CN113384697A - Multifunctional nano particle for tumor diagnosis and treatment integration, preparation and application - Google Patents
Multifunctional nano particle for tumor diagnosis and treatment integration, preparation and application Download PDFInfo
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- CN113384697A CN113384697A CN202110643807.7A CN202110643807A CN113384697A CN 113384697 A CN113384697 A CN 113384697A CN 202110643807 A CN202110643807 A CN 202110643807A CN 113384697 A CN113384697 A CN 113384697A
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Abstract
The invention discloses a tumor diagnosis and treatment integrated multifunctional nano particle and preparation and application thereof; the nanoparticles are composed of a drug transport carrier and a photoactivated drug; the nano particles have a cavity mesoporous structure and can carry a medicament into a body; the nano-carrier as a light converter can convert externally applied near infrared light into visible light. The multifunctional nano system is used for carrying and transporting the medicine to a tumor part through intravenous injection and accumulating, and near infrared light is converted into blue light in situ of the tumor, so that the light-activated medicine is stimulated to react with surrounding water to release active oxygen, and finally tumor cell apoptosis is caused. In addition, the gadolinium ion-doped nano-particles can be used as a magnetic resonance imaging agent for tumor imaging and real-time monitoring of the treatment process, and are helpful for realizing efficient treatment and early diagnosis of tumors, so that a new method is provided for detailed research of efficient nano-agents for cancer diagnosis and treatment.
Description
Technical Field
The invention belongs to the technical field of molecular imaging, and relates to a tumor diagnosis and treatment integrated multifunctional nanoparticle, and preparation and application thereof.
Background
Cancer is a leading cause of death worldwide, with the increase in life expectancy, the aging population, the rapid increase in new cases of cancer and the number of deaths, and the continuing increase in cancer burden worldwide, placing a tremendous physical, emotional, and economic burden on individuals, homes, communities, and health systems. Wherein, the incidence rate of breast cancer is the first of female malignant tumors, in 2020, the number of new breast cancer cases is about 226.1 ten thousand worldwide, which accounts for 24.5% of all female cases; 68.5 ten thousand death cases account for 15.5 percent of all female cases
The traditional tumor treatment methods, such as operations, chemotherapy, radiotherapy and the like, are often accompanied by the defects of fatal side effects, multidrug resistance, low treatment efficiency and the like. The development of nanoscience and nanotechnology has enriched anti-tumor treatment strategies. Among the various novel therapeutic strategies, Photodynamic therapy (PDT) has attracted considerable attention as a topical treatment. PDT is a new tumor therapy besides the traditional tumor therapy, has the advantages of strong selectivity, small wound, good curative effect, less adverse reaction, repeated treatment and the like, and is approved by food and drug administration in China and America as a treatment means for clinically treating malignant tumors. PDT activates photosensitizers by light of the appropriate wavelength to initiate a specific photochemical reaction that produces cytotoxic reactive oxygen species that can cause necrosis, apoptosis and/or autophagy in tumor cells. However, the use of photodynamic therapy in hypoxic environments and deep tumors is greatly limited due to its oxygen dependence and insufficient tissue penetration depth at the excitation wavelength. There is an urgent need to develop oxygen-independent Photoactivated chemotherapy (PACT) to generate active oxygen with cytotoxicity by near infrared light excitation.
In contrast to PDT, PACT utilizes a prodrug with a photocleavable protecting group that is activated by light-triggered deprotection to release the cytotoxic substance. Among various PACT reagents, small organic molecules have attracted much attention because of their easy chemical modification. (-) -Blebbistatin is a highly selective and reversible non-muscle myosin II ATPase inhibitor that activates rapidly under blue light (λ ex: 450-. Blebbistatin is oxygen-independent, but undergoes water-dependent protonation and excited state intramolecular proton transfer, triggering a local burst of hydroxyl radicals (. OH) under blue light irradiation, leading to cancer cell death through activated cysteine protease-associated apoptotic pathways. However, blue light has limited tissue penetration depth and skin phototoxicity, which presents a serious challenge for its clinical application in deep tissues. Therefore, the development of a multifunctional nano system based on the effective transportation and the on-demand generation of OH of the Blebbistatin under the irradiation of near infrared light has important clinical requirements and values.
Disclosure of Invention
The invention aims to design an oxygen-independent multifunctional nanoparticle for tumor diagnosis and treatment based on near infrared light triggering hydroxyl free radical generation and preparation and application thereof, aiming at the defects of the existing free radical therapy. Mesoporous silica is coated outside the gadolinium-doped up-conversion nano material, and a photoactivation drug Blebbistatin is loaded in the mesopores to carry the drug into the body, so that the oxygen-independent OH positioning release and the MR imaging of the tumor in the body of a mouse are realized. The UCSNs nano-molecule loaded with the photoactivation drug Blebbistatin designed by the invention can effectively treat tumors and accurately display focus.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, the invention provides a multifunctional nanoparticle integrated for tumor diagnosis and treatment, wherein the nanoparticle comprises drug transport carriers UCSNs and a light-activated drug Blebbistatin. The nanoparticles are capable of carrying a drug into the body; the nano-carrier can be used as a light converter to convert externally applied near infrared light into visible light.
As one embodiment of the invention, the nano-particles are mesoporous silica coated outside the gadolinium-doped upconversion nano-particles, and a photoactivation drug is loaded in the mesopores.
As one embodiment of the present invention, the loading of the photo-active drug in the nanoparticles is 10-15%.
As an embodiment of the invention, the upconversion nanoparticle is NaYF4:Yb/Tm@NaGdF4(ii) a The photoactivated drug is Blebbistatin.
As an embodiment of the present invention, the nanoparticles contain the rare earth elements Yb and Tm. Has the performance of up-conversion emission of blue light. In the nano particle, Y is Yb, Tm is Gd which is 1.5-1.7, 0.35-0.4, 0.01-0.03 and 1. As a specific example, Y: Yb: Tm: Gd: 1.6:0.38:0.02:1 in the nanoparticle.
As one embodiment of the present invention, the nanoparticle has a hollow mesoporous structure. Can be used as a carrier for drug delivery.
As an embodiment of the invention, the nanoparticle comprises a paramagnetic gadolinium ion. Is provided with T1Magnetic resonance imaging performance.
As an embodiment of the present invention, the nanoparticles do not rely on oxygen in the ambient environment to generate reactive oxygen species.
As an embodiment of the present invention, the nanoparticles controllably generate hydroxyl radicals at fixed points.
In a second aspect, the invention provides a method for preparing multifunctional nanoparticles for tumor diagnosis and treatment integration, which comprises the following steps:
s1, preparing NaYF by high-temperature thermal decomposition method4A Yb/Tm core;
s2, preparing NaYF by epitaxial growth method4:Yb/Tm@NaGdF4I.e., UCNPs;
s3, coating Mesoporous silicon dioxide outside UCNPs to prepare UCNPs @ Mesoporous Silica (SiO2) nanoparticules, namely UCSNs;
s4, preparation of UCSNs @ Blebbistatin: dissolving Blebbistatin in solvent, adding UCSNs, and stirring in dark environment for 20-28 hr; centrifuging to obtain the product.
In step S1, the shape of the inner core is approximately spherical, the uniformity is good, and the particle size distribution is uniform and is about 15 +/-2 nm.
In step S2, the UCNPs are approximately spherical in morphology, good in uniformity, and uniform in particle size distribution, which is about 20 ± 2 nm.
In step S4, the solvent is dimethyl sulfoxide.
As an embodiment of the present invention, step S1 specifically includes: adding yttrium chloride, ytterbium chloride and thulium chloride into oleic acid and octadecene; slowly heating the obtained mixed solution to 150 +/-5 ℃, and keeping for 0.8-1.5 hours to remove water; then stopping heating and cooling to room temperature, adding a methanol solution containing sodium hydroxide and ammonium fluoride, and stirring at room temperature for 30-40 minutes; heating to 100 +/-5 ℃ and continuously stirring for 0.8-1.5 hours, after no obvious bubbles are generated, condensing and vacuumizing to remove redundant methanol; then introducing argon gas and heating to 300 +/-10 ℃ and keeping for 1-2 hours; naturally cooling to room temperature, adding absolute ethyl alcohol, centrifugally collecting precipitate, re-dispersing the product in cyclohexane, precipitating with ethyl alcohol, centrifugally collecting; after multiple ethanol washes, the final product was dispersed in cyclohexane to obtain the core solution.
Wherein, the mol ratio of yttrium chloride, ytterbium chloride, thulium chloride, sodium hydroxide and ammonium fluoride is 1.5-1.7:0.35-0.4:0.01-0.03: 4.5-5.5: 8. as a specific example, the molar ratio of yttrium chloride, ytterbium chloride, thulium chloride, sodium hydroxide, and ammonium fluoride is 1.6:0.38:0.02: 5: 8.
as an embodiment of the present invention, step S2 specifically includes: adding gadolinium chloride into oleic acid and octadecene, stirring well, and heating to 150 + -5 deg.C for 0.8-1.5 hr; stopping heating, cooling to room temperature, dropwise adding the prepared core solution, mixing, heating to 80 + -2 deg.C, and maintaining for 15-25 min to evaporate the rest cyclohexane; cooling to room temperature, and slowly adding a methanol solution containing sodium hydroxide and ammonium fluoride; stirring for 30-40 min at room temperature, heating to 100 + -2 deg.C, stirring for 0.8-1.5 hr, and condensing and vacuumizing to remove excessive methanol; introducing argon into the reaction system, slowly heating to 300 +/-10 ℃ and keeping for 1-2 hours; gradually cooling the reaction solution to room temperature, adding absolute ethyl alcohol, centrifuging, collecting precipitate, re-dispersing the product in cyclohexane, precipitating with ethyl alcohol, centrifuging, and collecting; after three repeated washes with absolute ethanol, the final product was dispersed in cyclohexane to obtain a clear solution, i.e., a cyclohexane solution of UCNPs.
Wherein the mol ratio of gadolinium chloride, sodium hydroxide and ammonium fluoride is 1: 2-3: 3.5-4.5; the molar ratio of the gadolinium chloride to the inner core solution is 1: 1.8-2.2; the mass percentage concentration of UCNPs in the cyclohexane solution of UCNPs is 2.0-0.8%. As a specific example, the molar ratio of gadolinium chloride, sodium hydroxide and ammonium fluoride is 1: 2.5: 4; the molar ratio of the gadolinium chloride to the inner core solution is 1: 2; the mass percentage concentration of UCNPs in the cyclohexane solution of UCNPs was 2.5%.
As an embodiment of the present invention, step S3 includes:
s3-1, dissolving polyoxyethylene (5) nonyl phenyl ether in cyclohexane, stirring uniformly, then dropwise adding a cyclohexane solution of UCNPs, and mixing and reacting for 2.5-3.5 hours; then dropwise adding ammonia water, and sealing and stirring; injecting a cyclohexane solution of tetraethyl orthosilicate into a reaction system at a speed of 100 microliter per hour, and then sealing and stirring for 22-26 hours; adding methanol to terminate the reaction, centrifuging, washing, collecting, and finally dispersing in deionized water to obtain a solution I;
s3-2, dissolving hexadecyl trimethyl ammonium chloride and triethylamine in deionized water, and stirring for 1.2-1.8 hours at room temperature; dropwise adding the solution I, and continuously stirring for 1.2-1.8 hours; transferring to a water bath kettle at 70 +/-2 ℃ for preheating, dropwise adding tetraethyl orthosilicate, and continuously stirring for 0.8-1.2 hours; naturally cooling to room temperature, centrifuging, washing and collecting; dissolving the centrifugal product in a methanol solution of sodium chloride, stirring for 4-7 hours, centrifuging, washing, collecting, and dispersing the product in deionized water again to obtain a solution II;
s3-3, mixing polyvinylpyrrolidone, deionized water and the solution II at room temperature, stirring at a constant speed for 0.4-1.6 hours, heating to 95 +/-5 ℃, and keeping reacting for 3-5 hours; and naturally cooling to room temperature, centrifuging, washing, collecting, and finally dispersing the product into deionized water to obtain the UCSNs.
In step S3-1, the volume ratio of polyoxyethylene (5) nonylphenyl ether to a cyclohexane solution of UCNPs and tetraethyl orthosilicate is 1: 0.8-2.2: 0.1-0.3. As a specific example, the volume ratio of polyoxyethylene (5) nonylphenyl ether to a cyclohexane solution of UCNPs, tetraethylorthosilicate, is 1: 2: 0.2.
in step S3-2, the mass ratio of the hexadecyl trimethyl ammonium chloride to the triethylamine to the solution (i) to the tetraethyl orthosilicate is 95-105: 1: 1.8-2.2: 9-11. As a specific example, the mass ratio of cetyltrimethylammonium chloride, triethylamine, solution (r) and tetraethylorthosilicate is 100: 1: 2: 10.
in step S3-3, the volume ratio of polyvinylpyrrolidone to solution (II) is 0.1-0.3: 1; in step S4, the mass ratio of Bleb statin to UCSNs is 1: 3-5. As a specific example, the volume ratio of polyvinylpyrrolidone to solution (c) is 0.2: 1; in step S4, the mass ratio of Blebbistatin to UCSNs is 1: 4.
in a third aspect, the invention provides an application of the multifunctional nanoparticle for tumor diagnosis and treatment integration in preparation of a diagnosis and treatment integration preparation for tumors.
The invention prepares the multifunctional nano-system UCSNs with good uniformity, uniform particle size distribution, high stability and hollow cavity and mesoporous structureThe loaded prodrug Blebbistatin is combined with the up-conversion material and the photoactivation drug Blebbistatin for the first time, so that the tumor image-mediated efficient oxygen-independent release free radical treatment of the tumor is realized. The first combination refers to the combination of the performances of the two, and the up-conversion material is used as a light converter, which can effectively convert the low-energy and strong-penetrability near infrared light into high-energy and weak-penetrability blue light, and then excite the Blebbistatin to release OH. Specifically, UCNPs are polymers containing an inner core NaYF having the ability to convert near infrared light to blue light4Yb/Tm and having T1NaGdF for imaging performance4A shell layer; the UCSNs coat the mesoporous silicon dioxide outside the UCNPs, so that the water solubility of the UCSNs is improved, and the UCSNs have the performance of carrying drugs. The invention mainly utilizes blue light emitted by up-conversion particles to activate the photoactivation drug Blebbistatin to release ROS. The doped ions have an important role in up-conversion luminescence, rare earth Yb3+The wavelength of the exciting light is 980nm, and the exciting light can be used as an up-conversion sensitizer to improve the up-conversion efficiency; rare earth Tm2+It is able to convert the emitted blue-violet light.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention is a multifunctional nanoparticle integrated with tumor diagnosis and treatment, which consists of transport carriers UCSNs and a photoactivation drug Blebbistatin; the core part of the transport carrier is UCNP (upconverting material), and NaGdF is doped into the UCNP4Constructing inorganic gadolinium-based nanoprobe to realize T of tumor1MR imaging, further enabling the integration of the diagnosis and treatment of tumors.
2. Aiming at the tumor diagnosis and treatment integrated multifunctional nano particles, the carrier containing rare earth ions can be used as a light converter to convert near infrared light with low energy and strong penetrability into blue light with high energy and weak penetrability, so that the medicament Blebbistatin can be effectively photolyzed, OH can be controllably generated, and the limitation of the penetration depth of visible light tissues in the traditional PDT is broken through.
3. Aiming at the tumor diagnosis and treatment integrated multifunctional nano particles, the loaded prodrug Blebbistatin is selected, which does not depend on oxygen and can perform photochemical reaction with water to release active oxygen under the condition of blue light activation, so that the effective combination of PDT and light-activated chemotherapy is realized, the treatment effect is improved, and the defect of oxygen dependence of traditional PDT and the side effect of conventional chemotherapy are avoided.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is a schematic diagram of the synthesis and functional principle of UCSNs-B, wherein (A) is a schematic diagram of the synthesis of UCSNs-B; (B) schematic diagram of the generation of hydroxyl radical by UCSNs-B reaction;
FIG. 2 is a representation of a multifunctional nanoparticle, wherein: (A) transmission electron microscopy images of UCSNs; (B) hydrodynamic diameter of UCSN s-B dispersed in water, phosphate buffer solution and high sugar medium; (C)980nm laser (1W/cm)2) Irradiating NaYF4:Tm/Yb、NaYF4:Tm/Yb@NaGdF4And emission spectra of UCSNs; (D) 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) is used as a free radical trapping agent, and 980nm laser irradiation (1W/cm)210min) ESR spectra of UCSNs, Blebbistatin and UCSNs-B;
FIG. 3 is a graph of the magnetic susceptibility characterization of UCSNs-B, wherein: (A) UCSNs-B T containing different gadolinium ion concentrations1Weighting the MR image; (B) t is1A relaxation rate map;
FIG. 4 is a laser confocal image of tumor endocytosed Fluorescein Isothiocyanate (FITC) -labeled UCSN s-B (UCSNs-B-FITC) nanoparticles for establishing an in vitro cell model;
FIG. 5 is a schematic diagram showing the results of establishing an in vitro cell model and analyzing the ROS generated in the cells after different treatments of tumor cells;
FIG. 6 is a schematic diagram of the results of in vitro cell modeling and analysis of the effect of UCSNs-B on tumor cell survival, wherein: (A) cytotoxicity to tumor cells after 24/48 hours incubation of UCSNs; (B) cytotoxicity to tumor cells after 24/48 hours incubation with UCSNs-B; (C) UCSNs-B incubation with or without 980nm laser excitation (1W/cm) after 24 hours 210 minutes) cytotoxicity to tumor cells; (D) treating the tumor cells with different treatmentsToxicity comparison of (1);
FIG. 7 is a diagram of the results of flow cytometry analysis for establishing an in vitro cell model and analyzing the cell viability of tumor cells after different treatments;
FIG. 8 is a graph of the establishment of a tumor animal model for assessing the anti-tumor capacity of UCSNs-B, wherein: (A) tumor volume growth curves after treatment of different groups of tumor models; (B) tumor growth inhibition rates for each group of tumor models;
FIG. 9 shows H & E, TUNEL and Ki-67 staining images of various groups of tumor tissues after treatment in the establishment of tumor animal models;
FIG. 10 is a graphical representation of the toxicity studies H & E staining of each major organ in groups of tumor-bearing mice after treatment;
FIG. 11 shows the establishment of tumor animal models, mice T before and after tail vein injection of UCSNs-B1The MR images are weighted.
Detailed Description
The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be apparent to those skilled in the art that several modifications and improvements can be made without departing from the inventive concept. All falling within the scope of the present invention.
Example 1 preparation and characterization of multifunctional nanoparticles
The synthetic schematic diagram and the action principle of the multifunctional nanoparticle UCSNs-B are shown in figure 1, and the specific steps are as follows:
NaYF4preparation of the Yb (19%)/Tm (1%) core: yttrium chloride (485.38 mg), ytterbium chloride (147.25 mg), and thulium chloride (7.67 mg) were added to oleic acid (12 ml) and octadecene (30 ml). The resulting mixed solution was slowly heated to 150 ℃ and held for 1 hour to remove water. After the heating was then stopped and cooled to room temperature, 10 ml of a methanol solution containing sodium hydroxide (200 mg) and ammonium fluoride (296.3 mg) was added and stirred at room temperature for 35 minutes. Then, heating to 100 deg.C and stirring for 1 hr, vacuumizing 20 with condenser tube after no obvious bubble is generatedFor a minute to remove excess methanol. Followed by heating to 300 ℃ while passing argon and holding for 1.5 hours. Naturally cooling to room temperature, adding 20 ml of absolute ethyl alcohol, centrifuging to collect precipitate (11000r/min, 10min), re-dispersing the product in 5 ml of cyclohexane, precipitating with 20 ml of ethyl alcohol, centrifuging and collecting. After multiple ethanol washes, the final product was dispersed in 20 ml cyclohexane for further use;
NaYF4:Yb(19％)/Tm(1％)@NaGdF4(abbreviated as UCNPs) preparation: gadolinium chloride (371.7 mg) was added to 12 ml of oleic acid and 30 ml of octadecene, stirred well and heated to 150 ℃ for 1 hour. Stopping heating and cooling to room temperature, dropwise adding the prepared inner core solution, mixing uniformly and heating to 80 ℃, and maintaining for 20 minutes to evaporate the remaining cyclohexane. After cooling to room temperature, 10 ml of a methanolic solution of sodium hydroxide (100 mg) and ammonium fluoride (148.14 mg) were slowly added. After stirring at room temperature for 35 minutes, heat to 100 ℃ and continue stirring for 1 hour, followed by a 20 minute vacuum in a condenser tube to remove excess methanol. Argon gas was introduced into the reaction system, and the temperature was slowly raised to 300 ℃ and maintained for 1.5 hours. The reaction solution was gradually cooled to room temperature, 20 ml of absolute ethanol was added, the precipitate was collected by centrifugation (11000r/min, 10min), the product was redispersed in 5 ml of cyclohexane, precipitated with 20 ml of ethanol, and collected by centrifugation. After repeating the washing with absolute ethanol for three times, dispersing the final product in 20 ml of cyclohexane to obtain a clear solution;
UCNP@hmSiO2preparation of nanoparticles (UCSN): 1 ml of polyoxyethylenenonyl phenyl ether (5) was dissolved in 20 ml of cyclohexane, stirred for 1 hour, and then 2ml of a cyclohexane solution of UCNPs was slowly added thereto, followed by mixing and reacting for 3 hours. Then 0.14 ml of ammonia (30%) was slowly added dropwise, and stirred under sealed conditions for 2 hours. 200. mu.l of tetraethyl orthosilicate was dissolved in 1.8 ml of cyclohexane, and after 100. mu.l per hour of the solution was injected into the reaction system, the reaction system was stirred for 24 hours under sealed conditions. The reaction was then quenched by addition of methanol and the product was collected by centrifugation and washed 3 times with absolute ethanol to remove excess polyoxyethylene (5) nonylphenyl ether. The final product was dispersed in 10 ml of deionized water to give solution 1.2 g of tenHexaalkyltrimethylammonium chloride and 0.02 g of triethylamine were dissolved in deionized water and stirred at room temperature for 1.5 hours. The solution 1 prepared in the previous step was added dropwise and stirring was continued for 1.5 hours. The reaction system was transferred to a 70 ℃ water bath and preheated for 2 minutes, 200 microliters of tetraethyl orthosilicate was added dropwise to the solution, and stirring was continued for 1 hour. Naturally cooling to room temperature, and centrifugally collecting the reaction product (11000r/min, 10 min). Washed three times with absolute ethanol. And dissolving the centrifugal product in a methanol solution of sodium chloride with the mass fraction of 1 wt%, stirring for 6 hours, and centrifugally collecting precipitates. After three repeated washings, the centrifuged product was redispersed in 10 ml of deionized water to give solution 2. 0.25 g of polyvinylpyrrolidone, 10 ml of deionized water and the solution 2 were added to a round bottom flask, stirred at a constant speed for 0.5 hour at room temperature, and then heated to 95 ℃ and kept for reaction for 4 hours. After the heating is stopped, the solution is naturally cooled to the room temperature, and the product is collected by centrifugation. After ethanol cleaning for many times, finally dispersing the product into deionized water;
preparation of UCSNs @ Blebbistatin (UCSNs-B): 3 mg of Blebbistatin was dissolved in dimethyl sulfoxide, UCSNs were added, and the mixture was stirred in the dark for 24 hours. The product was centrifuged and washed three times with ethanol. The sample was redispersed in deionized water for further use.
Characterization of multifunctional nanoparticles: the morphology of nano-particle UCSNs is observed by adopting a transmission electron microscope, the particle size of UCSNs-B in different solvents is measured by adopting a particle size analyzer, the conversion luminescence condition of different nano-particles is analyzed by adopting an emission spectrometer, the capability of generating hydroxyl free radicals of different materials is measured by adopting an electron spin magnetic resonance spectroscopy, and the result is shown in figure 2, the particle size of the UCSNs is about 42nm, the UCSNs is regular spherical, the UCSNs is internally provided with a hollow structure, the particle size distribution is uniform, the hydrated particle size is about 122nm, the up-conversion luminescence can be realized under the excitation of 980nm laser, and the hydroxyl free radicals are released by reaction.
Example 2 magnetic susceptibility characterization of multifunctional nanoparticle UCSNs-B
Taking a proper amount of UCSNs-B solution samples, preparing solutions with different concentrations by using phosphate buffer solution, and obtaining gadolinium particlesThe concentrations are 0, 31, 62, 125, 250 and 500 mu mol/L in sequence, and the concentrations are respectively placed in a 2ml centrifugal tube. Then the clinical commonly used maduramicin (meglumine gadopentetate) is respectively prepared into solutions with corresponding gadolinium concentrations to be used as a control group. The tubes are placed on a plastic test tube rack in sequence. Phosphate buffer was used as a blank. T-test was performed using a clinical 3.0T MR System (discovery MR750, GE Medical System, USA) and small animal coil kit1And (5) Map sequence scanning to evaluate the imaging effect. The GE Function tool 4.6 special software is adopted to carry out T pair1And carrying out post-processing on the Map image.
Magnetic sensitivity As shown in FIG. 3A, T was gradually increased with gadolinium concentration as in the control group1The weighted MR imaging signals are gradually enhanced. Through measurement and calculation, T1The relaxation time is well linear with the contrast agent concentration. With different Gd in UCSNs-B solution3+And corresponding 1/T1For scatter plot, as shown in FIG. 3B, the fitted linear regression equation was that y is 1.58x +0.53 (R)2＝0.99，P<0.0001) of T1Relaxation Rate 1.58mM-1·s-1。
Example 3 qualitative analysis of phagocytic nanoparticles of UCSNs-B
MDA-MB-231 cells were seeded into 35mm confocal culture dishes (10 per dish)5Individual cells), incubated for 8 hours. After observing the cell adherence by a microscope, sequentially adding 1 ml of UCSNs-B culture solution marked by FITC probes for incubation for corresponding time according to set different time periods. Incubated material-containing medium was discarded and washed 3 times with PBS. DAPI stain (1mM) was added and incubated for 5 minutes. The phagocytosis of UCSNs-B (green fluorescence) by cells of different time groups is observed by a laser confocal microscope and photographed and recorded.
The MDA-MB-231 condition of endocytosing UCSNs-B nano particles is shown in figure 4, and it can be seen from a laser confocal image that the green fluorescence generated by UCSNs-B-FITC is gradually enhanced along with the extension of the incubation time, which indicates that the cell uptake of UCSNs-B is related to the incubation time, and proves that tumor cells have good phagocytosis on the UCSNs-B nano particles.
Example 4 intracellular GenerationQualitative study of ROS
MDA-MB-231 cells were seeded into confocal culture dishes and incubated for 8 hours. After adherence, incubation with the corresponding materials according to the groups Control, UCSNs, Blebbistatin, UCSNs-B, Control + NIR, UCSNs + NIR, Blebbistatin + NIR, UCSNs-B + NIR and UCSNs-B + NIR (hypoxic) for 24 hours, respectively, and for the NIR group after 24 hours of incubation with a 980nm laser (1W/cm)2) The irradiation was carried out for 10 minutes. After treatment, the cells were gently washed 3 times with PBS. After addition of the DCFH-DA (10. mu.M) probe, the incubation was carried out at 37 ℃ for 30 minutes in an incubator. DAPI stain (1mM) was added and incubated for 30 min. After the dye solution was poured off, the plate was washed 3 times with PBS. The ROS (green fluorescence) generation of the cells of different treatment groups was observed by a laser confocal microscope and recorded by photographing.
The intracellular OH production under various experimental conditions is shown in FIG. 5. After respectively incubating MDA-MB-231 cells with UCSNs-B, laser irradiation of 980nm is used for 10 minutes, obvious green fluorescence can be seen in the cells under both normal conditions and hypoxic conditions, and the result proves that the UCSNs-B can effectively generate OH independent of oxygen in tumor cells after being excited by near infrared light. In contrast, no significant green fluorescence signal was observed for the Control, UCSNs, Blebbistatin, UCSNs-B, Control + NIR, Blebbistatin + NIR, and UCSNs + NIR groups, indicating that intracellular OH levels were significantly increased after incubation with only UCSNs-B and irradiation with 980nm laser.
EXAMPLE 5UCSNs-B cytotoxicity assay
1) Quantitative analysis by a microplate reader:
MDA-MB-231 cells were plated at 10 per well4The density of individual cells was seeded in 96-well plates and incubated for 8 hours. After observing cell adherence by microscope, adding corresponding materials according to different groups respectively to incubate for corresponding time, and for group with NIR, using 980nm laser (1W/cm) after incubation of materials2) The irradiation was carried out for 10 minutes. The medium was discarded and a small amount of PBS was aspirated to wash off excess medium. Each well was filled with 100. mu.L of CCK-8 prepared in advance and stored in the dark. The 96-well plate was placed in an incubator and incubation continued for 30 minutes. The absorbance at 450nm of each treatment group of cells was measured using a microplate reader and the data was recordedAnd (5) line calculation and histogram drawing.
2) Flow cytometry fluorescence quantitative analysis:
MDA-MB-231 cells were plated at 4X 105After inoculation in 6-well plates, incubate for 8 hours. After observing cell adherence by microscope, adding corresponding materials according to the groups of Control, UCSNs, Blebbistatin, UCSNs-B, Control + NIR, UCSNs + NIR, Blebbistatin + NIR, UCSNs-B + NIR and UCSNs-B + NIR (hypoxic) for incubation for 24 hours, and using 980nm laser (1W/cm) for incubation for the group with NIR after incubation for 24 hours2) Irradiation was carried out for 10 minutes and incubation was continued for 6 hours. Adherent MDA-MB-231 cells were washed three times with PBS, digested with 0.25% trypsin-EDTA (1X) digest, and harvested by centrifugation. The supernatant was discarded, the cells were washed with the buffer in the kit, and the cells were collected by centrifugation. Redispersed in buffer to make the cell density 5X 105Cell suspension/mL. And adding 100 microliters of working solution into 200 microliters of cell suspension, uniformly blowing, and then putting the cell suspension into an incubator at 37 ℃ for incubation for 15-30 minutes. Cell viability was detected by flow cytometry and data was recorded for subsequent processing.
The viability of MDA-MB-231 cells was tested by CCK-8 after incubation with different concentrations of UCSNs or UCSNs-B (0, 20, 50, 100, 200, and 500. mu.g/mL) for 24 and 48 hours, respectively. As shown in FIG. 6A, even though the concentration of UCSNs was increased to 500. mu.g/mL, more than 80% of the cells survived after 48 hours of incubation with MDA-MB-231 cells, indicating that UCSNs have negligible cytotoxicity. However, after 48 hours of incubation of MDA-MB-231 cells with UCSNs-B (500. mu.g/mL), respectively, the cell survival rate was 76.5% (FIG. 6B). Subsequently, UCSNs-B after near-infrared laser activation were evaluated for cytotoxicity against MDA-MB-231 cells. As shown in FIG. 6C, with increasing doses of UCSNs-B, the survival rate of MDA-MB-231 cells was significantly decreased after 10 minutes of near-infrared laser irradiation. At an incubation dose of 500. mu.g/mL, the cell viability of MDA-MB-231 cells was approximately 27.3%. In contrast, the treatment of the Control, UCSNs, Blebbistatin, UCSNs-B, Control + NIR, UCSNs + NIR and Blebbistatin + NIR groups did not significantly cytotoxicity to MDA-MB-231 cells (FIG. 6D).
After MDA-MB-231 cells were treated in different groups, apoptosis was further detected by flow cytometry, and the results are shown in FIG. 7. The survival rate of the cells of Control, UCSNs-B, Control + NIR and UCSNs + NIR groups after treatment was greater than 80%. The numbers of apoptosis were slightly increased in the Blebbistatin and Blebbistatin + NIR groups. Only the cells of the UCSNs-B treatment group have obviously increased apoptosis under the conditions of normal or hypoxic after the near-infrared laser irradiation is increased, and only 14.5 percent of the cells survive, which shows that the UCSNs-B causes a series of chain reactions to realize oxygen-independent OH outbreak after the near-infrared laser irradiation, thereby effectively inducing the tumor cell apoptosis, and the synergistic effect of the UCSNs-B and the NIR obviously improves the effect of treating the tumor cells in vitro.
EXAMPLE 6 study of the in vitro therapeutic Effect of multifunctional nanoparticles
MDA-MB-231 tumor-bearing nude mice were randomly divided into 6 groups of 5 mice each. When the tumor volume increases to 50mm3At the time, different formulations were injected every other day from the tail vein of mice for 7 times, these groups being: contr ol, Blebbistatin, UCSNs, NIR, UCSNs-B, and UCSNs-B + NIR. The dosage of UCSNs-B is 20mg/kg, and the dosage of Blebbistatin is 2 mg/kg. For each treatment, mice in the NIR group only and mice in the UCSNs-B + NIR group were anesthetized 24 hours after injection by intraperitoneal injection of a 5% chloral hydrate solution prepared beforehand, followed by a 980nm laser (1W/cm)2) The irradiation was carried out for ten minutes. Tumor size and mouse body weight were measured every two days, recorded and calculated.
The tumor growth curves for each group were observed over 2 weeks of treatment and are shown in figure 8A. Compared with a control group injected with PBS, UCSNs-B and NIR have no obvious inhibition effect on tumor growth, and after the UCS Ns-B is excited by near-infrared laser, a large amount of OH is generated in a tumor microenvironment, so that the tumor growth is obviously inhibited. Further tumor suppression calculation showed that the tumor suppression rate of UCSNs-B + NIR on MDA-MB-231 tumor-bearing mice is about 96.5% at the highest, which is obviously higher than that of Blebbistatin (24.8%) (FIG. 8B). The UCSNs-B is proved to have obvious inhibition effect on the tumor under 980nm laser induction.
After each group of treatments was completed, one tumor tissue was taken out for section staining for each group. H & E staining was used to assess the damage caused to the tumors by the different treatment modalities, as shown in FIG. 9, the H & E staining images of the tumor tissues of the UCSNs-B + NIR treatment group showed larger interstitial spaces, indicating that UCSNs-B + NIR treatment caused greater cell damage to the tumor tissues. Also, to understand apoptosis in tumor tissues, fluorescence staining of each group of removed tumors was performed using deoxynucleotide terminal transferase mediated dUTP nick end labeling (TUNEL). Similar results were seen with significantly larger apoptotic or necrotic areas of UCS Ns-B + NIR treated tumor cells compared to the Control, UCSNs, Blebbistatin, UCSNs-B, NIR treated groups. Ki-67 antibody staining was further performed to evaluate tumor cell proliferation in the different treatment groups. Compared with other treatment groups, the UCSNs-B + NIR group has obvious inhibition effect on the proliferation activity of MDA-MB-231 tumor cells, and the results prove that the constructed nano system has the killing effect on tumors under the induction of 980nm laser.
Example 7 in vivo safety experiments of multifunctional nanoparticle UCSNs-B
All groups of nude mice in example 6 were treated for 2 weeks before, five major organs of heart, liver, spleen, lung and kidney of each group of mice were taken out for histological examination. As shown in FIG. 10, no obvious tissue injury or inflammation was observed in the major organs of the mice in each treatment group, indicating that UCSNs-B + NIR had no obvious toxic side effects on the major organs. These results further confirmed the biological safety of UCSNs-B material, which efficiently induced apoptosis of tumor cells by generating OH at a specific site only after 980nm laser irradiation.
Example 8 Performance evaluation of multifunctional nanoparticle UCSNs-B in vivo MR imaging
Tumor-bearing mice were randomly selected. Physiological saline containing UCSNs-B (20mg/kg) was injected from the tail vein. The 5% chloral hydrate solution prepared in advance is injected into the abdominal cavity for anesthesia, and a SIEMENS MAGNETON Verio 3.0T MR scanner is adopted to place the prone position of the mouse in a special small animal coil. Coronal and axial positions T1WI imaging scan, fig. 11.
In vivo MR imaging of MDA-MB-231 tumor-bearing mice by intravenous UCSNs-B, comparing pre-and post-injection T1By weighting the MR images, the MR imaging signals at the tumor position can be observed to be obviously enhanced after intravenous injection of UCSNs-B, which indicates that the UCSNs-B is an effective contrast agent for MR imaging in mice.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (10)
1. The multifunctional nanoparticle for tumor diagnosis and treatment integration is characterized in that the nanoparticle is composed of a drug transport carrier and a photoactivation drug.
2. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle is obtained by coating mesoporous silica outside gadolinium-doped upconversion nanoparticles and loading a photoactivation drug in the mesopores.
3. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 2, wherein the upconversion nanoparticle is NaYF4:Yb/Tm@NaGdF4(ii) a The photoactivated drug is Blebbistatin.
4. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle contains the rare earth elements Yb and Tm.
5. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle has a hollow mesoporous structure.
6. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle comprises paramagnetic gadolinium ions.
7. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle generates active oxygen independent of oxygen in the surrounding environment.
8. The multifunctional nanoparticle for tumor diagnosis and treatment integration according to claim 1, wherein the nanoparticle controllably generates hydroxyl radical at fixed point.
9. The preparation method of the multifunctional nanoparticle for tumor diagnosis and treatment integration according to any one of claims 1 to 8, wherein the method comprises the following steps:
s1, preparing NaYF by high-temperature thermal decomposition method4A Yb/Tm core;
s2, preparing NaYF by epitaxial growth method4:Yb/Tm@NaGdF4I.e., UCNPs;
s3, coating Mesoporous silicon dioxide outside UCNPs to prepare UCNPs @ Mesoporous Silica (SiO2) nanoparticules, namely UCSNs;
s4, preparation of UCSNs @ Blebbistatin: dissolving Blebbistatin in solvent, adding UCSNs, and stirring in dark environment for 20-28 hr; centrifuging to obtain the product.
10. Use of the multifunctional nanoparticles for tumor diagnosis and treatment according to any one of claims 1 to 8 for the preparation of a diagnosis and treatment integrated preparation for tumors.
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