CN112353752A - Light-driven drug delivery system for optic nerve recovery and preparation method and application thereof - Google Patents
Light-driven drug delivery system for optic nerve recovery and preparation method and application thereof Download PDFInfo
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- FYZFRYWTMMVDLR-UHFFFAOYSA-M trimethyl(3-trimethoxysilylpropyl)azanium;chloride Chemical compound [Cl-].CO[Si](OC)(OC)CCC[N+](C)(C)C FYZFRYWTMMVDLR-UHFFFAOYSA-M 0.000 claims abstract description 10
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0048—Eye, e.g. artificial tears
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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Abstract
The invention discloses a light-driven drug-loading system for optic nerve recovery and a preparation method thereof, and the preparation method of the drug-loading system mainly comprises the following steps: 1) preparing silica-surfactant composite nanoparticles (MSN) with a colloidal mesoporous structure; 2) preparing MSN-SH nano particles; 3) preparing gold nanoparticles; 4) preparing MSN-S-Au nano particles; 5) preparing Janus nano particles; 6) and (3) preparing the Janus nanoparticle drug delivery system. The drug delivery system provided by the invention reduces the release speed of the drug and improves the bioavailability. The N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride provided by the invention provides positive charges for the surface of the drug delivery system, and can effectively enhance the adhesion performance of the drug delivery system on a retina limiting membrane. The drug loading system provided by the invention has an asymmetric structure, generates a local temperature gradient in a near infrared region, and drives the colloidal mesoporous Janus nano particles to move towards the retina inner limiting membrane lesion area.
Description
Technical Field
The invention belongs to the field of high polymer materials, and relates to a light-driven drug-loading system for optic nerve recovery, and a preparation method and application thereof.
Background
At present, the causes of optic nerve damage are many, the common causes include trauma, ischemia, poisoning, demyelination, tumor compression, inflammation and the like, and the common pathogenesis of the damage is the conduction dysfunction of optic nerve. Among them, visual impairment is the most common and the most prominent clinical manifestations, and it often causes pain and swelling sensation in the posterior orbital region and blurred vision in the early stage, and then the symptoms worsen, and the vision is obviously reduced or even lost. Therefore, the invention has important significance in inventing the method for recovering the optic nerve conduction function. However, the repair function of the nerve at present is still a great challenge in the biology of the regeneration of nerve, and the promotion of nerve regeneration not only needs to regulate the microenvironment after injury, but also needs to ensure the survival of injured neurons. Continuous administration of the current epidermal growth factor receptor tyrosine kinase inhibitor (4- (3-chlorophenylamine) -6, 7-dimethoxyquinazoline) is proved to promote the survival and regeneration of neurons, but in some related researches, the phenomenon of optic nerve damage is caused by the phenomenon that the medicament is excessively high in concentration in an optic nerve crushing model. Therefore, it is important to prepare a drug delivery system capable of slowly releasing to prevent the local drug concentration from being too high.
The development and enhancement of sustained release drug delivery systems for ocular drug delivery and how to effectively deliver these drugs to the focal area and function remains a major challenge. In terms of the current research situation, intravitreal injection is the most direct drug delivery mode for treating posterior segment eye diseases at present, and can not only immediately deliver drugs into the intraocular environment, but also effectively improve the bioavailability of the drugs. However, the drug injected into the vitreous is released more rapidly and diffuses into the periphery of the vitreous, which may result in a concentration of drug reaching the focal zone that is not high enough to require repeated intravitreal injections for sustained delivery. And intravitreal injection is a very intolerable mode of administration for patients, and repeated injections are unacceptable to patients and can also cause associated potential complications (endophthalmitis, retinal detachment, intravitreal hemorrhage, and cataracts). However, the nano-encapsulated drug delivery system is a drug delivery system which can encapsulate drugs and can slowly release the drugs, not only can reduce the dosage of the drugs, but also can effectively achieve the treatment effect. However, the traditional nano-carrier has low degradation rate after releasing the drug, is easy to deposit in the vitreous body cavity and influences the metabolism of the body; and because the optic nervous system is at the rearmost end of eyes, the nanoparticles can not independently and quickly reach the focal region, and even the nanoparticles reaching the focal region can not be adhered, the nanoparticles can be quickly deposited at the bottom of the vitreous cavity, so that the treatment effect can not be achieved.
Therefore, in order to achieve significant and lasting functional recovery of the central nervous system, there is a need to develop a drug delivery system that allows the drug to reach the endoretinal focal region in a more efficient manner and to prolong the persistence of the drug on the intraretinal limiting membrane and to provide sustained release.
Disclosure of Invention
The invention aims to develop a light-driven drug delivery system for optic nerve recovery aiming at series of problems of traditional drugs for treating the central nervous system. The N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride provided by the invention provides positive charges for the surface of a drug delivery system, and can effectively enhance the adhesion performance of the drug delivery system on a retina limiting membrane; the drug loading system provided by the invention has an asymmetric structure, generates a local temperature gradient in a near infrared region, and drives the colloidal mesoporous Janus nano particles to move towards the direction of a focus region of an inner limiting membrane of a retina;
in order to achieve the purpose, the invention adopts the following technical scheme:
the invention discloses a preparation method of a light-driven Janus nanoparticle drug-loading system for optic nerve recovery, which comprises the following steps:
1) preparation of mesoporous silica nanoparticle MSN:
adding 0.1-1g of cetyl trimethyl ammonium bromide CTAB and 1-5ml of triethylamine into 100-250ml of distilled water, stirring and heating for 0.5-1.5 hours at the temperature of 60-80 ℃, then respectively adding 1-5ml of tetraethoxysilane and 1-10ml of ethanol into the solution, keeping the temperature and stirring for 1-3 hours, and then cooling to room temperature; next, centrifuging the suspension at 6000-;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 150-250mL of ethanol, uniformly mixing, adding 0.1-1mL of 95% 3-mercaptopropyltrimethoxysilane MPTMS, condensing and refluxing for 9-18 hours at 60-90 ℃, and centrifuging the suspension for 3-5 minutes at 6000-11000 rpm; to remove CTAB, MSN-SH was dispersed in 160-360mL of methanol and 12-24mL of hydrochloric acid; refluxing at 60-90 deg.C for 9-18 hr, centrifuging and vacuum drying to obtain MSN-SH nanoparticles;
3) preparing MSN-S-Au nanoparticles:
dispersing 1-10mg of MSN-SH nanoparticles prepared in step 2) in 1-10mL of Phosphate Buffered Saline (PBS) with pH7.4, and stirring 5-25mL of 0.5-2.5 × 10-4M chloroauric acid and 5-25mL of 0.5-2.5X 10-4Slowly dripping the mixed solution of the sodium citrate M into the MSN-SH suspension, slowly stirring for 4-5 hours, then quickly adding 0.2-4mL of 0.05-0.15M sodium borohydride solution into the mixed solution, stirring for 2-5 hours until the mixture becomes purple red, centrifuging to remove supernatant, and washing for 2-4 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride and the MSN-S-Au nano-particles prepared in the step 3) according to the mass ratio of 1: 1-2: 2-4, stirring for 10-15 hours at 60-90 ℃, and then mixing the dispersion with 1-4M acetic acid and ethanol in a volume ratio of 7: 3, dialyzing the mixture;
5) preparation of Janus nanoparticle drug delivery system:
firstly, dissolving 10-50mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline in 5-10mL of distilled water, then adding 40-200mg of Janus nanoparticles which are soaked in 5-10mM of glutathione for 9-18 hours at normal temperature into a 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, carrying out ultrasonic treatment for 1-2 hours, dropwise adding 2-8mL of PBS (pH7.4) into the solution, standing for 9-18 hours, finally centrifuging to remove supernatant, and washing for 2-4 times by using PBS (pH7.4) to obtain Janus nanoparticles containing 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
An optically-driven Janus nanoparticle drug delivery system for optic nerve recovery.
Application of Janus nanoparticle drug delivery system is characterized in that 1-10 mu L of drug delivery system containing 4- (3-chloroanilino) -6, 7-dimethoxyquinazoline and 10-100mg/mL is used in a rat optic nerve crush injury model for intravitreal administration by using a microinjector, and 4-30mW mu m of drug delivery system is used-2The power near infrared light irradiates the eyeground through the pupil, and the drug-carrying system can be diffused to the retina inner limiting membrane focal area to play a role and is used for treating acute central nervous system injury, degenerative diseases and the like.
Preferably, the wavelength range of the near-infrared light is 800-1100nm, the power range is 4-30mW, and the irradiation time range is 50-180 s.
Preferably, after the medicine carrying system is irradiated by near infrared light, the movement rate of the medicine carrying system can reach 24-160 mu m s-1。
Compared with the prior art, the invention has the beneficial effects that:
(1) the drug delivery system provided by the invention is nano particles, the diameter of the drug delivery system is 200-500 nm, and the drug delivery system is beneficial to penetrating through a vitreous cavity to reach an endoretinal focal zone; in addition, the mesoporous structure of the drug-loading system is also beneficial to improving the drug-loading rate;
(2) according to the drug delivery system provided by the invention, the gold nanoparticles have stronger plasma resonance absorption in a near-infrared region, so that local temperature gradients are generated on the inner surface and the outer surface of the gold nanoparticles which are tightly distributed on a hemisphere of the drug delivery system, and the speed of the mesoporous Janus nanoparticles is changed due to the higher temperature gradient on the inner surface, so that the drug delivery system is driven to move towards the direction of an inner limiting membrane focus of a retina;
(3) the surface of the drug-loading system modified by N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride provided by the invention shows positive charges, and the inner limiting membrane of human retina consists of fibronectin, laminin, type I collagen, type IV collagen and several proteoglycan (glycoconjugate) components and shows negative charges; so that the drug-loading system with positive charges reaches the vicinity of the focal region of the retina inner limiting membrane and is adhered to the retina inner limiting membrane with negative charges; therefore, the N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride can effectively enhance the adhesive property of the drug-loading system on the inner limiting membrane of the retina; thereby effectively solving the problem that the existing medicine carrying system is quickly deposited at the bottom of the vitreous cavity after reaching the focus area.
(4) The 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline provided by the invention can restore the function of optic nerve, so that a drug delivery system can be used for treating acute central nervous system injury and degenerative diseases (such as glaucoma);
(5) the light-driven drug delivery system provided by the invention effectively solves the problems that the existing drug delivery system is difficult to reach a focal zone at the back of an eye after being injected into a vitreous body, quickly diffuses to the periphery and has low bioavailability; meanwhile, the problem of repeated injection for many times in the existing vitreous injection treatment technology for the posterior segment eye diseases is also solved, so that the pain and the complications born by the eyes of a human body are relieved.
Detailed Description
The present invention will be further illustrated by the following examples.
In the examples of the present invention, the raw materials used are those commonly used in the art, and the methods used in the examples are those conventional in the art, unless otherwise specified.
Example 1
1) Mesoporous silica nanoparticle MSN) preparation:
adding 0.1g of cetyl trimethyl ammonium bromide CTAB and 2ml of triethylamine into 100ml of distilled water, stirring and heating for 0.5 hour at the temperature of 60 ℃, then respectively adding 2ml of tetraethoxysilane and 1ml of ethanol into the solution, keeping the temperature, stirring for 1 hour, and then cooling to room temperature; next, the suspension was centrifuged at 7000rpm for 3 minutes and washed 3 times to obtain mesoporous silica nanoparticle MSN;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 150mL of ethanol, uniformly mixing, adding 0.1mL of 3-mercaptopropyltrimethoxysilane (MPTMS, 95%), condensing and refluxing for 10 hours at 60 ℃, and centrifuging the suspension for 3 minutes at 7000 rpm; to remove CTAB, MSN-SH was dispersed in 180mL methanol and 12mL hydrochloric acid; after refluxing for 10 hours at 60 ℃, centrifuging and vacuum-drying the solution to obtain MSN-SH nano particles;
3) preparing MSN-S-Au nanoparticles:
1mg of MSN-SH nanoparticles from step 2) were dispersed in 1mL of PBS pH7.4, and then 5mL (0.5X 10) were added under stirring-4M) and 5mL (0.5X 10)-4M) slowly dropping the mixed solution of the sodium citrate into the MSN-SH suspension, slowly stirring for 4 hours, then quickly adding 0.2mL of 0.05M sodium borohydride solution into the mixed solution, stirring for 2 hours until the mixture becomes purple red, centrifuging to remove supernatant, and washing for 2 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride and the MSN-S-Au nanoparticles (1: 1: 2) after mixing well, stirring at 60 ℃ for 10 hours, and then mixing the dispersion with 1-4M acetic acid and ethanol (7: 3) dialyzing the mixture of (a);
5) preparation of Janus nanoparticle drug delivery system:
firstly, 10mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline is dissolved in 5mL of distilled water, then 40mg of Janus nano particles soaked in 5mM of glutathione for 9 hours at normal temperature are added into a 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, after 1 hour of ultrasonic treatment, 2mL of PBS with pH7.4 is added into the solution dropwise and is kept stand for 9 hours, and finally, the supernatant is centrifuged and washed for 2 times by PBS with pH7.4 to obtain Janus nano particles containing 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
6) The specific parameters of the drug-loading system are as follows:
the diameter of the drug-carrying system is 240nm, the Zeta potential in the PBS buffer solution is +17mV, and the movement rate can reach 35 mu m s-1；
7) The specific implementation method comprises the following steps:
near-infrared laser equipment is adopted to emit near-infrared light, the wavelength of the near-infrared laser equipment is 850nm, the power of the near-infrared laser equipment is 4mW, the near-infrared light is irradiated to the eye ground through the pupil of a rat optic nerve extrusion injury model, the irradiation time is 80s each time, the irradiation is carried out twice every day, the interval is at least two hours, and the required days are 30 days.
Example 2
1) Mesoporous silica nanoparticle MSN) preparation:
adding 0.4g of cetyl trimethyl ammonium bromide CTAB and 1ml of triethylamine into 150ml of distilled water, stirring and heating for 1 hour at the temperature of 70 ℃, then respectively adding 1ml of tetraethoxysilane and 4ml of ethanol into the solution, keeping the temperature, stirring for 1 hour, and then cooling to room temperature; next, the suspension was centrifuged at 7000rpm for 3 minutes and washed 3 times to obtain mesoporous silica nanoparticle MSN;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 150mL of ethanol, uniformly mixing, adding 0.4mL of 3-mercaptopropyltrimethoxysilane (MPTMS, 95%), condensing and refluxing for 12 hours at 70 ℃, and centrifuging the suspension for 3 minutes at 8000 rpm; to remove CTAB, MSN-SH was dispersed in 240mL methanol and 16mL hydrochloric acid; after refluxing for 12 hours at 70 ℃, centrifuging and vacuum-drying the solution to obtain MSN-SH nano particles;
3) preparing MSN-S-Au nanoparticles:
dispersing 4mg of MSN-SH nanoparticles prepared in step 2) in 4mL of PBS (pH 7.4), and stirring15ml(1.5×10-4M) and 15mL (1.5X 10)-4Slowly dripping the mixed solution of the sodium citrate of M) into the MSN-SH suspension, slowly stirring for 4.5 hours, then quickly adding 1.6mL of 0.1M sodium borohydride solution into the mixed solution, stirring for 3 hours until the mixture turns to purple red, centrifuging to remove supernatant, and washing for 3 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride and the MSN-S-Au nanoparticles (1: 1.5: 2.5) and stirred at 70 ℃ for 11 hours, and then the dispersion was purified with 1-4M acetic acid and ethanol (7: 3) dialyzing the mixture of (a);
5) preparation of Janus nanoparticle drug delivery system:
firstly, 20mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline is dissolved in 7mL of distilled water, then 120mg of Janus nanoparticles soaked in 8mM glutathione for 12 hours at normal temperature are added into a 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, after ultrasonic treatment for 1.5 hours, 4mL of PBS with pH7.4 is added into the solution and is kept stand for 12 hours, and finally, the supernatant is centrifuged and washed for 3 times by PBS with pH7.4 to obtain Janus nanoparticles containing 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
6) The specific parameters of the drug-loading system are as follows:
the diameter of the drug-carrying system is 300nm, the Zeta potential in the PBS buffer solution is +24mV, and the movement rate can reach 153 mu m s-1；
7) The specific implementation method comprises the following steps:
near-infrared laser equipment is adopted to emit near-infrared light, the wavelength of the near-infrared laser equipment is 900nm, the power of the near-infrared laser equipment is 20mW, the near-infrared light is irradiated to the eye ground through the pupil of a rat optic nerve extrusion injury model, the irradiation time is 110s each time, the irradiation is carried out twice every day, the interval is at least two hours, and the required days are 30 days.
Example 3
1) Mesoporous silica nanoparticle MSN) preparation:
adding 0.8g of cetyl trimethyl ammonium bromide CTAB and 3ml of triethylamine into 200ml of distilled water, stirring and heating for 1 hour at 75 ℃, then respectively adding 3ml of tetraethoxysilane and 6ml of ethanol into the solution, keeping the temperature, stirring for 2 hours, and then cooling to room temperature; next, the suspension was centrifuged at 9000rpm for 4 minutes and washed 4 times to obtain mesoporous silica nanoparticles MSN;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 200mL of ethanol, uniformly mixing, adding 0.8mL of 3-mercaptopropyltrimethoxysilane (MPTMS, 95%), condensing and refluxing for 14 hours at 80 ℃, and centrifuging the suspension for 4 minutes at 9000 rpm; to remove CTAB, MSN-SH was dispersed in 300mL methanol and 20mL hydrochloric acid; after refluxing for 14 hours at 80 ℃, centrifuging and vacuum-drying the solution to obtain MSN-SH nano particles;
3) preparing MSN-S-Au nanoparticles:
5mg of MSN-SH nanoparticles from step 2) were dispersed in 6mL of PBS pH7.4, and then 20mL (2.0X 10) were added under stirring-4M) and 20mL (2.0X 10)-4M) slowly dropping the mixed solution of sodium citrate into the MSN-SH suspension, slowly stirring for 5 hours, then quickly adding 2.4mL of 0.1M sodium borohydride solution into the mixed solution, stirring for 4 hours until the mixture turns to purple red, centrifuging to remove supernatant, and washing for 4 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride and the MSN-S-Au nanoparticles (1: 2: 3) after mixing well, stirring at 80 ℃ for 13 hours, and then mixing the dispersion with 1-4M acetic acid and ethanol (7: 3) dialyzing the mixture of (a);
5) preparation of Janus nanoparticle drug delivery system:
30mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline was dissolved in 8mL of distilled water, 160mg of Janus nanoparticles after being soaked in 8mM glutathione for 16 hours at normal temperature were added to the 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, after sonication for 1.5 hours, 6mL of PBS (pH7.4) was added dropwise to the solution and allowed to stand for 16 hours, and finally the supernatant was centrifuged and washed 4 times with PBS (pH7.4) to obtain Janus nanoparticles containing 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
6) The specific parameters of the drug-loading system are as follows:
the diameter of the drug-carrying system is 380nm, the Zeta potential in the PBS buffer solution is +35mV, and the movement rate can reach 145 mu m s-1；
7) The specific implementation method comprises the following steps:
near-infrared laser equipment is adopted to emit near-infrared light, the wavelength of the near-infrared laser equipment is 950nm, the power of the near-infrared laser equipment is 25mW, the near-infrared light is irradiated to the eye ground through the pupil of a rat optic nerve extrusion injury model, the irradiation time is 150s each time, the irradiation is carried out twice every day, the interval is at least two hours, and the required days are 30 days.
Example 4
1) Mesoporous silica nanoparticle MSN) preparation:
adding 1.0g of cetyltrimethylammonium bromide CTAB and 5ml of triethylamine into 250ml of distilled water, stirring and heating for 1.5 hours at 80 ℃, then respectively adding 5ml of tetraethoxysilane and 10ml of ethanol into the solution, keeping the temperature, stirring for 3 hours, and cooling to room temperature; next, the suspension was centrifuged at 10000rpm for 5 minutes and washed 4 times to obtain mesoporous silica nanoparticles MSN;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 250mL of ethanol, uniformly mixing, adding 1.0mL of 3-mercaptopropyltrimethoxysilane (MPTMS, 95%), condensing and refluxing for 16 hours at 90 ℃, and centrifuging the suspension for 5 minutes at 10000 rpm; to remove CTAB, MSN-SH was dispersed in 360mL methanol and 24mL hydrochloric acid; after refluxing for 16 hours at 90 ℃, centrifuging and vacuum-drying the solution to obtain MSN-SH nano particles;
3) preparing MSN-S-Au nanoparticles:
dispersing 10mg of MSN-SH nanoparticles prepared in step 2) in 10mL of PBS pH7.4, and then stirring 25mL (2.5X 10)-4M) and 25mL (2.5X 10)-4M) was slowly added dropwise to the MSN-SH suspension, and after stirring slowly for 5 hours, 4mL of 0.1 solution was addedQuickly adding a 5M sodium borohydride solution into the mixed solution, stirring for 5 hours until the mixture turns to be purple red, centrifuging to remove the supernatant, and washing for 4 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethylammonium chloride and the MSN-S-Au nanoparticles (1: 2: 4) after mixing well, stirring at 80 ℃ for 13 hours, and then mixing the dispersion with 1-4M acetic acid and ethanol (7: 3) dialyzing the mixture of (a);
5) preparation of Janus nanoparticle drug delivery system:
50mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline was dissolved in 10mL of distilled water, 200mg of Janus nanoparticles after being soaked in 10mM glutathione for 18 hours at normal temperature were added to the 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, after sonication for 2 hours, 8mL of PBS (pH 7.4) was added dropwise to the solution and allowed to stand for 18 hours, and finally the supernatant was centrifuged and washed 4 times with PBS (pH 7.4) to obtain Janus nanoparticles containing 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
6) The specific parameters of the drug-loading system are as follows:
the diameter of the drug-carrying system is 450nm, the Zeta potential in the PBS buffer solution is +45mV, and the movement rate can reach 120 mu m s-1；
7) The specific implementation method comprises the following steps:
near-infrared laser equipment is adopted to emit near-infrared light, the wavelength of the near-infrared laser equipment is 1100nm, the power of the near-infrared laser equipment is 30mW, the near-infrared light is irradiated to the eye ground through the pupil of the rat optic nerve extrusion injury model, the irradiation time is 180s each time, the irradiation is carried out twice every day, the interval is at least two hours, and the required days are 30 days.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (4)
1. A preparation method of a light-driven Janus nanoparticle drug-loading system for optic nerve recovery is characterized by comprising the following steps: the method comprises the following steps:
1) preparation of mesoporous silica nanoparticle MSN:
adding 0.1-1g of cetyl trimethyl ammonium bromide CTAB and 1-5ml of triethylamine into 100-250ml of distilled water, stirring and heating for 0.5-1.5 hours at the temperature of 60-80 ℃, then respectively adding 1-5ml of tetraethoxysilane and 1-10ml of ethanol into the solution, keeping the temperature and stirring for 1-3 hours, and then cooling to room temperature; next, centrifuging the suspension at 6000-;
2) preparing MSN-SH nano particles:
adding the MSN prepared in the step 1) into 150-250mL of ethanol, uniformly mixing, adding 0.1-1mL of 95% 3-mercaptopropyltrimethoxysilane MPTMS, condensing and refluxing for 9-18 hours at 60-90 ℃, and centrifuging the suspension for 3-5 minutes at 6000-11000 rpm; to remove CTAB, MSN-SH was dispersed in 160-360mL of methanol and 12-24mL of hydrochloric acid; refluxing at 60-90 deg.C for 9-18 hr, centrifuging the solution, and vacuum drying to obtain MSN-SH nanoparticles;
3) preparing MSN-S-Au nanoparticles:
dispersing 1-10mg of MSN-SH nanoparticles prepared in step 2) in 1-10mL of Phosphate Buffered Saline (PBS) with pH7.4, and stirring 5-25mL of 0.5-2.5 × 10-4M chloroauric acid and 5-25mL of 0.5-2.5X 10-4Slowly dripping the mixed solution of the sodium citrate M into the MSN-SH suspension, slowly stirring for 4-5 hours, then quickly adding 0.2-4mL of 0.05-0.15M sodium borohydride solution into the mixed solution, stirring for 2-5 hours until the mixture turns into mauve, centrifuging to remove supernatant, and washing for 2-4 times by PBS to obtain MSN-S-Au nanoparticles;
4) preparation of Janus nanoparticles:
mixing phenyltriethoxysilane, N-trimethoxysilylpropyl-N, N, N-trimethyl ammonium chloride and the MSN-S-Au nano-particles prepared in the step 3) according to the mass ratio of 1: 1-2: 2-4, stirring for 10-15 hours at 60-90 ℃, and then mixing the dispersion with 1-4M acetic acid and ethanol in a volume ratio of 7: 3, dialyzing the mixture;
5) preparation of Janus nanoparticle drug delivery system:
firstly, 10-50mg of 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline is dissolved in 5-10mL of distilled water, then 40-200mg of Janus nanoparticles soaked in 5-10mM of glutathione for 9-18 hours at normal temperature are added into a 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline solution, after 1-2 hours of ultrasonic treatment, 2-8mL of PBS with pH7.4 is dripped into the solution and is kept still for 9-18 hours, finally, the supernatant is centrifuged off and washed for 2-4 times by PBS with pH7.4 to obtain the Janus nanoparticles containing the 4- (3-chloroaniline) -6, 7-dimethoxyquinazoline.
2. An optically-driven Janus nanoparticle drug delivery system for optic nerve recovery prepared according to the preparation method of claim 1.
3. Use of the Janus nanoparticle drug delivery system of claim 2, wherein 1-10 μ L of a drug delivery system containing 4- (3-chloroanilino) -6, 7-dimethoxyquinazoline at 10-100mg/mL is administered intravitreally in a rat optic nerve crush injury model using a microinjector and 4-30mW μm-2The near infrared light of power irradiates the fundus through the pupil, and the drug-carrying system can be diffused to the retina inner limiting membrane focal zone and plays a role, and is used for treating acute central nervous system injury, degenerative diseases and the like.
4. The use according to claim 3, wherein the near-infrared light has a wavelength of 800-1100nm, a power of 4-30mW, and an irradiation time of 50-180 s.
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