CN114873629A - Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier - Google Patents

Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier Download PDF

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CN114873629A
CN114873629A CN202210695944.XA CN202210695944A CN114873629A CN 114873629 A CN114873629 A CN 114873629A CN 202210695944 A CN202210695944 A CN 202210695944A CN 114873629 A CN114873629 A CN 114873629A
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赵美霞
李林松
杨晓静
陈鹏威
赵雪杰
程冬
刘棒棒
程晓祎
汤显蛟
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Henan University
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Abstract

The invention relates to a preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier, which comprises the following steps: firstly, near-infrared light response nano-material hollow mesoporous copper sulfide nano-particles (HMCuS NPs) are synthesized, a chemotherapeutic drug Doxorubicin (DOX) is encapsulated by utilizing a unique cage-shaped structure of the HMCuS NPs, the drug loading capacity is greatly improved, then the outer surface of the HMCuS NPs is modified by a liver cancer targeting peptide 9R-P201 peptide to obtain the hollow mesoporous copper sulfide nano-drug HMCD9P with liver cancer targeting, and finally the combined treatment effect of nano-drug chemotherapy, photo-thermal treatment and photodynamic treatment is realized. In tumor-bearing mice experiments, the tumor-bearing mice treated with the HMCD9P + L group showed a tumor inhibition rate of about 88.2% under near infrared light irradiation. The HMCD9P can be used as a nano therapeutic agent for efficiently and accurately inducing chemotherapy, photo-thermal and photodynamic therapy, and has excellent anti-tumor effect and small side effect.

Description

Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier
Technical Field
The invention belongs to the technical field of biological medicine and health, and particularly relates to a preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier.
Background
Copper sulfide is used as a novel near-infrared light nano response material, and has good photo-thermal stability and biocompatibility. On the one hand, copper sulfide as a p-type semiconductor has a strong Local Surface Plasmon Resonance (LSPR) effect on NIR light, and the photothermal conversion efficiency is higher compared to other photothermal conversion materials. In addition, the copper sulfide absorbs NIR to generate heat to cause the expansion of biological tissues, can generate photoacoustic signals, can be used as an excellent photoacoustic imaging contrast agent, and can accurately position tumor parts/sizes/forms. On the other hand, under the irradiation of near infrared light, copper ions leaked from the copper sulfide can generate oxidation-reduction reaction with a buffer solution matrix in the surrounding environment of the tumor to generate hydroxyl radicals (∙ OH) for photodynamic therapy. Copper sulfide, unlike other NIR-responsive materials, can only produce a single heat or active oxygen for anti-tumor therapy. It can be used for photothermal therapy (PTT), photodynamic therapy (PDT) and photoacoustic imaging (PAT) at the same time, and has great advantages in tumor diagnosis and treatment.
Although copper sulfide is a photo-thermal nano-carrier material with great potential, the application of copper sulfide in preparing tumor treatment drugs still faces many challenges, such as: poor water dispersibility, low tumor cell targeting property and the like, and is difficult to realize the targeted transfer of the medicine and the high-efficiency and low-toxicity photo-thermal combined chemotherapy. Therefore, how to prepare the hollow mesoporous copper sulfide nano-drug carrier modified by the liver cancer targeting peptide to realize the application in preparing the drugs for treating tumors is a technical problem to be solved seriously.
Disclosure of Invention
The invention mainly aims to overcome the defects of the prior art and provides a preparation method of a hollow mesoporous copper sulfide nano-drug carrier.
The invention also aims to provide the application of the hollow mesoporous copper sulfide nano-drug carrier in drug loading.
The invention also provides a method for preparing the nano-drug by using the nano-drug carrier.
In order to achieve the above object, the present invention provides the following technical solutions:
a preparation method of a hollow mesoporous copper sulfide nano-drug carrier comprises the following steps:
step 1, dispersing a copper chloride dihydrate solution with the concentration of 0.4-0.6mol/L and polyvinylpyrrolidone (PVP-K30) in water (stirring for 2-8 min) at room temperature to obtain a mixed solution A; wherein, the concentration of the polyvinylpyrrolidone in the mixed solution A is 5-15 mg/mL, and the concentration of the copper chloride dihydrate is 0.1-0.3 mg/mL; further preferably, the mass ratio of the copper chloride dihydrate to the polyvinylpyrrolidone in the mixed solution A is 1: 40-60;
step 2, adding 10-30 mu L of 50% (mass percent) hydrazine hydrate solution with reduction effect into the mixed solution A, and stirring for 2-8 min to obtain a mixed solution B; wherein the volume ratio of the copper chloride dihydrate solution to the hydrazine hydrate solution is 1: 0.1-0.3;
step 3, adding 40-60 mL of sodium hydroxide solution providing alkaline condition pH =9 into the mixed solution B, and stirring for 2-8 min to obtain a mixed solution C; wherein the volume ratio of the copper chloride dihydrate solution to the sodium hydroxide solution is 1: 400-600;
step 4, adding 300 and 500 mu L of 330 mg/mL sodium sulfide nonahydrate solution into the mixed solution C, stirring for 2-8 min, and performing oil bath reaction for 1-4 h at the temperature of 30-90 ℃ to obtain a mixed solution D; wherein the volume ratio of the copper chloride dihydrate solution to the sodium sulfide nonahydrate solution is 1: 3-5;
step 5, under the condition of room temperature, firstly centrifuging the mixed solution D (11000-; dispersing the dark brown solid in water to obtain a product E, namely the nano-drug carrier; the solid-liquid ratio of the product E is 1 g: 3000-5000 ml. The solid-liquid ratio refers to the addition ratio of the dark brown solid to water.
Specifically, in step 1, the molecular weight of the polyvinylpyrrolidone (PVP-K30) is 50000-60000 Da.
The invention provides the hollow mesoporous copper sulfide nano-drug carrier prepared by the method.
The invention also provides the application of the nano-drug carrier in drug loading, for example, the nano-drug carrier is used for preparing drugs, in particular preparing anti-tumor drugs and the like.
The invention also provides a method for preparing the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using the nano-drug carrier, which comprises the following steps:
step a, performing ultrasonic treatment on the product E for 20-30 min by using an ultrasonic cell crusher at room temperature, adding 300 mg of thiol-containing coating 100-; wherein the mass ratio of the black brown solid in the sulfydryl-containing coating and the product E is 1-3: 1;
b, performing ultrasonic treatment on the product F for 20-30 min by using an ultrasonic cell crusher at room temperature, adding adriamycin (DOX) medicine, stirring for 2-48 h in a dark place, centrifuging, washing, performing freeze drying for 20-30 h under the conditions of low temperature and high vacuum, and re-dissolving by using a phosphate buffer solution to obtain a product G; wherein the mass ratio of the black brown solid in the adriamycin medicine and the product E is 1-3: 1;
step c, placing the 9R-P201 peptide into a phosphate buffer solution with the pH value of 7-9 at room temperature, adding carbodiimide hydrochloride and N-hydroxysuccinimide to activate carboxyl on the 9R-P201 peptide, and stirring for 20-40 min to obtain an activated 9R-P201 peptide solution H; wherein the mass ratio of the 9R-P201 peptide to the carbodiimide hydrochloride to the N-hydroxysuccinimide is 1: 0.3-0.7: 0.3-0.7;
d, mixing the product G with the activated 9R-P201 peptide solution H at room temperature, stirring for 12-48H in the dark, centrifuging, washing, and freeze-drying for 20-30H under the low-temperature high-vacuum condition (preferably, re-dissolving the product with ultrapure water, centrifuging, washing, and freeze-drying for 20-30H under the low-temperature high-vacuum condition) to obtain the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug I (HMCuS @ DOX-9R-P201, abbreviated as HMCD 9P); wherein the mass ratio of the 9R-P201 peptide to the adriamycin is 1: 1-3.
Specifically, in the step a, the mercapto-containing coating comprises beta-mercaptoethylamine, mercaptopropionic acid or thioglycolic acid and the like, and the mercapto-containing coating is mainly used as a bridge to connect HMCuS and 9R-P201 peptide.
Specifically, the liver cancer targeting peptide includes (such as 9R-P201 peptide, A54 peptide, SP94 peptide, AM-2 peptide, T7 peptide, BP9 peptide, X1 peptide, L5 peptide, etc.), such as 9R-P201 peptide. In step c, the 9R-P201 peptide is one of liver cancer targeting peptides, and the peptide sequence is as follows: AAAAAAAAAGSGSTHLATPSMTTLA is added.
The invention also provides the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug prepared by the method, and the nano-drug can be applied to the aspects of chemotherapy, thermotherapy, photodynamic combination therapy and the like. Namely, the invention provides a drug with chemotherapy-thermotherapy-photodynamic combined treatment function, which comprises the hollow mesoporous copper sulfide nano-drug carrier. The invention introduces the adriamycin medicine into the hollow mesoporous copper sulfide nano medicine carrier, and can be applied to the combined treatment of chemotherapy, photodynamic treatment, photothermal treatment and the like of cancers.
The invention introduces the liver cancer targeting peptide 9R-P201 peptide into the surface of the hollow mesoporous copper sulfide nano-drug carrier, and can be applied to the specific targeting of liver cancer.
Compared with the prior art, the hollow mesoporous copper sulfide nano-drug carrier has the following advantages:
1) taking copper chloride dihydrate, polyvinylpyrrolidone (PVP-K30), sodium hydroxide, hydrazine hydrate and sodium sulfide nonahydrate as raw materials, and taking the prepared dark brown solid as hollow mesoporous copper sulfide nano-particles; then taking the adriamycin medicine, beta-mercaptoethylamine, 9R-P201 peptide and hollow mesoporous copper sulfide nano particles as raw materials to obtain the liver cancer targeted peptide modified hollow mesoporous copper sulfide nano medicine. The raw materials adopted by the invention have low toxicity and high safety.
2) The hollow mesoporous copper sulfide nano-particles are synthesized in a low-temperature aqueous solution by adopting nontoxic and easily obtained polyvinylpyrrolidone (PVP-K30) as an active agent and a stabilizing agent, so that the operation is simple, the reaction condition is mild and controllable, and the cost is low; the surface of the hollow mesoporous copper sulfide nano-drug carrier is modified with the 9R-P201 peptide with liver cancer targeting, so that the hydrophilicity of the prepared hollow mesoporous copper sulfide nano-drug carrier with the liver cancer targeting modification in aqueous solution and the effect of specifically targeting the liver cancer are further improved.
3) The surface potential of the hollow mesoporous copper sulfide nano-drug carrier is negative, the negative potential is beneficial to the dispersion of the nano-drug carrier, the size is 100-150 nm, the size distribution is uniform and the dispersion is uniform, and the circulation in organisms is facilitated.
4) The invention can effectively combine the photodynamic and photothermal treatment effects of the hollow mesoporous copper sulfide material with the chemotherapy of the adriamycin medicine, thereby enhancing the photodynamic; the prepared liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-medicament has little toxicity to normal liver cells and strong toxicity to liver cancer tumor cells, and can realize the photo-thermal/photodynamic/chemotherapy combined treatment of tumors.
5) The preparation method has the characteristics of simple operation, high safety, mild reaction conditions, controllable reaction process and low cost, and the prepared hollow mesoporous copper sulfide nano-drug carrier has good hydrophilicity, small size, specific targeting and low reagent toxicity, and is beneficial to in vivo circulation.
Drawings
FIG. 1 shows the products E (HMCuS) (a) and G (HMCuS-NH) in example 1 2 Transmission Electron Microscopy (TEM) images of @ DOX) (b) and product I (HMCD 9P) (c);
FIG. 2 shows the results of example 1 for product E (HMCuS) and product F (HMCuS-NH) 2 ) Product G (HMCuS-NH) 2 @ DOX) and product I (HMCD 9P);
FIG. 3 shows the results of example 1 for product E (HMCuS) and product F (HMCuS-NH) 2 ) Product G (HMCuS-NH) 2 The Zeta potential maps of @ DOX), the 9R-P201 peptide and product I (HMCD 9P);
FIG. 4 shows the product E (HMCuS) and the product F (HMCuS-NH) of example 1 2 ) An infrared spectrum of (1);
FIG. 5 is the EDS diagram for product E (HMCuS) from example 1;
FIG. 6 is a graph of the in vitro release of product I (HMCD 9P) from example 1 at various pHs and with or without laser irradiation;
FIG. 7 is a graph showing the experimental hemolysis rate of product I (HMCD 9P) from example 1;
FIG. 8 shows the laser intensity at 808 nm (1W/cm) of product I (HMCD 9P) from example 1 2 ) Irradiating for 8 min to obtain temperature variation graph (a) with different concentrations and temperature variation graph (b) with different powers for irradiating for 8 min under 808 nm laser to obtain product I (HMCD 9P) with 100 μ g/mL;
FIG. 9 shows the 808 nm laser (1W/cm) of product I (HMCD 9P) of example 1 2 ) Irradiating for 5 min to obtain infrared thermal imaging images with different concentrations;
FIG. 10 shows the 808 nm laser (1W/cm) of product I (HMCD 9P) of example 1 2 ) Temperature profile over 5 laser on/off cycles with 100 μ g/mL of down-irradiation;
FIG. 11 is a graph of viability of product E (HMCuS) of example 1 on HePG2 cells before and after laser irradiation (a), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and doxorubicin inSurvival rate of HePG2 cells before and after irradiation with or without laser beam (b);
FIG. 12 is an image taken ex vivo of product I (HMCD 9P) of example 1 on the major organs of a H22 tumor-bearing mouse;
FIG. 13 shows the results of example 1, product I (HMCD 9P) vs. H22 tumor-bearing mice on a 808 nm laser (1W/cm) 2 ) Irradiating for 5 min, and imaging by infrared in vivo;
FIG. 14 shows the results of example 1 for product E (HMCuS), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and doxorubicin at the end of treatment of H22 tumor-bearing mice with or without laser irradiation (a) representative photographic images of the different groups, (b) digital images of the tumor tissue, (c) a graph of the change in mouse body weight, (d) a graph of tumor growth, and (e) a graph of the change in tumor weight;
FIG. 15 shows the results of example 1 for product E (HMCuS), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and adriamycin were stained with HE (Western blot) of tissue sections of Heart, liver Live, Spleen Spleen, Lung Lung and Kidney at the end of treatment of H22 tumor-bearing mice with or without laser irradiation;
FIG. 16 shows the results of example 1 for product E (HMCuS), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and doxorubicin the HE and TUNEL staining profiles of dissected tumor tissue sections at the end of treatment of H22 tumor-bearing mice with or without laser irradiation.
Detailed Description
For a further understanding of the invention, reference should be made to the following further description, taken in conjunction with the accompanying drawings and detailed description, but it is understood that the description is intended to further illustrate the features and advantages of the invention and is not intended to limit the scope of the invention.
Name and model of the experimental instrument:
U.S. Perkin-Elmer Lambda-850 UV Spectrophotometer;
japanese JEOL JEM-200CX transmission electron microscope;
a U.S. BioTek multifunctional microplate reader;
germany LEICA TCS SP8+ STED laser confocal microscope;
BD facverse flow cytometer in usa;
laboconco-FreeZone 6L freeze-drying system, usa;
an ultrasensitive multifunctional imager of American Cytiva and AI800 flours;
unless otherwise specified, room temperature refers to 25 ± 5 ℃.
Example 1
A preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier. The preparation method of the embodiment comprises the following steps:
step 1, dispersing 100 μ L of 0.5mol/L copper chloride dihydrate solution and 480 mg of polyvinylpyrrolidone (PVP-K30, molecular weight 50000-60000 Da) in 50mL of water at room temperature, and stirring for 5 min to obtain a product A. The concentration of polyvinylpyrrolidone in product A was 9.6 mg/mL and the concentration of copper chloride dihydrate was 0.17 mg/mL.
And 2, adding 26 mu L of 50% hydrazine hydrate solution into the product A, and stirring for 5 min to obtain a product B.
And 3, adding 50mL of a sodium hydroxide solution with the pH =9 into the product B, and stirring for 5 min to obtain a product C.
And step 4, adding 400 mu L of 320 mg/mL sodium sulfide nonahydrate solution into the product C, stirring for 5 min, and carrying out oil bath reaction for 2 h at the temperature of 60 ℃ to obtain a product D.
Step 5, under the condition of room temperature, firstly centrifuging the product D at 12000 rpm for 10 min, then washing the product D with ultrapure water for three times, and freeze-drying the product D under the condition of high vacuum (1 Pa) at low temperature (-80 ℃) for 24h to obtain a dark brown solid 50 mg; and dispersing the dark brown solid in 200 mL of ultrapure water to obtain a product E (HMCuS), namely the hollow mesoporous copper sulfide nano-drug carrier.
The invention also provides a method for preparing the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using the nano-drug carrier, which comprises the following steps:
step a, under the condition of room temperature, performing ultrasonic treatment on 200 mL of the product E by using an ultrasonic cell crusher for 25 min, then adding 100 mg of beta-mercaptoethylamine, stirring for 24h under the condition of 1000 rpm, centrifuging for 10 min at 12000 rpm, washing with ultrapure water for three times, and performing low-temperature (-80℃)) Freeze-drying under high vacuum (1 Pa) for 24h, and redissolving with 200 mL of ultrapure water to obtain a product F (HMCuS-NH) 2 )。
B, ultrasonically treating 200 mL of the product F with an ultrasonic cell crusher for 25 min at room temperature, placing the product F into a glass round-bottom flask, adding 50 mg of adriamycin (DOX) medicament into the glass round-bottom flask, stirring the mixture for 24h in a dark place at 1000 rpm, centrifuging the mixture for 10 min at 12000 rpm, washing the mixture for three times with ultrapure water, freeze-drying the mixture for 24h under a low-temperature (-80 ℃) high-vacuum (1 Pa), and re-dissolving the dried mixture with 200 mL of phosphate buffer solution with the pH =7.4 to obtain a product G (HMCuS-NH) 2 @DOX)。
And c, placing 50 mg of 9R-P201 peptide (manufacturer: Shanghai Qiangyao Biotechnology Co., Ltd., number: 04010020031) into phosphate buffer with pH =7.4 at room temperature, adding 30 mg of carbodiimide hydrochloride and 23 mg of N-hydroxysuccinimide for activation, and stirring for 30 min to obtain an activated 9R-P201 peptide solution H. The 9R-P201 peptide sequence is: AAAAAAAAAGSGSTHLATPSMTTLA are provided.
Step d, placing 200 mL of the product G in a glass round-bottom flask at room temperature, adding the activated 9R-P201 peptide solution H into the glass round-bottom flask, stirring for 24H in the dark at 1000 rpm, centrifuging for 10 min at 12000 rpm, washing for three times with ultrapure water, and freeze-drying for 24H under low-temperature (-80 ℃) high vacuum (1 Pa). Redissolving with 200 mL of ultrapure water, centrifuging at 12000 rpm for 15 min, washing with ultrapure water for 3 times, and freeze-drying at low temperature and high vacuum for 24h to obtain the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug I (HMCuS @ DOX-9R-P201, abbreviated as HMCD 9P).
The sizes and the dispersion degrees of TEM images of the hollow mesoporous copper sulfide and the compound are represented by a Transmission Electron Microscope (TEM), and the result is shown in figure 1. From fig. 1 it can be observed that: the prepared hollow mesoporous copper sulfide nano-drug carrier HMCuS is of a hollow mesoporous structure, and the hollow mesoporous structure is clear, small in size and uniform in appearance, and the size of the hollow mesoporous structure is 100-150 nm (see a in figure 1). In figure 1, b is the product HMCuS-NH after the completion of the doxorubicin loading 2 @ DOX, it was concluded that doxorubicin loading was successful, with a black material in the wells. Drawing (A)In 1, c is a product HMCD9P after the 9R-P201 peptide is connected, and a layer of transparent material is wrapped around the product, so that successful modification of the 9R-P201 peptide is proved.
The nanoparticles were scanned at full wavelength using uv absorption spectroscopy and the results are shown in figure 2. As can be seen in fig. 2: HMCuS and HMCuS-NH 2 The ultraviolet absorption is strong in the near infrared region, and the ultraviolet absorption is weak after DOX is loaded and 9R-P201 peptide is connected, probably because DOX is loaded in HMCuS and the modification of the 9R-P201 peptide influences the ultraviolet absorption.
The Zeta potential of the HMCuS nanoparticles and the components of the nanoparticles was studied using a Zeta potential meter, and the results are shown in FIG. 3. As can be seen in fig. 3: the potential value of HMCuS is-13.6 mV; modified amino HMCuS-NH 2 The potential value of (d) was changed to-2.5 mV; after loading DOX, the potential value is changed to 29.7 mV; the potential value was changed to 40.6 mV after the 9R-P201 peptide was attached.
Infrared spectroscopy for HMCuS-NH 2 The characterization results are shown in FIG. 4. The results in FIG. 4 show that: mercaptoethylamine at 2558 cm -1 A characteristic peak of S-H stretching vibration appears; in the presence of HMCuS-NH 2 The characteristic peak of the middle S-H stretching vibration disappears, and the characteristic peak of the C-N stretching vibration of the amino at 1210 cm-1 appears, which proves that the mercaptoethylamine is modified on the HMCuS.
The energy elements of the HMCuS were analyzed by transmission electron microscopy and the results are shown in FIG. 5. Fig. 5 shows: the method detects that Cu and S elements are mainly contained in the sample, and provides a basis for synthesizing the HMCuS.
In vitro drug release of HMCD9P was studied, and as shown in fig. 6, after 36 h of drug release experiments, the drug release rate of HMCD9P in pH 5.4 phosphate buffer was only 6.1% and 25.5% higher than that of pH 6.8 phosphate buffer and pH 7.4 phosphate buffer without 808 nm laser irradiation; when 808 nm laser is irradiated, the drug release rate of the corresponding laser group is increased compared with that of the non-laser group. Notably, the drug release rate in the phosphate buffer solution with pH 5.4+ L is up to 51.3% and 70.7% compared with the phosphate buffer solution with pH 6.8 and the phosphate buffer solution with pH 7.4. The result shows that the amide bond of the HMCD9P nano-drug is broken under the slightly acidic environment, then the hole of the hollow mesoporous material is opened to release the drug, and the aim of dual stimulus response type drug release is achieved. Wherein, the pH sensitive drug release characteristic of the DOX is that the acidic environment causes the protonation of the amino group in the DOX structure to cause the breakage of hydrogen bonds, thereby promoting the drug release; in addition, under the irradiation of near-infrared laser, the HMCuS generates heat, so that the viscosity of a surrounding medium is reduced, and the diffusion of the medicine is promoted. Therefore, after the nano-drug specifically targets liver cancer tumor cells, the release of DOX is promoted in an acidic environment and by external near-infrared laser irradiation. The dual stimulus response type drug release characteristic can enhance the anti-tumor effect of the drug at the tumor part.
Fig. 7 is a safety experiment of the hollow mesoporous copper sulfide nano-drug product I, and fig. 7 can see that: the hemolysis rate of HMCD9P NPs (NPs refer to nanoparticles, the same applies below) at 800. mu.g/mL is still less than 5%, indicating that the safety of the whole system is higher.
Preparing the obtained hollow mesoporous copper sulfide nano-drug product I into solutions with different concentrations by using water, and then using the solution with the particle size of 808 nm and the particle size of 1W/cm 2 The variation of the solution temperature is recorded by an FLIR thermal imaging instrument to obtain the temperature variation curve chart of the hollow copper sulfide nano-drug product I in the aqueous solution. As can be observed from FIG. 8, the graph of the change in concentration of (a) shows that the hollow mesoporous copper sulfide nano-drug carrier is subjected to a laser at 808 nm (1W/cm) when the concentration is 100 μ g/mL 2 ) Irradiating for 8 min to raise the temperature to about 52 deg.C; (b) shows a power change pattern of (1W/cm) at 808 nm with a laser at 100. mu.g/mL 2 ) The temperature can be raised to about 52 ℃ after the irradiation for 8 min; tumor cells can be killed, corresponding to the concentration change map. Therefore, the photothermal conversion property of the hollow mesoporous copper sulfide nano-drug carrier proves that the hollow mesoporous copper sulfide nano-drug carrier can be used as an excellent photothermal material for tumor photothermal treatment.
FIG. 9 shows that different concentrations (0, 10, 25, 50, 100 and 200. mu.g/mL) of HMCD9P NPs solutions received 1W/cm 2 After 5 min of laser irradiation, the temperature rose rapidly. The result shows that the HMCD9P NPs have excellent photothermal performance and can be used for anti-tumor treatment through photothermal therapy.
Fig. 10 is a graph for evaluating photo-thermal stability of nano-drugs through a plurality of laser on/off processes. In each cycle, the nano-drug solution is irradiated by laser for 5 min, and is naturally cooled to room temperature after the laser is turned off. The on/off cycles were repeated 5 times and the temperature profile was recorded during these cycles by plotting the temperature versus irradiation time. The results demonstrate that HMCD9P NPs have good photo-thermal stability.
In vitro cell inhibition
And (3) detecting the toxicity of the hollow mesoporous copper sulfide nano-drug carrier on tumor cells by using an MTT (methyl thiazolyl tetrazolium) experiment.
Using MTT method to treat DOX, HMCuS and HMCuS-NH 2 @ DOX, HMCD9P NPs were tested for in vitro tumor activity. HePG2 with good culture state is paved on cells at the bottom of a culture dish, the cells are firstly digested by pancreatin, the centrifuge is used for centrifugation, the supernatant is sucked out, 1 mL of culture medium (DMEM culture medium containing 1% of streptomycin and 10% of fetal calf serum) is added for uniformly blowing the cells, a proper amount of cell suspension is taken for dilution, the number of the cells in each hole is about 4500, and the cells are inoculated in a 96-well plate and cultured for 24 hours. Adding DOX, HMCuS and HMCuS-NH 2 @ DOX, HMCD9P NPs were diluted with medium to different concentrations, placed in tubes for use, each concentration containing 4 sub-wells, and a blank control group without inoculated cells and a negative control group without drug added were set for 24 hours of action. The laser control group experiments are divided into 8 groups, namely DOX group, DOX + L group, HMCuS + L group and HMCuS-NH group 2 @ DOX group, HMCuS-NH 2 @ DOX + L group, HMCD9P NPs group, HMCD9P NPs + L group, the laser group uses 808 nm laser (1W/cm) 4h after administration 2 5 min), and continuing to culture for 24 h; the non-laser group was incubated for 24h after dosing. Adding 50 muL 1 mg/mL MTT solution into each hole for acting for 4h, throwing a plate, adding 100 muL DMSO into each hole, shaking the table for 10 min, and measuring the light absorption value A at 570 nm by using a multifunctional microplate reader; by the formula: cell inhibition rate × 100% = (average OD value in negative group-average OD value in experimental group)/(average OD value in negative group-average OD value in blank group), inhibition rate of each concentration of sample on cells was calculated, and corresponding IC was calculated by software 50 The value is obtained.
As can be seen from FIG. 11, the results of cell proliferation rate of HePG2 indicate that the cell survival rate of the HMCuS NPs group is as high as about 50% at a concentration of 500. mu.g/mL, indicating that the vector has little toxicity to HePG2 cells. From this it can prove HMCuS NPs are nano materials with high biological safety. Next, it was examined whether or not the product G (HMCuS-NH) was irradiated with laser light 2 @ DOX), product I (HMCD 9P) and DOX have toxicity to HePG2 cells, the cell proliferation rate of each group is reduced under the irradiation of laser, and the phototherapy (thermal therapy and photodynamic therapy) effect is remarkable. Wherein HMCuS-NH 2 The @ DOX + L has higher cell proliferation rate than HMCD9P NPs + L, and is presumed to be caused by the fact that the 9R-P201 peptide modified nanoparticle promotes the uptake of cells. In addition, both phototherapy and chemotherapy reduce the rate of cell proliferation, but do not achieve the desired therapeutic effect. While the HMCD9P NPs + L group greatly reduced the cell proliferation rate to 12.35%, and showed higher cytotoxicity. This is mainly because the HMCD9P NPs group performs phototherapy (thermotherapy and photodynamic therapy) by near-infrared laser irradiation, and performs combination therapy for treating liver cancer by inhibiting tumor in cooperation with the chemotherapy effect of DOX.
In vivo tumor treatment
To evaluate the in vivo biodistribution of the hollow mesoporous copper sulfide nano-drug product I (HMCD 9P), HMCD9P NPs were injected into H22 mice via tail vein (administration dose: 5mg/kg mouse body weight), and after 1, 2, 4, 6, 8, 12, 24H injection, the mice were dissected for Heart, liver Live, Spleen spenen, Lung, Kidney and Tumor for fluorescence imaging, and the results are shown in fig. 12. As shown in fig. 12, the imaging result shows: after HMCD9P NPs injection, the fluorescence signal at the tumor part is gradually increased, reaches the maximum value after 6 h of injection, and the fluorescence begins to be reduced at 8 h. The time-dependent enhancement of the fluorescence signal at the tumor site may be attributed to HMCD9P NPs through the EPR effect and active specific targeting to liver cancer. Liver and kidney also have fluorescence due to metabolism, but organs such as heart, spleen, lung and the like have no obvious fluorescence signals, which shows that the multifunctional nano-drug carrier can specifically deliver nano-drugs and has low toxicity of the whole body.
In order to further study the in vivo anti-tumor effect of the hollow mesoporous copper sulfide nano-drug product I (HMCD 9P), a BALB/c mouse subcutaneous transplantation tumor model is constructed by selecting H22 cells, and the anti-tumor effect of the nano-drug is studied by tail vein injection combined with laser control. Selecting 2 mice to be quietDifferent formulations (Saline group normal Saline, HMCD9P NPs) were injected intravenously. Using 808 nm laser (1W/cm) 24h after intravenous injection 2 5 min), performing in vivo thermal imaging by using an infrared thermal imaging instrument, and detecting the temperature change in real time, wherein the result is shown in figure 13. As shown in fig. 13, the temperature rapidly increased to 57.8 ℃ at the tumor of mice injected with HMCD9P NPs during 5 min of laser irradiation. The rapid temperature rise may be due to the specific targeting of the nanoparticles and the high photothermal effect of HMCuS. The thermal imaging result shows that the HMCD9P NPs have good photothermal performance and can be used for tumor thermotherapy.
In addition, the mice were randomly divided into 7 groups of 5 mice each. A BALB/c mouse subcutaneous transplantation tumor model is constructed by using H22 cells, and the anti-tumor effect of the nano-drug is researched by tail vein injection (5 mg/kg mouse body weight) in combination with laser control. The tumor size of the mice was observed every day until the tumor volume was about 100 mm 3 In this case, 7 groups of mice were administered separately. Respectively comprises a control group (normal saline), a HMCuS group, a HMCuS + L group, a positive medicine DOX + L group, a HMCD9P NPs group and a HMCD9P NPs + L group. The preparation is administered every other day for seven times, and the body weight and tumor volume of mice are measured while the preparation is administered, and 808 nm laser (1W/cm) is used every other day 2 5 min) irradiated the tumor area. The tumor volume of the mice was calculated as V = W2 × L/2 (V represents the tumor volume, W represents the tumor minor axis, and L represents the tumor major axis), and the results are shown in fig. 14.
After 7 administrations, as shown in fig. 14, the weight gains of the mice in the HMCuS group, HMCuS + L group, HMCD9P NPs group, HMCD9P NPs + L group and the control group were similar, while the weight of the mice was significantly reduced by the positive drug group DOX and the positive drug DOX + L group, probably because the normal growth of the mice was prevented by the side effects of the positive drug. Compared with a control group, the HMCD9P NPs group and the HMCD9P NPs + L group have obvious inhibition effect on tumor growth, wherein the inhibition effect of the HMCD9P NPs + L group is the best, the tumor weight of the HMCD9P NPs + L group is only 0.098 g, which is far lower than that of the control group 0.832 g and that of the DOX group 0.351 g, and the tumor volume of mice of the HMCD9P NPs + L group is only 131.28 mm 3 Far below 398.83 mm of control group 3 And DOX group 207.13 mm 3 The tumor inhibition rate reaches 88.2 percent, which indicates that the nano-drugThe compound HMCD9P can better inhibit the growth of tumor under the condition of laser irradiation.
Hematoxylin-eosin (HE) staining was performed on tumor tissue and heart, liver, spleen, lung, kidney tissue sections, and tissue damage was observed using a fluorescence microscope. The hematoxylin dye is alkaline, and mainly makes chromatin in cell nucleus and ribosome in cytoplasm to be bluish; eosin is an acid dye that primarily causes components in the cytoplasm and extracellular matrix to appear red. The experimental results of fig. 15 show: compared with organs of a control group, the organs treated by the nano-drug HMCD9P, the nano-drug HMCD9P + L, the nano-carrier material HMCuS and the nano-carrier material HMCuS + L have no obvious change, which shows the biological safety of the nano-drug and the nano-material. However, liver, spleen and kidney tissues of free DOX and DOX + L were slightly damaged, indicating that DOX is toxic to mice. The results further confirm that the multifunctional nano-drug carrier synthesized by the application has good biocompatibility in organisms.
FIG. 16 shows that after H & E staining of paraffin sections of tumor control groups, tumor cells are densely arranged and a large amount of stroma is in the interior of the tumor cells. Compared with the control group, the tumor tissue section of the free DOX group can see partial tumor cell vacuole formation, but the tumor cell density is similar to that of the control group. However, in the tumor tissue sections of the nano-drug HMCD9P NPs + L treatment group, a large amount of vacuolization can be observed, and typical apoptosis morphological characteristics such as cytoplasm loss, chromatin contraction or fragmentation can be observed. TUNEL detects apoptosis in tumor tissues and can see that: the positive fluorescence signal of HMCD9P NPs + L is strongest. These morphological changes indicate that the anticancer effect of the nano-drug HMCD9P NPs + L is more significant, so that a large number of tumor cells in tumor tissues are killed.
In conclusion, the hollow mesoporous copper sulfide nano-drug carrier prepared by the invention has the advantages of good hydrophilicity, high safety, small size and specific targeting effect on liver cancer. According to the application, the near-infrared light response nano-material hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) are firstly synthesized, and the chemotherapeutic drug Doxorubicin (DOX) is encapsulated by utilizing the unique cage-shaped structure of the hollow mesoporous copper sulfide nanoparticles, so that the drug loading capacity is greatly improved. Appearance of the HMCuS NPsThe surface of the nano-copper sulfide nano-drug is modified by a liver cancer targeting peptide 9R-P201 peptide to obtain a hollow mesoporous copper sulfide nano-drug HMCuS @ DOX-9R-P201 (HMCD 9P) with liver cancer targeting, and finally the combined treatment effect of nano-drug chemotherapy, photo-thermal treatment and photodynamic treatment is realized. In vitro and in vivo studies, the nano-drug HMCD9P actively targets into HepG2 cells through liver cancer cell surface-specific receptor-mediated endocytosis, and then triggers the release of the drug in the Tumor Microenvironment (TME). Under irradiation with Near Infrared (NIR) light, HMCD9P is not only effective in converting near infrared light into heat for photothermal therapy, but also produces high levels of Reactive Oxygen Species (ROS) for photodynamic therapy. In tumor-bearing mouse experiments, in near infrared light (808 nm, 1W/cm) 2 5 min) HMCD9P NPs + L group treated tumor-bearing mice showed a tumor inhibition rate of about 88.2%. Therefore, the HMCD9P developed by the invention has great potential, can be used as a nano therapeutic agent for efficiently and accurately inducing chemotherapy, photothermal and photodynamic therapy, and has excellent anti-tumor effect and small side effect.

Claims (8)

1. A preparation method of a hollow mesoporous copper sulfide nano-drug carrier is characterized by comprising the following steps:
step 1, dispersing a copper chloride dihydrate solution with the concentration of 0.4-0.6mol/L and polyvinylpyrrolidone in water at room temperature to obtain a mixed solution A; in the mixed solution A, the concentration of polyvinylpyrrolidone is 5-15 mg/mL, and the concentration of copper chloride dihydrate is 0.1-0.3 mg/mL;
step 2, adding a 50% hydrazine hydrate solution into the mixed solution A, and stirring to obtain a mixed solution B; wherein the volume ratio of the copper chloride dihydrate solution to the hydrazine hydrate solution is 1: 0.1-0.3;
step 3, adding a sodium hydroxide solution with the pH =9 into the mixed solution B, and stirring to obtain a mixed solution C; wherein the volume ratio of the copper chloride dihydrate solution to the sodium hydroxide solution is 1: 400-600;
step 4, adding 310-330 mg/mL sodium sulfide nonahydrate solution into the mixed solution C, stirring, and performing oil bath reaction for 1-4 h at the temperature of 30-90 ℃ to obtain a mixed solution D; wherein the volume ratio of the copper chloride dihydrate solution to the sodium sulfide nonahydrate solution is 1: 3-5;
step 5, centrifuging and washing the mixed solution D at room temperature, and freeze-drying to obtain a dark brown solid; dispersing the dark brown solid in water to obtain a product E, namely the nano-drug carrier; the solid-liquid ratio of the product E is 1: 3000-5000.
2. The method for preparing a hollow mesoporous copper sulfide nano-drug carrier as claimed in claim 1, wherein in step 1, the molecular weight of the polyvinylpyrrolidone is 50000-60000 Da.
3. The hollow mesoporous copper sulfide nano-drug carrier prepared by the method of any one of claims 1 to 2.
4. The use of the nano-drug carrier of claim 3 for drug loading.
5. A method for preparing a liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using the nano-drug carrier of claim 4 is characterized by comprising the following steps:
step a, performing ultrasonic treatment on the product E at room temperature, adding a mercapto-containing coating, stirring for 2-48 h, centrifuging, washing, freeze-drying, and re-dissolving with ultrapure water to obtain a product F; wherein the mass ratio of the black brown solid in the sulfydryl-containing coating and the product E is 1-3: 1;
b, performing ultrasonic treatment on the product F at room temperature, adding an adriamycin medicament, stirring for 2-48 h in the dark, centrifuging, washing, freeze-drying, and redissolving by using a phosphate buffer solution to obtain a product G; wherein the mass ratio of the black brown solid in the adriamycin medicine and the product E is 1-3: 1;
step c, placing the 9R-P201 peptide into a phosphate buffer solution with the pH value of 7-9 at room temperature, adding carbodiimide hydrochloride and N-hydroxysuccinimide, and stirring for 20-40 min to obtain an activated 9R-P201 peptide solution H; wherein the mass ratio of the 9R-P201 peptide to the carbodiimide hydrochloride to the N-hydroxysuccinimide is 1: 0.3-0.7: 0.3-0.7;
d, mixing the product G with the activated 9R-P201 peptide solution H at room temperature, stirring for 12-48H in a dark place, centrifuging, washing, and freeze-drying to obtain the compound; wherein the mass ratio of the 9R-P201 peptide to the adriamycin is 1: 1-3.
6. The method for preparing the hollow mesoporous copper sulfide nano-drug modified by the liver cancer targeting peptide according to claim 5, wherein in the step a, the mercapto-containing coating comprises beta-mercaptoethylamine, mercaptopropionic acid or thioglycolic acid.
7. The method for preparing the hollow mesoporous copper sulfide nano-drug modified by the liver cancer targeting peptide according to claim 5, wherein in the step c, the 9R-P201 peptide has the liver cancer targeting peptide sequence as follows: AAAAAAAAAGSGSTHLATPSMTTLA are provided.
8. The hollow mesoporous copper sulfide nano-medicament modified by the liver cancer targeting peptide prepared by the method of any one of claims 5 to 7.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014065893A (en) * 2012-09-06 2014-04-17 Matsumoto Yushi Seiyaku Co Ltd Hollow particle and adhesive composition containing the same
CN105056243A (en) * 2015-07-22 2015-11-18 郑州大学 Pharmaceutical composition of hyaluronic acid modified magnetic hollow mesoporous copper sulfide as well as preparation method and application of pharmaceutical composition
CN105126113A (en) * 2015-08-31 2015-12-09 郑州大学 Preparation method and application of transferrin modified hollow mesoporous copper sulfide/artesunate nanoparticles
CN108324955A (en) * 2018-01-26 2018-07-27 东华大学 A kind of preparation method of the hollow mesoporous silicon targeted nano medicine-carrying compound of extra small copper sulfide load
CN110384799A (en) * 2019-08-26 2019-10-29 同济大学 PH responsiveness composite nano materials, preparation based on hollow copper sulfide and ruthenium complex and its application in treating cancer drug
CN112850779A (en) * 2021-03-12 2021-05-28 南京师范大学 Hollow Cu7S4Nano cubic structure and preparation method and application thereof
CN113082213A (en) * 2021-03-10 2021-07-09 武汉科技大学 Hollow copper sulfide nano-drug carrier, preparation method and application
CN113376132A (en) * 2021-06-07 2021-09-10 青岛科技大学 Mesoporous-based copper sulfide composite material, preparation method and detection method

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014065893A (en) * 2012-09-06 2014-04-17 Matsumoto Yushi Seiyaku Co Ltd Hollow particle and adhesive composition containing the same
CN105056243A (en) * 2015-07-22 2015-11-18 郑州大学 Pharmaceutical composition of hyaluronic acid modified magnetic hollow mesoporous copper sulfide as well as preparation method and application of pharmaceutical composition
CN105126113A (en) * 2015-08-31 2015-12-09 郑州大学 Preparation method and application of transferrin modified hollow mesoporous copper sulfide/artesunate nanoparticles
CN108324955A (en) * 2018-01-26 2018-07-27 东华大学 A kind of preparation method of the hollow mesoporous silicon targeted nano medicine-carrying compound of extra small copper sulfide load
CN110384799A (en) * 2019-08-26 2019-10-29 同济大学 PH responsiveness composite nano materials, preparation based on hollow copper sulfide and ruthenium complex and its application in treating cancer drug
CN113082213A (en) * 2021-03-10 2021-07-09 武汉科技大学 Hollow copper sulfide nano-drug carrier, preparation method and application
CN112850779A (en) * 2021-03-12 2021-05-28 南京师范大学 Hollow Cu7S4Nano cubic structure and preparation method and application thereof
CN113376132A (en) * 2021-06-07 2021-09-10 青岛科技大学 Mesoporous-based copper sulfide composite material, preparation method and detection method

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