CN111956801A - Nano-drug system for optically controlling release of CO and adriamycin and preparation and application thereof - Google Patents
Nano-drug system for optically controlling release of CO and adriamycin and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a nano-drug system for optically controlling release of CO and adriamycin, and preparation and application thereof. The nano-drug system takes polydopamine as a nano-carrier, and pentacarbonyl manganese bromide and adriamycin are loaded on the polydopamine. The preparation method of the nano-drug system is simple, the dopamine hydrochloride is dispersed into double distilled water to obtain dopamine hydrochloride solution, NaOH solution is added, multiple times of centrifugal separation are carried out to obtain polydopamine, the polydopamine is dispersed into the double distilled water, under the condition of vigorous stirring, ethanol solution of manganese pentacarbonyl bromide and double distilled water solution of adriamycin are added, after rotating stirring at room temperature, black solution is obtained, supernatant is removed through centrifugal separation, and the obtained precipitate is the PDA-DOX-CO nano-particles. The nano-drug system can controllably release CO and adriamycin under the irradiation of near-infrared light, effectively inhibit the growth of tumors, and has good long-circulating function, biocompatibility and stability.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a nano-drug system for optically controlling release of CO and adriamycin, and preparation and application thereof.
Background
It is well known that there is no safe and effective treatment for malignant tumors to date. The surgical method is difficult to completely remove tumor tissue, and the conventional chemotherapy is to kill cancer cells by orally or intravenously injecting anticancer drugs to the tumor site through the blood circulation system. However, in the conventional chemotherapy, mainly by intravenous administration, the small molecule drug itself cannot achieve specific distribution in vivo, the drug is distributed in the whole body of a patient, and can kill cancer cells and normal tissue cells, so that the application of the small molecule chemotherapy drug is usually accompanied by many side effects, and the small molecule chemotherapy drug has less accumulation in tumor sites and low drug utilization rate, so that the large dose use of the chemotherapy drug becomes necessary, and the toxic and side effects on normal tissues are more serious. These side effects place a great burden on patients, seriously affect the treatment efficiency of chemotherapy, and easily induce drug resistance in cancer cells. For example, as an anthracycline antineoplastic agent commonly used in clinical practice, adriamycin (DOX) enters tumor cells through cell membranes and acts on DNA, thereby achieving the purpose of resisting tumors. Adriamycin has wide cancer types for treatment, has a certain killing effect on each period of cancer cells, has the characteristics of wide anti-tumor spectrum and good curative effect, and is considered to be one of the most effective chemotherapeutic drugs. However, doxorubicin is highly toxic, and dose-dependent irreversible cardiomyopathy, bone marrow suppression, alopecia, digestive tract symptoms and the like can occur after long-term application, and the clinical application of doxorubicin is limited due to the existence of multidrug resistance.
Therefore, researchers try to prepare a drug carrier to deliver tumor treatment drugs into tumor cells in a targeted manner, and the drugs can be controllably released under a specific stimulation condition, so that the physicochemical distribution condition of the drugs in a human body is changed, and finally, efficient cancer treatment is realized under the condition that the self limitation of the chemotherapy drugs is eliminated as much as possible. Drug carriers can bind to and effect the effective loading of drug molecules in a variety of ways. There are two general categories of non-covalent interactions and covalent bonding, depending on the interaction force between the drug carrier and the drug molecule when loaded. Non-covalent interactions refer to drug loading by means of hydrogen bonding, electrostatic interactions, pi-pi stacking, co-precipitation, and the like. Covalent bonding refers to the loading of the drug molecule by the auxiliary carrier through chemical bonding. The difference in loading pattern greatly affects and may even completely alter the drug release behavior and confers different environmental responsiveness to the drug system. Meanwhile, single or multiple environmental response capabilities can be realized through selection of the drug carrier. The intelligent drug system with environmental response capability can be stable in normal physiological media and protect drug molecules from premature leakage. Subsequently, the tumor cells are enriched by blood circulation and active or passive targeting, and enter the tumor cells under the corresponding endocytosis. Finally, the nanoparticle realizes the release of the loaded drug/prodrug molecule in the presence of endogenous stimulation or exogenous stimulation of cells and achieves the purposes of inhibiting the growth of tumor cells or killing the tumor cells. The research of different environmental responsiveness greatly expands and enriches the design of a medicine system, and provides better guarantee for realizing more accurate intelligent medicine administration.
An ideal drug carrier must satisfy the following three conditions simultaneously: 1) stable, the drug carrier must be able to circulate for long periods in the body; 2) targeting, high drug loading rate, long circulation in the organism, and the drug carrier can directionally deliver the drug to the focus site or enrich the focus site; 3) after reaching the target position, the drug molecules can be effectively released from the carrier and enter cytoplasm to finally kill tumor cells, and are not released or are slightly released in the delivery process; 4) good biocompatibility and no toxic and side effect. The choice of the drug carrier is critical. The size effect of the nano particles enables the nano particles to have unique and excellent material characteristics, different types of drugs can be loaded on the surfaces or the inner spaces of the nano particles, and the drugs can be passively targeted to tumor tissues through the EPR effect by applying the size effect of the nano materials, so that the enrichment capacity is improved. However, the currently published drug delivery system can only satisfy one to two conditions. For example, most of the amphiphilic polymer carriers studied at present can self-assemble in water to form micelles, which are used for encapsulating chemotherapeutic drugs. After the drug is loaded by the polymer particles, the leakage of the drug in blood circulation can be reduced, the toxicity is reduced, and the tumor position of the drug is increasedAnd (4) accumulating. However, many drugs entrapped in polymer particles are not released rapidly and efficiently after being delivered to tumor tissues and cells, and slow and low-dose drug release can cause drug resistance in cells, thereby increasing the difficulty of treatment. The nanometer technology based on DOX is more mature and comprises the following steps: PEGylated liposomes or liposomes
And other nanomaterials in clinical trials, e.g. micelles
Livatag nanoparticles or polymer-drug conjugates PK1 and PK 2. Although these nanoparticles modified with hydrophilic polymers or surfactants have longer circulation time in blood, they are mainly used as monotherapy and still cannot fundamentally solve the existing problems. The drug content in the drug system is low, typically below 10% (w/w), due to the introduction of the drug carrier in the drug system. Too low a drug content means that many repeated administrations are required for the treatment, which not only seriously affects the treatment efficiency but also imposes a great burden on the patient.
Meanwhile, researchers have also actively tried various methods other than chemotherapy, such as photothermal therapy, in which a photothermal agent is irradiated with laser light to cause energy conversion to generate local high temperature to effectively kill tumor cells. The treatment mode can greatly reduce the toxic and side effects of the whole body treatment, effectively shorten the treatment period and simultaneously has wide anticancer spectrum. However, the single photothermal therapy also has disadvantages that the radiation is incomplete to cause the recurrence of the tumor under the condition of the deviation of tumor positioning or laser focusing; or over-irradiation to damage normal tissue in cases where tumor boundaries are poorly resolved; it is also difficult to effectively perform a targeted therapy during the metastatic spread of tumors. But also radiotherapy, photodynamic therapy, etc. However, poor targeting, limited lethality to cancer cells, and damage to normal cells greatly limit the application of these therapies.
As can be seen, any single treatment modality has difficulty achieving the desired treatmentHas therapeutic effect. Combination therapy is considered a promising strategy to improve the efficiency of treatment and minimize side effects. For example: combines photothermal therapy and chemical therapy, and realizes local temperature rise of tumor tissues and drug slow release under the action of exogenous stimulation in the presence of a photothermal conversion reagent. These photothermal conversion agents mainly include four types: organic compounds and polymers, metal-based nanomaterials (gold materials or palladium materials), carbon materials, metal-oxygen-sulfur-group nanomaterials. Some TMOCs photothermal conversion materials having a two-dimensional planar structure, e.g. MoS2、WS2Etc., which have an ultra-large specific surface area. The material is a better drug delivery carrier after hydrophilic or biocompatible modification is carried out on the surface of the material. In addition, polymer molecules or biological macromolecules are modified on the surface of the nanometer material to construct an inorganic/organic hybrid material system, and the affinity effect of the surface polymer or biological macromolecules on the medicine is utilized to realize medicine loading. For example, Zhouqi Meng et al, In an article entitled "NIR-Laser-Switched In Vivo Smart nanoparticles for synergistic Photothermals and Chemotherapy of tumors" (adv. Mater.2016,28,245-253), disclose a copper-based hybrid material for use In combination Chemotherapy-Photothermal therapy, which was first prepared by polymerization to form a MEO2MA@MEO2MA-co-OEGMA gel, and growing CuS therein to obtain G-CuS hybrid material. The obtained G-CuS material has good load on DOX and is sensitive to temperature. Under the induction of 915nm laser, G-CuS-DOX is heated locally. When the temperature exceeds 42 ℃, the polymer configuration begins to reverse and the DOX drug is rapidly released. The material is applied to chemotherapy-photothermal combined treatment of cancers, and can effectively inhibit the growth of tumors. Such a system provides a good strategy for constructing an intelligent combination therapy nano-platform controlled in vitro. However, these reported photothermal conversion agents may have the following problems. On one hand, most of the photothermal conversion materials are complicated to prepare and have harsh conditions. The high-temperature hot injection method can prepare the nano material with uniform size and excellent performance. However, due to the presence of surface long-chain hydrocarbons, the resulting nanomaterials are generally hydrophobic and require further surface modification. The high boiling point and high toxicity used in the hot injection methodThe organic solvent further increases the biological toxicity of the material. On the other hand, the low efficiency of photothermal conversion will also limit its practical application in photothermal therapy. Some photothermal conversion materials have weak absorption in the near infrared region and low photothermal conversion efficiency. Therefore, in the photothermal treatment process, the injection dosage of the nano-drug needs to be increased or the laser application power needs to be increased, so that a good treatment effect can be obtained, but the toxic and side effects of the material can also be increased.
In summary, due to the drug action and the complexity of the preparation of the carrier material, the current combination therapy mainly focuses on the combination of multiple treatment methods (such as the combination of photothermal therapy and single chemotherapeutic drug), or the combination of the single chemotherapeutic drug loaded by the nano drug delivery carrier and specific exogenous stimulation, and at present, a nano drug system with high-efficiency treatment capability for combining multiple chemotherapeutic drugs and multiple treatment methods to treat tumors against cancers is not available.
Disclosure of Invention
In view of the above, the present invention aims to provide a nano-drug system for optically controlling release of CO and DOX, in which a nano-drug delivery carrier polydopamine is loaded with manganese pentacarbonyl bromide (mn (CO))5Br) and Doxorubicin (DOX), in combination with photothermal therapy. The nano-drug system is simple to prepare, and has good long-circulating function, biocompatibility and stability.
The purpose of the invention can be realized by the following technical scheme:
in a first aspect of the present invention, a nano-drug system for light-controlled release of carbon monoxide (CO) and Doxorubicin (DOX) is provided, wherein Polydopamine (PDA) is used as a nano-carrier, and manganese pentacarbonyl bromide (mn (CO))5Br) and Doxorubicin (DOX).
In a second aspect of the present invention, there is provided a method for preparing the above-mentioned nano-drug system for light-controlled release of carbon monoxide (CO) and Doxorubicin (DOX), comprising the following steps:
(1) at room temperature, dispersing dopamine hydrochloride into double distilled water to obtain dopamine hydrochloride solution; adding NaOH solution into the mixture under vigorous stirring, rotationally stirring the mixture to obtain black solution, performing low-speed centrifugal separation to obtain supernatant, performing high-speed centrifugal separation on the supernatant, and removing the supernatant to obtain precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain manganese pentacarbonyl bromide solution; dissolving adriamycin into double distilled water to obtain adriamycin solution;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the polydopamine under vigorous stirring, obtaining a black solution after rotating and stirring the mixture at room temperature, and removing the supernatant through high-speed centrifugal separation to obtain a precipitate, namely the PDA-DOX-CO nano particles.
In the preferred technical scheme, the low-speed centrifugation refers to 400-600 rpm centrifugation, and the high-speed centrifugation refers to 10000-12000 rpm centrifugation.
In one embodiment of the present invention, a method for preparing a nano-drug system for light-controlled release of carbon monoxide (CO) and Doxorubicin (DOX) comprises the following steps:
(1) dispersing dopamine hydrochloride into double distilled water at room temperature to obtain 1-2 mg/mL dopamine hydrochloride solution; adding NaOH solution with the concentration of 0.8-1.2 mol/L into the mixture under vigorous stirring, rotationally stirring the mixture for 5-8 hours at 800-1000 rpm to obtain black solution, centrifuging the black solution for 5-10 minutes at 400-600 rpm, centrifuging the separated supernatant for 5-10 minutes at 10000-12000 rpm, removing the supernatant, and obtaining precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain a manganese pentacarbonyl bromide solution with the concentration of 1.8-2.2 mg/mL; dissolving adriamycin into double distilled water to obtain an adriamycin solution with the concentration of 1.2-1.6 mg/mL;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the double distilled water under vigorous stirring, rotationally stirring the mixture at room temperature of 800-1000 rpm for 5-8 hours to obtain a black solution, centrifuging the black solution at 10000-12000 rpm for 5-10 minutes, removing supernatant, and obtaining precipitate, namely PDA-DOX-CO nano particles;
wherein the mass ratio of the dopamine hydrochloride to the manganese pentacarbonyl bromide to the adriamycin is 15:0.9: 0.7-15: 1:0.8, the molar ratio of the dopamine hydrochloride to the NaOH is (1.6-1.3) to 1, and the volumes of double distilled water in the step (1) and the step (3) are the same.
In one embodiment of the present invention, a method for preparing a nano-drug system for light-controlled release of carbon monoxide (CO) and Doxorubicin (DOX) comprises the following steps:
(1) at room temperature, dispersing dopamine hydrochloride into double distilled water to obtain 2mg/mL dopamine hydrochloride solution; adding NaOH solution with the concentration of 1mol/L under vigorous stirring, rotationally stirring at 1000rpm for 5 hours to obtain black solution, centrifuging at 400rpm for 5 minutes, separating to obtain supernatant, centrifuging at 10000rpm for 5 minutes, removing the supernatant, and obtaining precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain a manganese pentacarbonyl bromide solution with the concentration of 2 mg/mL; dissolving adriamycin into double distilled water to obtain an adriamycin solution with the concentration of 1.6 mg/mL;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the double distilled water under vigorous stirring, rotationally stirring the mixture for 5 hours at room temperature and 1000rpm to obtain a black solution, centrifuging the black solution for 5 minutes at 10000rpm, and removing supernatant to obtain precipitate, namely the PDA-DOX-CO nano particles;
wherein the mass ratio of the dopamine hydrochloride to the manganese pentacarbonyl bromide to the adriamycin is 15:1:0.8, the molar ratio of the dopamine hydrochloride to the NaOH is 1.58:1.2, and the volumes of double distilled water in the step (1) and the step (3) are the same.
The PDA-DOX-CO nano-particles are the nano-drug system for optically controlling the release of carbon monoxide (CO) and adriamycin (DOX).
The mass ratio of the dopamine hydrochloride, the manganese pentacarbonyl bromide and the adriamycin is the mass ratio of the dopamine hydrochloride, the manganese pentacarbonyl bromide and the adriamycin which actually take part in the reaction.
In a third aspect, the present invention provides the use of the above-mentioned nano-drug system for the controlled release of carbon monoxide (CO) and Doxorubicin (DOX) in tumor therapy.
In a specific example of the present invention, in the above application, the nano-drug system for light-controlled release of carbon monoxide and doxorubicin is applied simultaneously with near-infrared irradiation in a wavelength range between 600 and 1000 nm.
In one embodiment of the present invention, in the above application, the nano-drug system for light-controlled release of carbon monoxide and doxorubicin is applied simultaneously with 808nm near-infrared light irradiation.
In the invention, the room temperature is 20-25 ℃.
In the nano-drug system for optically controlling release of carbon monoxide (CO) and adriamycin (DOX), the nano-carrier PDA has good biocompatibility, the manganese pentacarbonyl bromide is used as a CO donor, the DOX is a small-molecular antitumor drug, the adriamycin (DOX) is adsorbed on the nano-carrier PDA through pi-pi action, and Mn (CO)5Br was attached to the nanocarrier PDA by chelation. Under the irradiation of near-infrared light of 600-1000 nm (particularly under the stimulation of near-infrared light of 808 nm), the nano-carrier PDA strongly absorbs and effectively converts the heat, the DOX nano-drug is rapidly released, the manganese pentacarbonyl bromide releases CO gas, and the combined effect of the DOX and the CO under the irradiation of the near-infrared light is enhanced. The nano-drug system is simple to prepare and has good biocompatibility and stability.
The nano-drug system can generate heat under the stimulation of near infrared light of 808nm so as to release CO and DOX according to requirements, ensure that CO gas is accumulated at a focus position in a specific high concentration, and realize targeted transportation and controllable release. The rapid and free diffusion of gas molecules in vivo caused by the ways of directly inhaling, orally taking or injecting gas into the abdomen to release molecular drugs and the like is avoided. Meanwhile, the problem of poor controllable slow-release CO function caused by poor water solubility of the transition carbonyl metal compound is solved. In addition, in the nano-drug system, CO can not only target mitochondria to destroy the function of the respiratory chain, induce the respiratory metabolism disorder of tumor cells, but also enhance the chemotherapy and killing effect of DOX on the tumor cells, thereby enhancing the tumor treatment effect.
Compared with the prior art, the nano-drug system for optically controlling the release of CO and DOX has the following beneficial technical effects:
1) the source is simple, and the price is low; the preparation method is simple and feasible, and is suitable for mass production.
2) Can stably exist in a physiological environment without any surface modification, has good biocompatibility and can ensure the biological safety in a human body.
3) Excellent photothermal conversion efficiency and stable photothermal conversion performance.
4) The near infrared light of CO and DOX triggers controlled release.
5) The respiratory metabolism abnormality induced by CO in the tumor microenvironment and the cell apoptosis induced by DOX supplement each other, and the treatment effect of the tumor is further improved.
Drawings
FIG. 1 is a transmission electron micrograph of the PDA-DOX-CO nanoparticles prepared in example 1.
FIG. 2 is a surface element distribution diagram of the PDA-DOX-CO nanoparticles prepared in example 1.
FIG. 3 is the elemental content scale of the PDA-DOX-CO nanoparticles prepared in example 1.
FIG. 4 is a graph comparing the UV absorption spectra of the PDA-DOX-CO nanoparticles prepared in example 1 with those of PDA and DOX.
FIG. 5 is a graph of photo-thermal temperature rise of PDA-DOX-CO nanoparticle solutions prepared in example 1 at different concentrations, with PBS as a control.
FIG. 6 is a comparison of CCK-8 activity measurements for HCT-116 with different nano-treatment groups.
FIG. 7 is a graph comparing the flow apoptosis of HCT-116 cells after different nano-treatment groups.
FIG. 8 is a quantitative analysis of the apoptosis of FIG. 7.
FIG. 9 is a graph comparing the effect of different nanotherapeutic groups on mitochondrial membrane potential of HCT-116.
FIG. 10 is a comparison of thermal imaging of different nanotherapeutic groups on HCT-116 tumor mouse models.
FIG. 11 is a graph comparing the results of temperature-raising tests performed on HCT-116 tumor mouse models in different nano-treatment groups.
FIG. 12 is a graph comparing the body weight changes of different nano-treatment groups acting on HCT-116 tumor mouse model.
FIG. 13 is a graph comparing the tumor volume changes of different nano-treatment groups acting on HCT-116 tumor mouse model.
FIG. 14 is a graph comparing the anti-tumor effect of different nano-therapeutic groups after being applied to HCT-116 tumor mouse model.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the accompanying drawings and specific examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the scope of the present invention.
The following examples do not specify particular techniques or conditions, according to the techniques or conditions described in the literature in the field or according to the product description. The reagents or instruments used are not indicated by manufacturers, and are all conventional products available on the market.
EXAMPLE 1 preparation of PDA-DOX-CO Nanometers
(1) At room temperature (24 ℃), dispersing 30mg dopamine hydrochloride into 15mL double distilled water, adding 120 mu L NaOH solution with the concentration of 1mol/L under vigorous stirring, rotationally stirring at the speed of 1000 r/min for 5 hours to obtain a black solution, centrifuging at 400rpm for 5 minutes, separating to obtain a supernatant, centrifuging the supernatant at 10000rpm for 5 minutes, and removing the supernatant to obtain a precipitate, namely PDA (poly dopamine).
(2) 20mg of Mn (CO)5Br was dissolved in 10mL of absolute ethanol to give Mn (CO)5Br solution; 8mg of Doxorubicin (DOX) was dissolved in 5mL of double distilled water to obtain a DOX solution.
(3) Dispersing the PDA obtained in the step (1) into 15mL double distilled water, and adding the Mn (CO) obtained in the step (2) into the double distilled water during the vigorous stirring process5Br solution 1mL and DOX solution 1mL (i.e., Mn (CO) actually participating in the reaction)5Br of only 2mg and DOX of only 1.6mg actually participating in the reaction) at room temperature, and after stirring at 1000rpm for 5 hours, a black solution was obtained and centrifuged at 10000rpmAfter 5 minutes, the supernatant was removed and the resulting precipitate was the final product.
Structural characterization
The microscopic morphology of the final product obtained in example 1 was observed using a transmission electron microscope, as shown in FIG. 1. The transmission electron microscope shows that the final product obtained in example 1 is spherical nanoparticles with uniform particle size distribution and an average particle size of 207 nm.
The final product obtained in example 1 was analyzed for element distribution and content using X-ray energy spectroscopy (EDS). The surface element distribution is shown in fig. 2, and it can be seen that C, N, O, Mn elements exist in the surface elements of the final product obtained in example 1; the overall elemental distribution is shown in fig. 3, which also shows the presence of C, N, O, Mn elements as surface elements in the final product obtained in example 1. Thus, Mn (CO) can be determined5Br has been successfully immobilized, i.e. the CO donor has been successfully immobilized. That is, the final product obtained in example 1 was successfully loaded with Mn (CO)5Br in PDA.
FIG. 4 shows a graph comparing the UV absorption spectra of the final product obtained in example 1 with PDA and DOX. The specific test process is as follows:
a certain amount of PDA (the product obtained in the step (1) of the example 1) is dissolved in double distilled water, and a PDA standard solution with the concentration of 100 mug/mL is accurately prepared; a certain amount of the final product prepared in example 1 was dissolved in double distilled water to prepare a final product standard solution with a concentration of 100. mu.g/mL accurately; meanwhile, a DOX standard solution with a final concentration of 9 mug/mL is prepared.
100 μ L of each of the solutions was added to a 96-well plate, and then their UV absorbance values were measured using a multi-functional microplate reader, to obtain a UV absorption spectrum contrast chart (FIG. 4). According to the display of FIG. 4: the final product obtained in example 1 has the same absorption peak with DOX at about 488nm, while PDA (without loaded DOX) has no specific significant absorption peak at 488 nm. This indicates that DOX has been successfully loaded on the final product from example 1.
From the results shown in FIGS. 2 to 4, it is understood that DOX and a CO donor Mn (CO) were successfully supported on PDA in the final product obtained in example 15Br is added. Further referring to the case that the final product obtained in example 1 is nano particles as shown in FIG. 1, the final product obtained in example 1 is named PDA-DOX-CO nano.
Test of photothermal conversion Property
Dissolving a certain amount of the PDA-DOX-CO nano particles which are final products obtained in the example 1 into double distilled water to respectively prepare sample solutions with the concentrations of 100 mu g/mL and 50 mu g/mL; after sonication, 200. mu.L of the sample solution was placed in a 96-well plate. A PBS control group was also set up with PBS (pH 7.4) as the control sample solution.
Irradiating with 808nm laser, and recording the temperature change of each sample solution with infrared thermal imaging instrument. As a result, as shown in FIG. 5, the power density was 2W/cm2The temperatures of 100 mu g/mL and 50 mu g/mL sample solutions are respectively increased to 57 ℃ and 42 ℃ within 5 minutes under the irradiation of 808nm near-infrared laser, and the temperature of a PBS control group is hardly changed, which shows that the final product PDA-DOX-CO nano obtained in example 1 has excellent photo-thermal conversion performance.
Example 2 apoptosis assay
The cell line used in the invention is human colon cancer HCT-116 cell. HCT-116 cells are commercially available from the Shanghai academy of sciences.
HCT-116 cells were cultured in 96-well plates, 10 per well4Individual cells, randomly divided into the following 5 groups (n ═ 5):
PBS (pH 7.4) + NIR (near Infrared), PDA-CO + NIR (near Infrared), PDA-DOX-CO + NIR (near Infrared).
PDA was prepared by the method of step (1) of example 1.
The PDA-CO is prepared according to the following steps: PDA was prepared by the method of step (1) of example 1, and 20mg of Mn (CO)5Br was dissolved in 10mL of absolute ethanol to give Mn (CO)5Br solution; dispersing the PDA into 15mL double distilled water, adding 1mL Mn (CO) while stirring vigorously5Br solution, stirring at room temperature at 1000rpm for 5 hr to obtain black solution, centrifuging at 10000rpm for 5 min, removing supernatant to obtain precipitate PDA-CO。
The PDA-DOX is prepared according to the following steps: PDA was prepared by the method of the step (1) of example 1, 8mg of Doxorubicin (DOX) was dissolved in 5mL of double distilled water to obtain DOX solution, and the above PDA was dispersed in 15mL of double distilled water, and 1mL of DOX solution was added during vigorous stirring, and after stirring at 1000rpm for 5 hours at room temperature, black solution was obtained and centrifuged at 10000rpm for 5 minutes to remove the supernatant, and the obtained precipitate was PDA-DOX.
In each of the above groups, solutions having a concentration of 0. mu.g/mL, 6. mu.g/mL, 12. mu.g/mL, 25. mu.g/mL, 50. mu.g/mL, 100. mu.g/mL were prepared for each group under NIR (near infrared) conditions: the power density is 1W/cm2Irradiating the cells for 3 minutes by using a near infrared laser with wavelength of 808nm, respectively treating the HCT-116, detecting the cell activity by using CCK-8 (a CCK-8 kit is purchased from Kyoki Biotechnology Co., Ltd.), detecting the apoptosis by using flow cytometry, and quantitatively analyzing the damage condition of mitochondrial membrane potential by using JC-1 probe dyeing.
The CCK-8 cell viability detection result is shown in FIG. 6, wherein, in the PBS + NIR group, the cell viability hardly changes at each concentration, which indicates that the single near infrared ray has little influence on the cell viability; PDA + NIR group, cell activity decreased to around 80% at a concentration of 100 μ g/mL (i.e., cell activity decreased by nearly 20% after PDA addition); in the PDA-CO + NIR group, the cell activity is reduced to about 70% at a concentration of 100. mu.g/mL (i.e., the cell activity is reduced by nearly 30% after the addition of PDA-CO); in the PDA-DOX + NIR group, the cell activity is reduced to about 50% at a concentration of 100. mu.g/mL (i.e., the cell activity is reduced by nearly 50% after the PDA-DOX is added); in the PDA-DOX-CO + NIR group, the cell activity decreased to about 10% at a concentration of 100. mu.g/mL (i.e., the cell activity decreased by nearly 90% after the addition of PDA-DOX-CO). This shows that the final product PDA-DOX-CO + NIR group obtained in example 1 has a very strong inhibitory effect on HCT-116 cells, and compared with the other four control groups, the final product PDA-DOX-CO + NIR group obtained in example 1 has a significantly enhanced inhibitory effect on HCT-116 cells, and the effect is obviously higher than the simple addition of PDA, DOX and CO, which shows that the NIR enhances the combined effect of DOX and CO while promoting the release of DOX and CO.
After HCT-116 cells are treated by the different nano-treatment groups (the concentration of each group is 100 mu g/mL), the detection result of Annexin V-FITC/PI double-staining apoptosis is shown in figure 7, and figure 8 is a quantitative analysis of figure 7, wherein the apoptosis ratios of the PBS + NIR group, the PDA-CO + NIR group, the PDA-DOX + NIR group and the PDA-DOX-CO + NIR group are respectively 8.2%, 26.9%, 33.3%, 40.6% and 89.8%. This shows that the final product PDA-DOX-CO + NIR group obtained in example 1 has a very strong inhibitory effect on HCT-116 cells, and compared with the other four control groups, the final product PDA-DOX-CO + NIR group obtained in example 1 has a significantly enhanced inhibitory effect on HCT-116 cells.
Since mitochondria are closely associated with apoptosis, where disruption of the mitochondrial transmembrane potential (Δ ψ) is considered to be one of the earliest events in the course of the apoptotic cascade, it occurs before the appearance of the apoptotic features of the nucleus (chromatin condensation, DNA fragmentation) and apoptosis is irreversible once the mitochondrial transmembrane potential collapses. Therefore, the effect of different nanotherapeutic groups (each group at a concentration of 100. mu.g/mL) on the mitochondrial membrane potential of HCT-116 was also investigated, and the results are shown in FIG. 9. In FIG. 9, it can be seen that the PDA-DOX-CO + NIR group red fluorescence (corresponding to the dark bars in FIG. 9) is significantly attenuated in intensity and the green fluorescence (corresponding to the light bars in FIG. 9) is significantly enhanced, indicating a significant drop in the mitochondrial membrane potential. The membrane potential (delta psi) of normal HCT-116 cell mitochondria has polarity, JC-1 is quickly taken into mitochondria depending on the polarity of delta psi and multimers are formed in mitochondria due to the increase of concentration, and the emission of the multimers is red fluorescence; when the cell is in apoptosis, the transmembrane potential of the mitochondria is depolarized, JC-1 is released from the mitochondria, the intensity of red light is weakened, and the red light exists in cytoplasm in a monomer form and emits green fluorescence. Thus, the situation in FIG. 9 illustrates that the PDA-DOX-CO + NIR group induced apoptosis of HCT-116 cells is significantly superior to the other groups.
As can be seen from the combination of fig. 7 to 9: in the above apoptosis experimental results, HCT-116 cells treated with PDA-DOX-CO + NIR group showed: the HCT-116 cell activity is reduced, the total apoptosis number is up to 89.8%, and the mitochondrial membrane potential is obviously reduced, which shows that the compound has an excellent function of killing tumor cells. Compared with the other four control groups, the PDA-DOX-CO + NIR group has more remarkable tumor cell killing capacity.
Example 3 animal experiments
The mouse tumor model was constructed as follows:
male Nude mice (Nude mice, from Silik Bio Inc.) 6-8 weeks old and 20-22g in weight were used as animal models, and HCT-116 cells with good growth were collected by centrifugation (1000rpm, 4 minutes) and washed with PBS (pH 7.4), and the resulting cell suspension (cell density 1X 10)7One/mouse) was injected subcutaneously into the right shoulder of the mouse, taking care to observe the growth of the tumor and to measure the size of the tumor. The size of the tumor is measured and calculated by a vernier caliper, and the specific calculation formula is as follows: w ═ V2xL/2, where V represents the tumor size (volume), W is the width of the tumor, and L is the length of the tumor.
When the tumor grows to about 100mm3In the meantime, mice were randomly divided into 5 groups, administered by tail vein injection, and irradiated with near infrared light (power density of 1W/cm) 12 hours after administration 23 minutes for light), the temperature change at the tumor site of the mice was continuously monitored and recorded during the light using a thermal imager. The specific grouping is as follows: (concentration of each group was 100. mu.g/mL)
1) PBS + NIR (near infrared): a blank control group was injected with a PBS (PH 7.4) solution and subjected to near-infrared light irradiation 12 hours after administration;
2) PDA + NIR (near infrared): injecting PDA solution (PDA dose is 2mg/kg mouse weight), and irradiating with near infrared ray 12 hr after administration;
3) PDA-CO + NIR (near Infrared): injecting PDA-CO solution (PDA-CO dose is 2mg/kg mouse body weight), and irradiating with near infrared light 12 hours after administration;
4) PDA-DOX + NIR (near Infrared): injecting PDA-DOX solution (PDA-DOX dose is 2mg/kg mouse weight), and irradiating with near infrared ray 12 hr after administration;
5) PDA-DOX-CO + NIR (near Infrared): PDA-DOX-CO solution (PDA-DOX-CO dose is 2mg/kg mouse body weight) is injected, and near infrared light irradiation is carried out 12 hours after administration.
The above administration and light treatment processes were performed 1 time, respectively, and then the physical conditions of the mice were continuously observed, and the body weight and tumor volume of the model mice were measured every two days. After 14 days, the mice were sacrificed and their tumors and heart, liver, spleen, lung, kidney were removed and blood stains were washed away with PBS (PH 7.4) solution. The removed tumor and main organs were fixed with 4% paraformaldehyde, and the tumor size and morphology were photographed and weighed.
The thermal imaging results of different nanotherapeutic groups on HCT-116 tumor mouse model are shown in FIG. 10. In FIG. 10, the changes in the temperature at the tumor sites of the mice in the PBS + NIR (near infrared) group, PDA-CO + NIR (near infrared) group, PDA-DOX + NIR (near infrared) group, and PDA-DOX-CO + NIR (near infrared) group at 30 seconds, 60 seconds, 120 seconds, and 240 seconds of light irradiation are recorded, respectively. Fig. 10 shows that the tumor site temperature and the illumination time are positively correlated, and the temperature reaches a maximum at 240 seconds of illumination.
The results of the temperature-raising test of different nano-treatment groups on the HCT-116 tumor mouse model are shown in FIG. 11, the PDA + NIR (near infrared) group, the PDA-CO + NIR (near infrared) group, the PDA-DOX + NIR (near infrared) group and the PDA-DOX-CO + NIR (near infrared) group all show excellent photothermal temperature-raising effects, the temperature-raising effect and the illumination time are in positive correlation, and the temperature reaches the maximum value when the illumination is carried out for 240 seconds. The PDA nanometer substrate is proved to have better temperature rising effect and photo-thermal response effect.
The results of the weight change of the different nano-treatment groups on the HCT-116 tumor mouse model are shown in fig. 12, and in fig. 12, no signs of weight loss of the mouse were observed when the mouse weight was continuously monitored for 14 days, and the mouse status was good, indicating that the nano-particles involved in the present invention have no adverse effect on the mouse.
The results of the changes in tumor volume of the HCT-116 tumor mouse model by the different nano-treatment groups are shown in fig. 13, and in fig. 13, the tumor volume of the mouse is monitored for 14 consecutive days, and the tumor growth conditions of the PDA + NIR (near infrared) group, PDA-CO + NIR (near infrared) group, PDA-DOX + NIR (near infrared) group, and PDA-DOX-CO + NIR (near infrared) group are all inhibited after the light treatment, wherein the tumor volume of the PDA-DOX-CO + NIR (near infrared) group is significantly decreased, which proves that the PDA-DOX-CO + NIR (near infrared) group has an excellent inhibitory effect on the tumor.
The tumor status of different nano-treatment groups acting on the HCT-116 tumor mouse model is shown in FIG. 14, and it can be seen from FIG. 14 that the tumors of other groups of mice are reduced compared with the PBS + NIR (near infrared) group, wherein the tumors of 3 mice in the PDA-DOX-CO + NIR (near infrared) group are completely eliminated, and the tumor inhibition rate reaches 60%, which indicates that the PDA-DOX-CO + NIR combined treatment well inhibits the proliferation of the tumors of the mice.
As shown in FIGS. 10-14, the PDA + NIR (near infrared), the PDA-CO + NIR (near infrared), the PDA-DOX + NIR (near infrared), and the PDA-DOX-CO + NIR (near infrared) all showed tumor inhibition effects at different degrees, wherein the PDA-DOX-CO + NIR treatment effect is most obvious, and part of tumors in tumor-bearing mice are completely eliminated. Therefore, the PDA-DOX-CO nanometer material has excellent photo-thermal conversion efficiency, can release CO and DOX according to needs under the trigger of NIR irradiation, enhances the combined effect of the DOX and the CO, particularly enhances the chemotherapy effect of the DOX by the CO, and promotes the anti-tumor effect.
Claims (9)
1. A nano-drug system for optically controlling release of carbon monoxide and adriamycin is characterized in that polydopamine is used as a nano-carrier, and pentacarbonyl manganese bromide and adriamycin are loaded on the polydopamine.
2. The method of preparing a nano-drug system for the controlled release of carbon monoxide and doxorubicin as claimed in claim 1, comprising the steps of:
(1) at room temperature, dispersing dopamine hydrochloride into double distilled water to obtain dopamine hydrochloride solution; adding NaOH solution into the mixture under vigorous stirring, rotationally stirring the mixture to obtain black solution, performing low-speed centrifugal separation to obtain supernatant, performing high-speed centrifugal separation on the supernatant, and removing the supernatant to obtain precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain manganese pentacarbonyl bromide solution; dissolving adriamycin into double distilled water to obtain adriamycin solution;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the polydopamine under vigorous stirring, obtaining a black solution after rotating and stirring the mixture at room temperature, and removing the supernatant through high-speed centrifugal separation to obtain a precipitate, namely the PDA-DOX-CO nano particles.
3. The method for preparing the nano-drug system for the light-operated release of carbon monoxide and adriamycin according to claim 2, wherein the low-speed centrifugation is 400-600 rpm centrifugation, and the high-speed centrifugation is 10000-12000 rpm centrifugation.
4. The method of preparing a light controlled release carbon monoxide and doxorubicin nanomedicine system according to claim 2, comprising the steps of:
(1) dispersing dopamine hydrochloride into double distilled water at room temperature to obtain 1-2 mg/mL dopamine hydrochloride solution; adding NaOH solution with the concentration of 0.8-1.2 mol/L into the mixture under vigorous stirring, rotationally stirring the mixture for 5-8 hours at 800-1000 rpm to obtain black solution, centrifuging the black solution for 5-10 minutes at 400-600 rpm, centrifuging the separated supernatant for 5-10 minutes at 10000-12000 rpm, removing the supernatant, and obtaining precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain a manganese pentacarbonyl bromide solution with the concentration of 1.8-2.2 mg/mL; dissolving adriamycin into double distilled water to obtain an adriamycin solution with the concentration of 1.2-1.6 mg/mL;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the double distilled water under vigorous stirring, rotationally stirring the mixture at room temperature of 800-1000 rpm for 5-8 hours to obtain a black solution, centrifuging the black solution at 10000-12000 rpm for 5-10 minutes, removing supernatant, and obtaining precipitate, namely PDA-DOX-CO nano particles;
wherein the mass ratio of the dopamine hydrochloride to the manganese pentacarbonyl bromide to the adriamycin is 15:0.9: 0.7-15: 1:0.8, the molar ratio of the dopamine hydrochloride to the NaOH is (1.6-1.3) to 1, and the volumes of double distilled water in the step (1) and the step (3) are the same.
5. The method of preparing a light controlled release carbon monoxide and doxorubicin nanomedicine system according to claim 2, comprising the steps of:
(1) at room temperature, dispersing dopamine hydrochloride into double distilled water to obtain 2mg/mL dopamine hydrochloride solution; adding NaOH solution with the concentration of 1mol/L under vigorous stirring, rotationally stirring at 1000rpm for 5 hours to obtain black solution, centrifuging at 400rpm for 5 minutes, separating to obtain supernatant, centrifuging at 10000rpm for 5 minutes, removing the supernatant, and obtaining precipitate, namely polydopamine;
(2) dissolving manganese pentacarbonyl bromide in absolute ethyl alcohol to obtain a manganese pentacarbonyl bromide solution with the concentration of 2 mg/mL; dissolving adriamycin into double distilled water to obtain an adriamycin solution with the concentration of 1.6 mg/mL;
(3) dispersing the polydopamine obtained in the step (1) into double distilled water, adding the manganese pentacarbonyl bromide solution and the adriamycin solution obtained in the step (2) into the double distilled water under vigorous stirring, rotationally stirring the mixture for 5 hours at room temperature and 1000rpm to obtain a black solution, centrifuging the black solution for 5 minutes at 10000rpm, and removing supernatant to obtain precipitate, namely the PDA-DOX-CO nano particles;
wherein the mass ratio of the dopamine hydrochloride to the manganese pentacarbonyl bromide to the adriamycin is 15:1:0.8, the molar ratio of the dopamine hydrochloride to the NaOH is 1.58:1.2, and the volumes of double distilled water in the step (1) and the step (3) are the same.
6. The use of the light-controlled release carbon monoxide and doxorubicin nano-drug system of claim 1 in tumor therapy. .
7. The application of the nano-drug system for optically controlling the release of carbon monoxide and adriamycin prepared by the preparation method of any one of claims 2 to 5 in tumor treatment.
8. Use according to claim 6 or 7, wherein the light-controlled release of carbon monoxide and doxorubicin nanomedicine system is administered simultaneously with irradiation with near infrared light in the wavelength range between 600 and 1000 nm.
9. The use of claim 8, wherein the nano-drug system for the controlled release of carbon monoxide and doxorubicin is administered simultaneously with irradiation with near infrared light at 808 nm.
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