CN115970002B - Multifunctional anti-tumor nano-drug delivery system and preparation method and application thereof - Google Patents
Multifunctional anti-tumor nano-drug delivery system and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a multifunctional anti-tumor nano-drug delivery system, a preparation method and application thereof, wherein the multifunctional anti-tumor nano-drug delivery system comprises: the preparation method comprises the steps of taking polylactide-glycolide as a carrier to co-load nano particles of hydrophilic chemotherapeutic drugs and hydrophobic anti-angiogenesis drugs, and coating polydopamine on the surfaces of the nano particles. The preparation method of the drug delivery system is simple and easy to operate, firstly, the nanometer particles are prepared from the polylactide-glycolide, the hydrophilic chemotherapy drug and the hydrophobic anti-angiogenesis drug by using an improved double-emulsion method, the package of the two drugs is realized, and then the nanometer compound coated by the polydopamine is prepared by a self-assembly method, so that the synergistic therapeutic effect of photo-thermal, chemotherapy and anti-tumor angiogenesis is realized.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a multifunctional anti-tumor nano-drug delivery system and a preparation method and application thereof, and in particular relates to a multifunctional anti-tumor nano-drug delivery system combining anti-tumor angiogenesis, chemotherapy and photothermal treatment, and a preparation method and application thereof.
Background
Cancer is a complex disease involving multiple pathogenesis, whose occurrence and progression is associated with a series of consecutive mutations in cells that support tumor cell survival and are therapeutic targets for most chemotherapeutic drugs. One of the challenges faced in tumor therapy is the inherent and acquired resistance of tumors to chemotherapeutic agents. Thus, inhibition of a single mechanism by a single drug may not achieve efficient inhibition of a tumor. In combination chemotherapy, two or more therapeutic agents are used simultaneously for cancer treatment, and these agents can act synergistically on different pathogenesis targets, thereby achieving a more efficient cancer treatment effect relative to single drug treatment. The combined administration mode can not only reduce the dosage of the medicine and the toxic and side effects of chemotherapy, but also improve the curative effect, realize the high-efficiency treatment of cancer and provide a new treatment mode for cancer research.
Research shows that angiogenesis plays an important role in the development and metastasis of tumors, and that anti-angiogenesis can be used as a potential target for tumor treatment. Further studies have shown that combination therapy with anti-angiogenic and other chemotherapeutic agents may lead to better therapeutic results and that this strategy is applicable to the treatment of most tumors. Therefore, combining anti-tumor angiogenesis therapy with other therapeutic approaches is an effective means to further expand the application of anti-angiogenesis therapies.
Photothermal therapy (photothermal therapy, PTT) uses a photothermal conversion agent to capture energy in light and convert it to thermal energy, causing a rapid rise in ambient temperature, thereby causing tumor cell death. Among the different modes of treatment of tumors, photothermal therapy has some unique advantages: the tumor site can be precisely targeted by using the external laser irradiation with adjustable dose, and the damage to surrounding healthy tissues can be reduced to the minimum; photothermal therapy is an efficient and noninvasive treatment means, and is applicable to various types of cancers.
PDA is one of the main pigments of natural melanin, has strong absorption in the near infrared region, and combines the excellent biocompatibility, so that the PDA can become a new generation of ideal photo-thermal conversion reagent to overcome the defects of the currently available photo-thermal conversion reagent, such as: the problems of poor biocompatibility of the inorganic photo-thermal reagent and poor water solubility, easy photo-bleaching and difficult accumulation of tumor parts of the organic photo-thermal reagent. The PDA has the following significant advantages: firstly, film can be adhered on the surfaces of various materials; secondly, because of various functional groups carried on the surface of the PDA, based on Michael addition and/or Schiff base reaction, the further biological functional modification on the surface of the PDA nano-particle can be easily realized; thirdly, the PDA has good free radical scavenging capability, the 120 mu g polydopamine coating can effectively scavenge 85% of DPPH free radicals, and the polydopamine coating can weaken the original side effects of biological materials, such as reducing inflammatory reaction of polylactic acid materials and the like; fourth, polydopamine is biodegradable in vivo and has no toxic or side effects. The polydopamine nanoparticles can also be used as nano drug carriers for drug delivery not only because they have good water solubility, excellent biocompatibility and biodegradability, but also because their surfaces can achieve drug molecule payloads through interaction forces.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a multifunctional anti-tumor nano-drug delivery system and a preparation method and application thereof, in particular to a multifunctional anti-tumor nano-drug delivery system combining anti-tumor angiogenesis, chemotherapy and photothermal treatment and a preparation method and application thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a multifunctional anti-tumor nano-drug delivery system comprising: the preparation method comprises the steps of taking polylactide-glycolide as a carrier to co-load nano particles of hydrophilic chemotherapeutic drugs and hydrophobic anti-angiogenesis drugs, and coating polydopamine on the surfaces of the nano particles.
The poly (lactide-co-glycolide) (PLGA) has the advantages of quality stability, biocompatibility, biodegradability, mechanical strength, degradation speed adjustability and good plasticity, and is a framework material of a common nano controlled release system. According to the invention, polydopamine is selected as a coating material for photothermal treatment, polylactide-glycolide is selected as a framework material, the biocompatibility of the polydopamine and glycolide is good, and hydrophilic chemotherapeutic drugs and hydrophobic anti-angiogenesis drugs are coated in the same nanoparticle, so that the co-delivery of the chemotherapeutic drugs and the anti-angiogenesis drugs is realized, and finally, a multifunctional anti-tumor nano drug delivery system combining anti-tumor angiogenesis, chemotherapy and photothermal treatment is obtained, the inhibition of the anti-angiogenesis effect of CA4 on the tumor vasculature and the high cytotoxicity of the chemotherapeutic drug DOX are utilized to kill tumor cells, and then non-invasive photothermal treatment is assisted, so that not only is nano drug enrichment targeted to tumor sites promoted, but also drug release rate is improved, and a good treatment effect on tumors is realized under the cooperation of various treatment strategies.
The invention takes breast cancer cells MDA-MB-231 as a model, detects the killing effect of the multifunctional anti-tumor nano drug delivery system (PDA@PLGA/DC) on breast cancer cells, and in vitro researches show that: PDA@PLGA/DC plays a role in synergy of the two drugs, and the auxiliary photothermal treatment shows more excellent curative effect on tumor cells. In vivo tumor-bearing nude mice are used as models, and the PDA@PLGA/DC is also proved to have very obvious tumor growth inhibition effect, stronger anti-tumor capability and therapeutic advantage.
The invention applies two materials with good biocompatibility, prepares the drug-loaded nano-particles with good anti-tumor effect, and provides a valuable thought for treating breast cancer.
Preferably, the mass ratio of the polydopamine, the polylactide-glycolide, the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenic drug is (0.1-10): 1-100): 0.1-10): 1-100; preferably (1-5): (10-50): (0.5-1.5): (10-50); more preferably (1.5-2): (15-20): (1-1.5): (20-25).
The specific point values in the above (0.1 to 10) may be selected from 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; specific point values in the above (1-100) may be selected from 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, etc.; other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
In the drug delivery system, when the mass ratio of the polydopamine, the polylactide-glycolide, the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenic drug meets the specific proportioning relationship, the stability and the pharmacodynamic activity of the system are more excellent.
Preferably, the particle size of the multifunctional anti-tumor nano-drug delivery system is 170-200nm, for example 170nm, 175nm, 180nm, 185nm, 190nm, 200nm, etc., and other specific point values within the numerical range can be selected, so that the details are not repeated here.
The particle size of the drug delivery system is controlled within 170-200nm, and the drug delivery system has good capability of passively targeting tumor parts, so that the anti-tumor effect is further promoted.
Preferably, the hydrophilic chemotherapeutic agent comprises doxorubicin hydrochloride.
Preferably, the hydrophobic anti-angiogenic drug comprises combretastatin A4.
Doxorubicin (DOX) has been widely used clinically as an anticancer drug of low molecular weight DNA interaction, however, because of its serious side effects on normal tissues, its use in tumor therapy is hindered, and thus, the controlled release of doxorubicin and targeting of tumor tissues to reduce its side effects is a clinical challenge to be solved urgently. Combretastatin A4 (CA 4) is an anti-angiogenic agent that disrupts new blood vessels and inhibits the formation of new blood, however, the hydrophobicity of CA4 limits its clinical immediate use and the monotherapy model of CA4 has great limitations.
The drug delivery system realizes the co-loading of the doxorubicin and the CA4, so that the toxic and side effects of the doxorubicin can be reduced, and better clinical application of the CA4 can be realized.
Preferably, the molecular weight of the polylactide-glycolide is 15000-30000Da, for example 15000Da, 18000Da, 20000Da, 22000Da, 24000Da, 26000Da, 28000Da, 30000Da, etc.
Preferably, the polylactide-glycolide has LA: ga=50:50-85:15, e.g. 50:50, 65:45, 70:30, 75:25, 80:20, 85:15, etc.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
The present invention can obtain different degradation modes by adjusting the ratio of polylactic acid (PLA) to polyglycolic acid (PGA) and the relative molecular weight of polylactide-glycolide, and more preferably the molecular weight range of 15000-30000Da and the range of LA: ga=50:50-85:15.
In a second aspect, the present invention provides a method for preparing the multifunctional antitumor nano-drug delivery system according to the first aspect, the method comprising:
(1) Mixing the polylactide-glycolide solution with a hydrophilic chemotherapeutic drug solution and a hydrophobic anti-angiogenesis drug solution, and performing first emulsification treatment to obtain colostrum;
(2) Mixing the formed colostrum with a surfactant solution, and performing a second emulsification treatment to obtain a complex emulsion;
(3) Removing the organic solvent in the complex emulsion, and centrifuging and purifying the residual solution to obtain double-drug-carrying nano particles;
(4) Dispersing the double-drug-carrying nano particles in a buffer solution, mixing with a dopamine hydrochloride solution, centrifuging and purifying to obtain the multifunctional anti-tumor nano drug delivery system.
The preparation method of the drug delivery system is simple and easy to operate, firstly, nanometer particles are prepared from poly (lactide-co-glycolide) (PLGA), hydrophilic drugs and hydrophobic drugs by an improved double-emulsion method, the two drugs are wrapped, and then the self-assembly method is used for preparing the polydopamine-coated nanometer compound, so that the nanometer compound has the synergistic therapeutic effects of photo-thermal treatment, chemotherapy and anti-tumor angiogenesis.
Preferably, the concentration of the hydrophilic chemotherapeutic agent solution of step (1) is 0.5-3mg/mL, e.g., 0.5mg/mL, 1mg/mL, 1.5mg/mL, 2mg/mL, 2.5mg/mL, 3mg/mL, etc.
The concentration of the hydrophilic chemotherapeutic agent solution is not particularly required, but in order to further improve the use effect of the chemotherapeutic agent, the concentration of the hydrophilic chemotherapeutic agent is preferably 0.5-3mg/mL.
Preferably, the concentration of the hydrophobic anti-angiogenic drug solution of step (1) is 5-25mg/mL, e.g. 5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, etc.
The concentration of the hydrophobic anti-angiogenic drug solution is not particularly required in the present invention, but in order to further enhance the use effect of the anti-angiogenic drug, the concentration of the anti-angiogenic drug is preferably 5-25mg/mL.
The hydrophobic anti-angiogenic drug can be dissolved in dimethyl sulfoxide (DMSO) to form a completely dissolved solution, and then the two drugs are simultaneously entrapped by using an improved double-emulsion method, so that a good entrapment effect can be obtained.
Preferably, the mass ratio of polylactide-glycolide to hydrophilic chemotherapeutic agent in the mixed solution obtained in step (1) is (5-15): (0.5-3), e.g. 5:0.5, 5:1, 5:2, 5:3, 10:0.5, 10:1, 10:2, 10:3, 15:0.5, 15:1, 15:2, 15:3, etc.; the mass ratio of polylactide-glycolide to hydrophobic anti-angiogenic drug is (5-15): (5-25), e.g. 5:5, 5:10, 5:15, 5:20, 5:25, 10:5, 10:10, 10:15, 10:25, 15:5, 15:10, 15:15, 15:20, 15:25, etc.
When the mass ratio of the polylactide-glycolide to the hydrophilic chemotherapeutic agent and the mass ratio of the polylactide-glycolide to the hydrophobic anti-angiogenic agent are within the specific ranges, the prepared drug delivery system has better activity and better stability.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
Preferably, the emulsification treatment in step (1) and step (2) is performed by ultrasonic emulsification and/or high pressure homogenization.
Preferably, the emulsification treatment of step (1) employs a phacoemulsification process with a power of 5-10%, e.g., 5%, 6%, 7%, 8%, 9%, 10%, etc.; the time is 1-5min, such as 1min, 2min, 3min, 4min, 5min, etc.
Preferably, the emulsification treatment of step (2) is performed by ultrasonic emulsification with a power of 20-40%, e.g. 20%, 25%, 30%, 35%, 40%, etc.; the time is 3-10min, such as 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min, etc.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
Preferably, the surfactant of step (2) comprises any one or a combination of at least two of sodium cholate, polyvinyl alcohol or poloxamer.
Sodium cholate is more preferred as a surfactant component in the present invention because it can better target the hydrophilic drug, hydrophobic drug and carrier polylactide-glycolide related to the present invention to achieve better emulsification and entrapment effects, thereby further improving the activity of the drug delivery system.
Preferably, the concentration of the surfactant solution is 0.5-5%, e.g., 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, etc.
The amount of surfactant used in the present invention is not particularly limited, and in order to further enhance the activity of the drug delivery system, the concentration of the surfactant solution is preferably 0.5 to 5%.
Preferably, the organic solvent is removed in step (3) by rotary evaporation or magnetic stirring.
Preferably, the purification in step (3) and step (4) is performed by a water wash method or a post-dialysis water wash method.
Preferably, the mass ratio of dopamine hydrochloride to dual drug delivery nanoparticle in step (4) is 1 (2-10), such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc.
Preferably, the buffer of step (4) is Tris buffer at ph=7.5-9.5.
Preferably, the mixing in step (4) is for a period of time ranging from 12 to 36 hours, for example 12 hours, 15 hours, 20 hours, 24 hours, 28 hours, 30 hours, 33 hours, 36 hours, etc.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
The preparation method is simple and easy to implement, solves the problem of compounding hydrophilic drugs and hydrophobic drugs in the drug delivery system, and shows that the multifunctional anti-tumor nano-drug delivery system has good tumor treatment effect by combining the chemotherapeutic drugs and the anti-angiogenesis drugs with photothermal treatment through in vitro cytotoxicity test, in vivo distribution condition, in vivo anti-tumor experiments of animals and the like.
In a third aspect, the present invention provides an application of the multifunctional anti-tumor nano-drug delivery system according to the first aspect in preparing a tumor therapeutic drug.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, polydopamine is selected as a coating material for photothermal treatment, polylactide-glycolide is selected as a framework material, the biocompatibility of the polydopamine and glycolide is good, and hydrophilic chemotherapeutic drugs and hydrophobic anti-angiogenesis drugs are coated in the same nanoparticle, so that the co-delivery of the chemotherapeutic drugs and the anti-angiogenesis drugs is realized, and finally, a multifunctional anti-tumor nano drug delivery system combining anti-tumor angiogenesis, chemotherapy and photothermal treatment is obtained, the inhibition of the anti-angiogenesis effect of CA4 on the tumor vasculature and the high cytotoxicity of the chemotherapeutic drug DOX are utilized to kill tumor cells, and then non-invasive photothermal treatment is assisted, so that not only is nano drug enrichment targeted to tumor sites promoted, but also drug release rate is improved, and a good treatment effect on tumors is realized under the cooperation of various treatment strategies. The preparation method of the drug delivery system is simple and easy to operate, firstly, nanometer particles are prepared from poly (lactide-co-glycolide) (PLGA), hydrophilic drugs and hydrophobic drugs by using an improved double-emulsion method, the package of the two drugs is realized, and then the nanometer compound coated by polydopamine is prepared by a self-assembly method, so that the synergistic therapeutic effects of photo-thermal treatment, chemotherapy and anti-tumor angiogenesis are realized.
Drawings
FIG. 1 is a transmission electron microscope image of the multifunctional antitumor nano-drug delivery system prepared in example 1;
FIG. 2 is a graph showing the particle size distribution of the multifunctional antitumor drug delivery system prepared in example 1;
FIG. 3 is a graph showing the particle size of the multifunctional antitumor nano-drug delivery system measured by a laser particle sizer at different times;
FIG. 4 is a graph showing the temperature change of a multifunctional anti-tumor nano-drug delivery system at different concentrations under laser irradiation;
FIG. 5 is a graph of cumulative release rates of doxorubicin hydrochloride (A) and combretastatin A4 (B) in vitro for a multifunctional antitumor drug nano-delivery system;
FIG. 6 is a graph of in vitro cytotoxicity results for a multifunctional anti-tumor nanomedicine delivery system;
FIG. 7 is a graph showing the profile of a multifunctional anti-tumor nano-drug delivery system in tumor-bearing nude mice;
fig. 8 is a graph of statistical results of in vivo antitumor effects of the multifunctional antitumor nano-drug delivery system.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The following examples relate to some of the raw material sources as follows:
polylactide/glycolide (LA/ga=75:25, molecular weight 20,000 da) was purchased from biotech limited, jinan, china; dopamine hydrochloride, sodium cholate were purchased from Sigma-Aldrich company, usa; doxorubicin hydrochloride was purchased from beijing toyobion limited, china; combretastatin A4 was purchased from switzerland biochemistry limited in china; CCK-8 cytotoxicity kits were purchased from the Japan Tonic chemical institute; transmission electron microscopy, FEI, tecnai G2 20S-TWIN,200kV; malvern Zetasizer nano ZS gauge, UK, malvern Instruments, UK; maestro small animal fluorescence imaging system, CRI in the united states; thermal infrared imager, flukeTi27, usa.
Example 1
The embodiment provides a multifunctional anti-tumor nano-drug delivery system, which is prepared by the following steps:
(1) Dissolving CA4 in dimethyl sulfoxide to form 10mg/mL CA4 solution;
(2) Dissolving PLGA in methylene dichloride to form a PLGA solution of 10 mg/mL;
(3) Adding 1mL of 2mg/mL DOX HCl solution into a centrifuge tube filled with 1mL of 10mg/mL PLGA solution, adding 1mL of 10mg/mL CA4 solution, placing into an ultrasonic cell crusher for ultrasonic emulsification, setting the power to be 8%, placing the centrifuge tube into an ice bath, and performing ultrasonic treatment for 3 minutes to form colostrum;
(4) Adding 4mL of 1% sodium cholate aqueous solution into the formed colostrum, setting the power of an ultrasonic cell crusher to 30%, and performing ultrasonic emulsification again for 5 minutes to form a compound emulsion;
(5) Removing dichloromethane from the double emulsion by rotary evaporation with a rotary evaporator, pouring the remaining solution into a centrifuge tube, centrifuging at 12000rpm for 20 minutes, and washing with deionized water three times to prepare double-drug-carrying nanoparticles (PLGA/DC NPs);
(6) 2mg of the prepared double drug-loaded nanoparticle (PLGA/DC NPs) was dispersed in 1mL of Tris buffer (10 mmol/L, pH=8.5), then 1mL of 1mg/mL dopamine hydrochloride solution was added, and the two were uniformly mixed and stirred for 24 hours to prepare a gray black solution. After centrifugation at 15000rpm for 20 minutes, washing with deionized water for three times, and obtaining PDA coated double-drug-loaded nano particles (PDA@PLGA/DC NPs), namely the multifunctional anti-tumor nano drug delivery system.
Example 2
The embodiment provides a multifunctional anti-tumor nano-drug delivery system, which is prepared by the following steps:
(1) Dissolving CA4 in dimethyl sulfoxide to form 10mg/mL CA4 solution;
(2) Dissolving PLGA in methylene dichloride to form 15mg/mL PLGA solution;
(3) Adding 1mL of 2mg/mL DOX HCl solution into a centrifuge tube filled with 1mL of 10mg/mL PLGA solution, adding 1mL of 10mg/mL CA4 solution, placing into an ultrasonic cell crusher for ultrasonic emulsification, setting the power to be 5%, placing the centrifuge tube into an ice bath, and performing ultrasonic treatment for 5 minutes to form colostrum;
(4) Adding 4mL of 1.5% sodium cholate aqueous solution into the formed colostrum, setting the power of an ultrasonic cell crusher to 35%, and performing ultrasonic emulsification again for 4 minutes to form a compound emulsion;
(5) Removing dichloromethane from the double emulsion by rotary evaporation with a rotary evaporator, pouring the remaining solution into a centrifuge tube, centrifuging at 12000rpm for 20 minutes, and washing with deionized water three times to prepare double-drug-carrying nanoparticles (PLGA/DC NPs);
(6) 2mg of the prepared double drug-loaded nanoparticle (PLGA/DC NPs) was dispersed in 1mL of Tris buffer (10 mmol/L, pH=8.0), then 1mL of 1mg/mL dopamine hydrochloride solution was added, and the two were uniformly mixed and stirred for 36 hours to prepare a gray black solution. After centrifugation at 15000rpm for 20 minutes, washing with deionized water for three times, and obtaining PDA coated double-drug-loaded nano particles (PDA@PLGA/DC NPs), namely the multifunctional anti-tumor nano drug delivery system.
Test example 1
The PDA coated double-drug-loaded nanoparticles (PDA@PLGA/DC NPs+NIR) prepared in example 1 and example 2 are observed under a transmission electron microscope, and the products in the visual field are in a typical sphere shape and have the particle size of about 185 nm. A transmission electron micrograph of the sample of example 1 is shown in FIG. 1 (scale: 200 nm).
The particle diameters of the PDA-coated double-drug-loaded nanoparticles prepared in example 1 and example 2 were measured by a laser particle sizer and were 190.4.+ -. 0.18nm and 192.7.+ -. 0.41nm, respectively. The particle size distribution of the sample of example 1 is shown in FIG. 2.
The sample prepared in example 1 was left at 30℃for 10 days, and its particle diameter was measured by a laser particle sizer to evaluate its stability, and the results are shown in FIG. 3.
Test example 2
The test example detects the temperature change condition of the PDA coated double-drug-loaded nano particles (PDA@PLGA/DC NPs) prepared in the example 1 with different concentrations under the in-vitro laser irradiation, and the specific method is as follows:
placing physiological saline and sample solutions with different concentrations into a centrifuge tube, irradiating with 808nm laser, and irradiating physiological saline and sample solutions with different concentrations with laser (806 nm,1W/cm 2 5 minutes) and drawing a temperature change curve within 5 minutes at different concentrations according to the temperature change of the temperature change, and the result is shown in fig. 4.
As can be seen from FIG. 4, the temperature rise of PDA@PLGA/DC NPs under laser irradiation has a significant concentration dependence. When the PDA@PLGA/DC NPs concentration is 150 μg/mL, the temperature can be raised to 54℃in 5 min.
Test example 3
The test example detects the in vitro release conditions of doxorubicin hydrochloride and combretastatin A4 in the PDA coated double-drug-loaded nano-particles (PDA@PLGA/DC NPs) prepared in example 1, and the specific method is as follows:
the in vitro release behaviour of doxorubicin hydrochloride and combretastatin A4 (CA 4) was studied by dialysis, transferring 3mL of the sample solution into a dialysis bag (molecular weight cut-off 3500 Da), placing it in 40mL of PBS (pH 5.2) solution, and then dialyzing in a thermostatic water bath shaker (37 ℃ C., 100 rpm). According to the experimental settings, different components were subjected to different laser irradiation (806 nm,1W/cm 2 5 minutes). At different set time points, 1mL of supernatant was taken out, and the same volume of fresh buffer was added to make up. The concentration of the accumulated released doxorubicin hydrochloride was calculated by measuring absorbance at 480nm with an ultraviolet-visible spectrophotometer (UV-vis) (general analysis TU-1810 ultraviolet-visible spectrophotometer, china, beijing), and the concentration of the accumulated released CA4 was calculated by measuring absorbance at 294nm with an ultraviolet-visible spectrophotometer (UV-vis) (general analysis TU-1810 ultraviolet-visible spectrophotometer, china, beijing). And is plotted accordingly at pH 5.2 with laser irradiation (806 nm,1W/cm 2 5 minutes) and in vitro release profiles of DOX and CA4 in samples at different times without laser irradiation, the results are shown in figure 5.
As can be seen from fig. 5, the cumulative drug release percentages of DOX and CA4 were significantly higher when irradiated with laser than when not irradiated with laser, and CA4 and DOX reached about 55% and 53% in an acidic environment (pH 5.2). Therefore, the release of the drug in the PDA@PLGA/DC NPs is facilitated under the irradiation of external laser, the drug release percentage of the acidic environment in the simulated tumor cells is higher, and the stronger anti-tumor treatment effect is facilitated.
Test example 4
This test example evaluates the cytotoxicity of the PDA-coated, dual drug loaded nanoparticle (pda@plga/DC NPs) prepared in example 1, as follows:
MDA-MB-231 cells were seeded into 96-well cell culture plates for overnight, and then incubated with a gradient concentration sample solution for 24 hours. Cytotoxicity assays were performed with CCK-8 kit. To investigate the effect of photothermal treatment, MDA-MB-231 cells were seeded in 96-well cell culture plates overnight, and then incubated with a gradient concentration sample solution for 12 hours, followed by laser (806 nm,1W/cm 2 ) After 5 minutes of irradiation and 12 hours of incubation, cytotoxicity was detected using the CCK-8 kit. And thus the cell survival curves at different nano-drug composition concentrations were plotted, and the results are shown in fig. 6.
As can be seen from fig. 6, pda@plga/DC NPs exert a dual drug combination effect, and the auxiliary photothermal treatment shows more excellent curative effect on tumor cells, and the cell survival rate is less than 10%.
Test example 5
The present test example evaluates the in vivo distribution of the PDA coated dual drug loaded nanoparticle (pda@plga/DC NPs) prepared in example 1, as follows:
18-20g of female BALB/c nude mice were purchased from the Peking Vitolith laboratory animal center, peking China. All animal operations were performed according to the national center for nano science and technology, guidelines for laboratory animal care and use, and were approved by the national Institutes of Animal Care and Use (IACUC), conforming to the laws associated with laboratory animals in china. By subcutaneous inoculation of the right leg of female BALB/c nude mice with 1X 10 6 The MDA-MB-231 cells construct a triple negative breast cancer model. When the tumor grows to about 100mm 3 In the case of using nanoparticles of the entrapped fluorescent dye IR-780 (concentration of IR 780: 100 mg/mL), tail vein injection was performed, and in vivo fluorescence distribution of mice was recorded by photographing using a Maestro small animal fluorescence imaging system at 0h, 2h, 4h, 8h and 24h, respectively, and the results are shown in FIG. 7.
As can be seen from FIG. 7, the fluorescence signal was significantly distributed in the mice after 2 hours of injection. Fluorescent signals showed a high trend to tumor sites after 8 hours of injection. At 12 and 24h, there was a very strong fluorescent signal at the tumor site, indicating that PDA@PLGA/DC NPs could effectively accumulate at the tumor site.
Test example 6
The test example evaluates the in vivo antitumor effect of the PDA coated double-drug-loaded nanoparticle (PDA@PLGA/DC NPs) prepared in example 1, and the specific method is as follows:
by subcutaneous inoculation of 1X 10 in the right armpit leg of female BALB/c nude mice 6 The MDA-MB-231 cells construct a triple negative breast cancer model. When the tumor grows to about 100mm 3 At this time, mice with MDA-MB-231 tumors were randomly divided into 5 groups (5 per group). Physiological Saline (Saline), empty nanocarriers plus laser irradiation groups (PDA@PLGA NPs+NIR), DOX & HCl nanoparticle groups alone (PDA@PLGA/D NPs), CA4 nanoparticle groups alone (PDA@PLGA/C NPs), co-loaded DOX and CA4 plus laser irradiation nanoparticle groups (PDA@PLGA/DC NPs+NIR), respectively.
The size of the tumor volume of the mice was recorded with vernier calipers. Tumor volume calculation formula: v=l×w 2 And/2, wherein L represents the length of the tumor, W represents the width of the tumor, and the statistical result is shown in FIG. 8.
As can be seen from fig. 8, the monotherapy regimens (pda@plga nps+nir, pda@plga/D NPs, pda@plga/C NPs) showed very limited anti-tumor efficacy compared to the control group, reaching 10% -30% tumor inhibition effect. In contrast, pda@plga/DC nps+nir showed very pronounced tumor growth inhibition, with almost complete inhibition of tumor growth, indicating that pda@plga/DC nps+nir has a stronger anti-tumor capacity, showing the therapeutic advantage of the multifunctional nano-drug system.
The applicant states that the present invention is described by the above examples to illustrate the multifunctional antitumor nano-drug delivery system of the present invention and the preparation method and application thereof, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be practiced depending on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (19)
1. A multifunctional anti-tumor nano-drug delivery system, characterized in that the multifunctional anti-tumor nano-drug delivery system comprises: taking polylactide-glycolide as a carrier to co-load nano particles of hydrophilic chemotherapeutic drugs and hydrophobic anti-angiogenesis drugs, and polydopamine coated on the surfaces of the nano particles;
wherein the loading mode is that the polylactide-glycolide wraps the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenesis drug in the same nanoparticle;
the multifunctional anti-tumor nano-drug delivery system is prepared by adopting the following method, wherein the method comprises the following steps of:
(1) Mixing the polylactide-glycolide solution with a hydrophilic chemotherapeutic drug solution and a hydrophobic anti-angiogenesis drug solution, and performing first emulsification treatment to obtain colostrum;
(2) Mixing the formed colostrum with a surfactant solution, and performing a second emulsification treatment to obtain a complex emulsion;
(3) Removing the organic solvent in the complex emulsion, and centrifuging and purifying the residual solution to obtain double-drug-carrying nano particles;
(4) Dispersing the double-drug-carrying nano-particles in a buffer solution, mixing with a dopamine hydrochloride solution, centrifuging and purifying to obtain the multifunctional anti-tumor nano-drug delivery system;
the mass ratio of the polydopamine, the polylactide-glycolide, the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenesis drug is (1-5): 10-50): 0.5-1.5): 10-50;
the hydrophilic chemotherapeutic drug is doxorubicin hydrochloride;
the hydrophobic anti-angiogenesis drug is combretastatin A4;
the tumor is breast cancer.
2. The multifunctional antitumor nano-drug delivery system according to claim 1, wherein the mass ratio of the polydopamine, the polylactide-glycolide, the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenic drug is (1.5-2): 15-20): 1-1.5): 20-25.
3. The multifunctional antitumor nano-drug delivery system according to claim 1, wherein the multifunctional antitumor nano-drug delivery system has a particle size of 170-200 nm.
4. The multifunctional antitumor nanomedicine delivery system of claim 1 wherein the polylactide-glycolide has a molecular weight of 15000-30000 Da.
5. The multifunctional antitumor nanomedicine delivery system of claim 1, wherein LA: GA = 50:50-85:15 in the polylactide-glycolide.
6. The method of preparing a multifunctional antitumor nanomedicine delivery system according to any one of claims 1-5, wherein the method of preparing comprises:
(1) Mixing the polylactide-glycolide solution with a hydrophilic chemotherapeutic drug solution and a hydrophobic anti-angiogenesis drug solution, and performing first emulsification treatment to obtain colostrum;
(2) Mixing the formed colostrum with a surfactant solution, and performing a second emulsification treatment to obtain a complex emulsion;
(3) Removing the organic solvent in the complex emulsion, and centrifuging and purifying the residual solution to obtain double-drug-carrying nano particles;
(4) Dispersing the double-drug-carrying nano-particles in a buffer solution, mixing with a dopamine hydrochloride solution, centrifuging and purifying to obtain the multifunctional anti-tumor nano-drug delivery system;
the mass ratio of the polydopamine, the polylactide-glycolide, the hydrophilic chemotherapeutic drug and the hydrophobic anti-angiogenesis drug is (1-5): 10-50): 0.5-1.5): 10-50;
the hydrophilic chemotherapeutic drug is doxorubicin hydrochloride;
the hydrophobic anti-angiogenesis drug is combretastatin A4;
the tumor is breast cancer.
7. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 6, wherein the concentration of the hydrophilic chemotherapeutic drug solution in the step (1) is 0.5-3mg/mL.
8. The method of claim 6, wherein the concentration of the hydrophobic anti-angiogenic drug solution in step (1) is 5-25mg/mL.
9. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 6, wherein the emulsification treatment in step (1) and step (2) adopts a phacoemulsification method and/or a high-pressure homogeneous emulsification method.
10. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 9, wherein the emulsification treatment in the step (1) adopts a ultrasonic emulsification method, the power is 5-10%, and the time is 1-5 min.
11. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 9, wherein the emulsification treatment in the step (2) adopts a ultrasonic emulsification method, the power is 20-40%, and the time is 3-10 min.
12. The method of claim 6, wherein the surfactant in step (2) comprises any one or a combination of at least two of sodium cholate, polyvinyl alcohol, and poloxamer.
13. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 6, wherein the concentration of the surfactant solution is 0.5-5%.
14. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 6, wherein the step (3) of removing the organic solvent adopts a rotary evaporation method or a magnetic stirring method.
15. The method of claim 6, wherein the purification in step (3) and step (4) is performed by a water washing method or a post-dialysis water washing method.
16. The method for preparing a multifunctional antitumor nano-drug delivery system according to claim 6, wherein the mass ratio of the dopamine hydrochloride to the dual drug-carrying nano-particles in the step (4) is 1 (2-10).
17. The method of claim 6, wherein the buffer in step (4) is Tris buffer with ph=7.5-9.5.
18. The method of claim 6, wherein the mixing in step (4) is performed for a period of time ranging from 12 to 36 h.
19. Use of the multifunctional antitumor nano-drug delivery system according to any one of claims 1-5 for the preparation of a breast cancer treatment drug.
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