CN113144216A - ICG-MSNs nano material and preparation method and application thereof - Google Patents
ICG-MSNs nano material and preparation method and application thereof Download PDFInfo
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- CN113144216A CN113144216A CN202110305580.5A CN202110305580A CN113144216A CN 113144216 A CN113144216 A CN 113144216A CN 202110305580 A CN202110305580 A CN 202110305580A CN 113144216 A CN113144216 A CN 113144216A
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- 239000002086 nanomaterial Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 33
- 201000007270 liver cancer Diseases 0.000 claims abstract description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 21
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- 239000000377 silicon dioxide Substances 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
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- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- 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
- A61K47/54—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 the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses an ICG-MSNs nano material, a preparation method and application thereof, ICG-COOH and NH2-MSNs are covalently linked and ICG provides specific targeting and retention of liver cancer lesions and simultaneously exerts photothermal therapyThe silicon dioxide mesoporous nanospheres release the medicine slowly and control to realize integration of phototherapy and chemotherapy, different medicines are coated to prepare a medicine-carrying compound, and the two compounds are simultaneously used for combined treatment, so that a treatment means integrating diagnosis, treatment and chemotherapy and photothermal therapy is realized, and the treatment effect is enhanced.
Description
Technical Field
The invention relates to a liver targeting nano-drug sustained and controlled release ICG-MSNs nano-material with photo-thermal therapy-chemotherapy integration, a preparation method thereof and application thereof to a targeting liver cancer treatment drug, belonging to the technical field of targeting nano-drug-loaded materials.
Background
The incidence of liver cancer is 6 th and the fatality rate is 4 th in all tumors in the global scope, the prevalence situation is more serious in China, the incidence rate is 4 th and the lethality rate is 2 nd, and the liver cancer often has targeted drug resistance, so that the curative effect is not ideal, and a new drug for treating liver cancer is urgently needed to be developed, so that the survival rate of liver cancer patients is improved.
The nanometer material attracts more and more attention in the field of drug release, and the drug can be directionally released in tumor tissues by encapsulating the drug in a nanometer carrier and endowing the carrier with targeting property and stimulation responsiveness through modification. The inorganic material silicon dioxide mesoporous has unique advantages in structure and performance: the mesoporous silica has the characteristics of adjustable particle size, capability of controlling the particle size of the mesoporous silica within 50-300 nm, suitability for endocytosis of living cells, easy functionalized surface, good biocompatibility, low toxicity and the like.
Indocyanine Green (ICG) is approved by the FDA in the united states to be used as a clinical near-infrared contrast agent, and also belongs to a good photosensitizer, which can absorb light energy and convert it into heat energy or generate singlet oxygen to perform tumor killing action under irradiation of near-infrared light, and is also called as photothermal therapy (PTT).
When the liver is cancerated to cause damage to liver cells and capillary bile ducts, and the secretion and excretion functions of the liver cells and the capillary bile duct cells in the damaged liver tissues are disordered, the ICG is retained in the pathological change tissues, so that the ICG is accumulated in the liver cancer tissues, the liver cancer can be retained for 1-2 weeks, the fluorescence is delayed to disappear, the liver cancer pathological change tissues are specifically marked, the pathological change tissues and normal tissues form strong fluorescence contrast, and the position and the size of a liver focus are displayed in real time, so that the high clinical application value is embodied in liver tumor surgery.
Disclosure of Invention
According to the invention, indocyanine green (ICG) is used as a targeted guiding substance for liver cancer treatment by utilizing the characteristic of specific labeling of liver cancer by ICG, Mesoporous Silica (MSNs) is used as a carrier, insoluble anticancer drugs are included by utilizing the adsorption effect of silica, the indocyanine green and the Mesoporous Silica (MSNs) are connected through covalent bonds (ICG-MSNs), an ICG-MSNs nano particle delivery system is constructed, the indocyanine green is used as a liver cancer targeted drug loading system, different drugs can be loaded to form a drug loading compound, and multiple drugs are simultaneously administered for combined treatment, so that the treatment effect is enhanced.
The invention provides an ICG-MSNs nano particle, which is ICG-COOH and NH2the-MSNs are obtained by covalent bond connection, the ICG is a target liver pathological change part and is used as a photo-thermal therapy medicament, and the silicon dioxide mesoporous nanospheres play a role in sustained and controlled release of the medicament, so that the liver cancer part is specifically identified and is retained in the liver, and a phototherapy and chemotherapy integrated nanoparticle release system can be realized.
The invention also provides a preparation method of the ICG-MSNs nano material, which comprises the following specific steps:
(1) adding 1, 1, 2-trimethylbenzindole (1.0g, 4.8mmol) and ethyl iodide (1.1g, 7.2mmol) into acetonitrile (40mL), heating and refluxing at 85 ℃ for 24h, concentrating in vacuum until the solution is completely volatilized to obtain a residue, adding diethyl ether (80mL) into the residue, and repeatedly washing the obtained solid with diethyl ether to obtain a compound 1;
(2) to acetonitrile (MeCN) (240mL) in which 1, 1, 2-trimethylbenzindole (5.7g, 27.2mmol) is dissolved, 6-iodohexanoic acid (8.6g, 35.4mmol) is added, then the mixture is heated under reflux at 105 ℃ for 4 days, the reaction mixture is concentrated in vacuo, ether (500mL) is added to the residue, and the resulting solid is washed repeatedly with ether to give compound 2;
(3) adding the compound 1(8.0g, 22.0mmol) and glutarenal dianiline hydrochloride (6.3g, 22.0mmol) into acetic anhydride (160mL), heating the suspension at 100 ℃ for 1h, cooling, pouring the reaction mixture into water (900mL), and repeatedly washing the obtained solid with water to obtain dark red solid, namely the compound 3;
(4) adding compound 2(0.10g, 0.31mmol) and compound 3(0.15g, 0.31mmol) to pyridine (2mL), stirring at 40 deg.C for 30 min, removing the solvent at 55 deg.C in vacuo with a rotary evaporator, and purifying the residue by chromatography on silica gel, gradient eluting with chloroform-methanol (volume ratio 100: 1-10: 1) to give a dark green solid as ICG-COOH;
(5) ICG-COOH (68.75mg, 0.16mmol) and N, N-Carbonyldiimidazole (CDI) (79.92mg, 0.496mmol) were dissolved in 10mL of dimethylformamide, stirred for 1 hour to activate the carboxyl group of ICG-COOH, and then the activated solution was dropped into the aminated modified silica Nanoparticles (NH)2-MSNs) (27.33mg, 0.032mmol) and 4-dimethylaminopyridine DMAP (60mg, 0.496mmol) in 2mL dimethylformamide, stirring for 24 hours, centrifuging the reaction mixture at 15000rmp for washing, and lyophilizing to obtain ICG-MSNs nanoparticles.
The amination modified silicon dioxide nano particle MSNs-NH2The preparation method comprises the following steps: adding 1.0g of Mesoporous Silica Nanoparticles (MSNs) into 50mL of toluene, stirring to uniformly disperse the mesoporous silica nanoparticles, then dropwise adding 1.0mL of 3-Aminopropyltriethoxysilane (APTES), refluxing for 24 hours at 100 ℃, after the reaction is finished, respectively washing with ethanol and water for three times, centrifugally separating, and freeze-drying to obtain the aminated modified silica Nanoparticles (NH)2-MSNs); the Mesoporous Silica Nanoparticles (MSNs) may be commercially available or prepared according to the prior art.
The invention also provides application of the ICG-MSNs nano material in preparation of anti-liver cancer drugs, in particular application of the ICG-MSNs nano material as a drug active ingredient in preparation of targeted liver cancer treatment drugs, and simultaneously can be used as a drug delivery system to target drug delivery to liver cancer parts, namely ICG-MSNs are dissolved in absolute ethyl alcohol, stirred at room temperature in a dark place, centrifuged at high speed to remove most of ethanol in reaction liquid and dried to obtain an ICG-MSNs @ anti-cancer drug inclusion compound, and the anti-cancer drugs are targeted to liver cancer cells.
The ICG in the ICG-MSNs nano material can be specifically targeted to a liver cancer part and has a liver cancer retention effect, but has no targeting effect on a normal liver, only has targeting effect on the liver cancer, and the ICG targets a liver pathological change part and is used as a photo-thermal therapy medicament, so that phototherapy and chemotherapy integration can be realized.
Drawings
FIG. 1 is ICG-COOH1H-NMR spectrum;
FIG. 2 shows photothermal test of ICG-COOH (graphs a, b, c are the maximum temperature change after 5min of infrared irradiation with methanol, free ICG, ICG-COOH, respectively) (before left irradiation, after right irradiation);
FIG. 3 shows MSNs and MSNs-NH2Fourier transform-infrared spectrogram of (a);
FIG. 4 is a Fourier transform-infrared spectrum of MSNs, ICG-COOH, ICG-MSNs;
FIG. 5 is photothermal imaging of liver-retaining mice (fig. a, b, c are the highest temperature changes before, 5min, 10min irradiation of the molding nude mice, respectively);
FIG. 6 is a picture of a detained living body after intravenous injection of ICG-MSNs at a nude mouse end of a tumor transplanted in situ (pictures a, b and c respectively model fluorescence distribution of small animal living body images after 24h, 48h and 96h of intravenous injection of ICG-MSNs @ cy5.5 (left ICG and right cy5.5) at the nude mouse end);
FIG. 7 is a graph showing the distribution of each organ after 96h retention (FIGS. a and b are the distribution of ICG and cy5.5 fluorescence after tail vein injection of ICG-MSNs96h, respectively).
Detailed Description
The essential features and the remarkable advantages of the present invention will be further elucidated below by means of examples and figures, without the scope of protection of the invention being limited in any way to the examples. The raw materials used in the examples are commercially available, and unless otherwise specified, the methods of operation and the raw materials used are well known.
Example 1
The preparation method of ICG-COOH comprises the following specific steps:
adding 1, 1, 2-trimethylbenzindole (1.0g, 4.8mmol) and ethyl iodide (1.1g, 7.2mmol) into acetonitrile (40mL), heating and refluxing at 85 ℃ for 24h, concentrating in vacuum until the solution is completely volatilized to obtain a residue, adding diethyl ether (80mL) into the residue, and repeatedly washing the obtained solid to obtain a compound 1, wherein the reaction process is shown as the following I;
(2) to acetonitrile (MeCN) (240mL) in which 1, 1, 2-trimethylbenzindole (5.7g, 27.2mmol) was dissolved, 6-iodohexanoic acid (8.6g, 35.4mmol) was added, the mixture was heated at 105 ℃ under reflux for 4 days, the reaction mixture was concentrated in vacuo, ether (500mL) was added to the residue, and the resulting solid was washed with ether repeatedly to give Compound 2, the reaction course of which is shown in II below;
(3) compound 1(8.0g, 22.0mmol) and glutarenal dianiline hydrochloride (6.3g, 22.0mmol) were added to acetic anhydride (160mL), the suspension was heated at 100 ℃ for 1h, after cooling, the reaction mixture was poured into water (900mL), and the resulting solid was washed with water repeatedly to give a dark red solid, compound 3, the reaction course of which is shown in the following iii:
(4) adding compound 2(0.10g, 0.31mmol) and compound 3(0.15g, 0.31mmol) to pyridine (2mL), stirring at 40 deg.C for 30 minutes, removing the solvent at 55 deg.C under vacuum with a rotary evaporator, purifying the residue by silica gel chromatography, and gradient eluting with chloroform-methanol (volume ratio 100: 1, 90: 1, 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30: 1, 20: 1, 10: 1) to obtain dark green solid compound 4, i.e. ICG-COOH, the reaction process is as shown in IV below;
FIG. 1 is ICG-COOH1H-NMR spectrum according to FIG. 11As a result of H-NMR, it was found that,1h NMR (200MHz, CDCl3) d 1.4(t, J ═ 6.8Hz,3H), 1.5-2.0 (m,6H),1.9(s,12H),2.4(t, J ═ 6.6Hz,2H),4.2(m,4H),6.1(d, J ═ 13.4Hz, 1H), 6.3(d, J ═ 13.7Hz, 1H), 6.7(t, J ═ 12.7Hz, 2H), 7.3-8.2 (m, 15H), indicating successful synthesis of ICG-COOH.
In order to verify that the obtained ICG-COOH still has the same photosensitive effect as ICG, 1mL of methanol (1mL), 1mL of free ICG (40. mu.g/mL of methanol as a solvent), and 1mL of ICG-COOH (40. mu.g/mL of methanol as a solvent) were placed in a centrifuge tube, respectively, and a 808-nm laser irradiation tube (1.2W/cm)25min), and an infrared thermography image of the highest temperature obtained by a Fotric 225-1 infrared thermal imaging camera shows that fig. 2 is an infrared light irradiation temperature change diagram of ICG-COOH, wherein a, b and c are respectively the maximum temperature change (before left irradiation and after right irradiation) after the infrared light irradiation of methanol, free ICG and ICG-COOH is performed for 5min, and the maximum temperatures of the methanol, the free ICG and the ICG-COOH after the laser irradiation reach 28.4 ℃, 49.3 and 53.3 ℃ respectively, which is enough to prove the photothermal effect.
Example 2
NH2The preparation method of the-MSNs comprises the following specific steps:
(1) dissolving 2.0g of trimethylhexadecylammonium chloride (CTAC) in 20mL of deionized water, heating to 95 ℃, stirring and dissolving, then adding 50 mu L of Triethanolamine (TEA), continuously stirring for 1 hour, then dropwise adding 1.5mL of Tetraethoxysilane (TEOS), continuously reacting for 1 hour until white suspension is generated, centrifugally separating at 10000rpm to obtain precipitate, namely silicon dioxide nanoparticles, refluxing the precipitate in a mixed solution of hydrochloric acid/methanol (5mL of hydrochloric acid and 20mL of methanol) for 6 hours, centrifugally separating to obtain precipitate, repeating the refluxing operation for three times to remove a template agent CTAC, finally washing the obtained precipitate with ethanol and deionized water for three times respectively, centrifuging and freeze-drying to obtain mesoporous silicon dioxide nanoparticles (MSNs);
(2) adding 1.0g of MSNs into 50mL of toluene, stirring to uniformly disperse the MSNs, then dropwise adding 1.0mL of 3-Aminopropyltriethoxysilane (APTES), refluxing for 24 hours, washing with ethanol and water for three times after the reaction is finished, and performing centrifugal separation and freeze drying to obtain the aminated and modified silicon dioxide Nanoparticles (NH)2-MSNs)。
FIG. 3 shows MSNs and MSNs-NH2Fourier transform-infrared spectrogram of (a); as can be seen from the figure, MSNs-NH2Curve of (2) at 1673cm-1，1591cm-1A new absorption peak appears nearby, indicating-NH2The group is bonded to the mesopores.
Example 3
The ICG-MSNs are synthesized by carboxyl and NH of ICG-COOH2-amide reaction between amino groups of MSNs, the specific steps being as follows:
ICG-COOH (68.75mg, 0.16mmol) and CDI (79.92mg, 0.496mmol) were dissolved in 10mL of dimethylformamide, stirred for 1 hour to activate the carboxyl group of ICG-COOH, and then the activated ICG solution was added dropwise with NH2-MSNs (27.33mg, 0.032mmol) and DMAP (60mg, 0.496mmol) in 1.2mL dimethylformamide, after stirring for 24h, the reaction mixture was centrifuged at 15000rpm and lyophilized to give ICG-MSNs.
FIG. 4 is a Fourier transform-infrared spectrum of MSNs, ICG-COOH, ICG-MSNs; as can be seen from the figure, the curve of ICG-MSNs is 3260cm-1And 1671cm-1An absorption peak appeared nearby, indicating that ICG is bonded to NH2-on MSNs.
Example 4
Application test, experimental animals: 30 male nude mice, 6-8 weeks old, with weight (20 +/-2) g, purchased from the experimental animal center of Luoyu biology corporation, were bred in the SPF level of the experimental animal house of Kunming university, and the animals took food water freely at room temperature (22 +/-2) DEG C and 50% relative humidity, and the experiment was started after two weeks, and the specific steps were as follows:
(1) culturing mouse-derived H22 liver cancer cells: placing mouse H22 liver adenocarcinoma cells in 1640 culture medium containing 10% fetal calf serum and 1% penicillin-streptomycin, placing at 37 deg.C and 5% CO2Culturing in incubator, changing culture solution 1 time every 1 day, digesting and passaging with 0.25% pancreatin once every 2 days, collecting cells when cell confluence rate reaches 90%, centrifuging to remove supernatant, adding normal saline, blowing, suspending cells in normal saline, dyeing trypan blue (mixing cell suspension and trypan blue solution with mass fraction of 0.4% at a volume ratio of 9:1, mixing and dyeing), measuring cell activity more than 95%, counting cells, adjusting cell concentration to 2 × 105a/mL cell suspension is ready for use;
(2) the in-situ transplantation liver cancer mouse modeling method comprises the following steps: aseptically extracting ascites of mice inoculated with H22 hepatoma cell strain, adding PBS, mixing, centrifuging at 1000rpm/min for 5min, discarding supernatant, repeatedly washing with PBS, centrifuging for 2 times, resuspending cells with aseptic normal saline, counting cells under microscope, detecting cell survival rate > 95% by trypan blue staining method, and adjusting cell concentration to 1.2 × 107Placing on ice for use, anesthetizing by intraperitoneal injection of 5% chloral hydrate (0.6mL/100g) mice, taking supine position, fixing on the experimental plate, sterilizing skin with iodophor, making incisions longitudinally along abdominal midline under xiphoid process, cutting skin and peritoneum layer by layer, fully exposing left lobe of liver, and extracting 50 μ L H22 cell suspension (containing cell number 6 × 10) with 50 μ L microinjector6Respectively), puncturing the liver at an angle of 20 degrees by about 0.5cm, slowly injecting the cell suspension, staying for a moment, pulling out the needle after injection, immediately and lightly pressing the needle hole with sterile gauze until the surface of the liver does not seep blood, closing the abdomen layer by layer, continuously feeding after the operation, and freely taking food and intaking water.
In order to verify the photothermal effect of ICG-MSNs in liver cancer mice, ICG-MSNs (1.5mg/kg, solvent is physiological saline) are injected to the original displacement through tail veinIn the nude mice, after intravenous injection for 96h, the liver of the mice was irradiated with 808 nm laser (1W/cm)25min), obtaining an infrared thermal imaging image of the highest temperature by a Fotric 225-1 infrared thermal imaging camera, and as shown in figure 5, obtaining an infrared light irradiation imaging image of the liver of a liver retention mouse, wherein a, b and c in the image are respectively the highest temperature change of a molding nude mouse before irradiation, 5min of irradiation and 10min of irradiation, and the infrared thermal image shows that the highest temperature of the liver of the molding nude mouse reaches 50 ℃ and 68.6 ℃ respectively after 5min of laser irradiation and 10min of irradiation, which is enough to prove the photothermal effect.
In order to verify the retention effect of ICG-MSNs in liver cancer mice, ICG-MSNs @ cy5.5(1.5mg/kg) is dissolved in physiological saline and then is injected into in-situ transplantation molding nude mice by 0.1mL through tail vein, and the preparation method of ICG-MSNs @ cy5.5 is as follows: accurately weighing 10mg of ICG-MSNs and dissolving in 2mL of dimethylformamide, accurately weighing 2mg of cyanine dye 5.5(cy5.5) and adding into the solution for overnight stirring for 24h, centrifuging the obtained solution at 15000rpm for 10min at a high speed, and repeatedly washing with methanol for three times to obtain ICG-MSNs @ cy 5.5; the ICG fluorescence distribution in the body of the mouse is analyzed by a fluorescence imaging and photoacoustic imaging system at 6h, 24h and 96h after intravenous injection, when the mouse is sacrificed at 96h after administration, the fluorescence in each organ and tumor is evaluated by a living body imaging system, as shown in figure 6, the residence living body pictures after the in-situ transplantation of tumor ICG-MSNs at the tail of the mouse are shown, in the pictures, a, b and c respectively model the ICG-MSNs at the tail of the mouse are injected at the tail of the mouse at the tail of 5.524h, 48h and 96h, the ICG and the cy5.5 fluorescence distribution after the 96h of the living body of the mouse are imaged (left ICG, cy5.5), and the results show that the ICG-MSNs are always specifically retained in the liver, and the specific targeting effect and the slow and controlled release in the liver can be achieved.
In order to verify the retention condition of ICG-MSNs @ cy5.5 in the organs of a liver cancer mouse, ICG-MSNs @ cy 5(1.5 mg/mL, solvent is physiological saline) is injected into a liver cancer nude mouse intravenously for 3 days, then the organs are taken, the fluorescence distribution of ICG and cy5.5 in the heart, liver, spleen, lung and kidney is observed, fig. 7 is a picture of the distribution of the organs after 96h retention, wherein a is the ICG-MSNs @ cy5 injected into the tail vein, the ICG fluorescence distribution after 96h is observed, and b is the cy5.5 fluorescence distribution after 96h is injected into the tail vein, and the results are observed, the retention conditions of the fluorescence of the heart, liver, spleen, lung, kidney ICG and cy5.5 in the model mouse are all in the liver, which shows that the ICG-MSNs are specific and control the retention and release of the drugs in the liver cancer mouse.
The invention dissolves ICG-MSNs in absolute ethyl alcohol, is stirred at room temperature in a dark place, is centrifuged at high speed to remove most of ethyl alcohol in reaction liquid, is dried to obtain the ICG-MSNs @ anticancer drug inclusion compound, and is used for targeting delivering the anticancer drugs to liver cancer cells.
Claims (7)
1. An ICG-MSNs nano material is characterized in that the nano material is ICG-COOH and NH2-MSNs are obtained by covalent bonding.
2. The preparation method of the ICG-MSNs nano-materials in the claim 1 is characterized by comprising the following specific steps:
(1) adding 1.0g of 1, 1, 2-trimethylbenzindole and 1.1g of ethyl iodide into 40mL of acetonitrile, heating and refluxing at 85 ℃ for 24h, concentrating in vacuum, adding 80mL of diethyl ether into the residue, and repeatedly washing the obtained solid with diethyl ether to obtain a compound 1;
(2) adding 8.6g of 6-iodohexanoic acid to 240mL of acetonitrile in which 5.7g of 1, 1, 2-trimethylbenzindole was dissolved, heating and refluxing the mixture at 105 ℃ for 4 days, concentrating under vacuum, adding 500mL of diethyl ether to the residue, and repeatedly washing the obtained solid with diethyl ether to obtain Compound 2;
(3) adding 8.0g of the compound 1 and 6.3g of glutarenal anilide hydrochloride into 160mL of acetic anhydride, heating the suspension at 100 ℃ for 1h, cooling, pouring the reaction mixture into water, and repeatedly washing the obtained solid with water to obtain a dark red solid, namely the compound 3;
(4) adding 0.10g of compound 2 and 0.15g of compound 3 to 2mL of pyridine, stirring at 40 ℃ for 30 minutes, rotary evaporating at 55 ℃, purifying the residue by silica gel chromatography, and performing chloroform-methanol gradient elution to obtain a dark green solid ICG-COOH;
(5) 68.75mg of ICG-COOH and 79.92mg of N, N-Carbonyldiimidazole (CDI) were dissolved in 10mL of Dimethylformamide (DMF), and stirred for 1 hour, the mixture was dropped into 2mL of dimethylformamide to which 27.33mg of amino-modified silica nanoparticles and 60mg of 4-Dimethylaminopyridine (DMAP) were added, and after stirring for 24 hours, the reaction was centrifuged, washed, and lyophilized to obtain ICG-MSNs nanoparticles.
3. The method for preparing ICG-MSNs nanomaterials of claim 2 wherein the amino-modified silica nanoparticles are prepared by the following steps: adding 1.0g of mesoporous silica nanoparticles into 50mL of toluene, stirring to uniformly disperse the mesoporous silica nanoparticles, then dropwise adding 1.0mL of 3-aminopropyltriethoxysilane, refluxing for 24 hours at 100 ℃, washing with ethanol and water for three times after the reaction is finished, and performing centrifugal separation and freeze drying to obtain the aminated modified silica nanoparticles.
4. The method of claim 3, wherein the mesoporous silica nanoparticles are commercially available or prepared according to the prior art.
5. The method for preparing ICG-MSNs nano-materials according to claim 2, wherein the gradient of chloroform-methanol gradient elution is 100: 1 to 10: 1 by volume.
6. The use of ICG-MSNs nanomaterials of claim 1 in the preparation of anti-liver cancer drugs.
7. The application of the ICG-MSNs nano-material in preparing anti-liver cancer drugs according to claim 6, in particular to the application of the ICG-MSNs nano-material in preparing targeted liver cancer treatment drugs as a drug active ingredient, and the ICG-MSNs nano-material is used as a drug delivery system to specifically target and deliver the drugs to liver cancer parts.
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