-oxygen-carrying mitochondrial targeted photodynamic therapy nanoplatform of claim 1 wherein the inorganic silicon source is TEOS and the organosilicon source is BTSE in a volume ratio of 1:0.05-0.5.
7. The self-oxygen-carrying mitochondrial targeting photodynamic therapy nanoplatform of claim 1 wherein during synthesis of the eccentric hollow mesoporous organic silica, inorganic silica is removed by hydrothermal reaction in a water bath at 80 ℃ for 12 hours to form the eccentric hollow mesoporous organic silica.
8. Use of the self-carrying oxygen mitochondrial targeting photodynamic therapy nano-platform according to any one of claims 1-7 in the preparation of antitumor drugs.
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