CN113521301A - LDH (layered double hydroxide) nanoparticle-based drug for loading salinomycin and albumin paclitaxel together as well as preparation method and application thereof - Google Patents

LDH (layered double hydroxide) nanoparticle-based drug for loading salinomycin and albumin paclitaxel together as well as preparation method and application thereof Download PDF

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CN113521301A
CN113521301A CN202110533463.4A CN202110533463A CN113521301A CN 113521301 A CN113521301 A CN 113521301A CN 202110533463 A CN202110533463 A CN 202110533463A CN 113521301 A CN113521301 A CN 113521301A
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ldh
sal
salinomycin
albumin
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许铁峰
高雨帆
刘建萍
张立明
钟鸣
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First Affiliated Hospital Of Hainan Medical University
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Abstract

The invention discloses a method for loading salinomycin and albumin paclitaxel based on layered double hydroxide nanoparticles, which comprises the following steps: loading salinomycin on the LDH nano particles by using a high-temperature coprecipitation ion exchange method to obtain Sal/LDH nano particles; continuously adding the Sal/LDH nano particle suspension into a mixed solution of serum albumin and albumin paclitaxel dropwise, stirring at a high speed, continuously adding the serum albumin solution into the reaction solution dropwise to prepare a Sal/LDH @ Nab-PTX nano particle solution, and freeze-drying to obtain the Sal/LDH @ Nab-PTX nano drug with a Sal intercalation layer and a Nab-PTX coating. The Sal/LDH @ Nab-PTX nano-drug prepared by the method has uniform particle size and pH responsiveness, can explosively release the drug in a weak acid tumor environment, can inhibit breast cancer 4T1 cells at a low dose, has a remarkable synergistic effect, overcomes the limitation of single drug treatment, and reduces the side effect.

Description

LDH (layered double hydroxide) nanoparticle-based drug for loading salinomycin and albumin paclitaxel together as well as preparation method and application thereof
Technical Field
The invention relates to a novel anti-tumor drug, in particular to a drug based on LDH nano-particles loaded with salinomycin and albumin paclitaxel and a preparation method and application thereof.
Background
Breast cancer is the malignant tumor disease with the highest incidence rate in women at present, and seriously threatens the health of women. Except for surgical intervention, chemical drug therapy is a clinically effective treatment method, but has the problems of serious toxic and side effects, multi-drug resistance and the like. At present, the paclitaxel chemotherapeutic drugs widely used in breast cancer treatment in clinical practice, such as albumin-bound paclitaxel nanoparticles (Nab-PTX), Nab-PTX is easily soluble in water and safe in administration, and can increase the accumulation of Nab-PTX in tumor tissues through targeted binding of albumin on the surface of nanoparticles and SPARC overexpressed by cancer cells, so as to enhance the curative effect, but Nab-PTX has weak killing ability on breast cancer stem cells causing breast cancer recurrence, metastasis and drug resistance. Salinomycin (Sal) has strong capability of inhibiting breast cancer stem cells, is 100 times stronger than paclitaxel, can kill tumor stem cell subsets in mice, inhibit the generation of new tumor cells, and inhibit the growth rate of existing tumors. However, salinomycin is difficult to dissolve in water, and toxic and side effects on nerves and muscles of organisms are main reasons limiting clinical application of salinomycin.
Layered Double Hydroxide (LDH) Nanoparticles (NPs) have potential application values in the biomedical field, and can be used as a high-performance Magnetic Resonance Imaging (MRI) contrast agent for cancer diagnosis by uniformly doping various combinations of divalent and trivalent metal cations into a magnesium-aluminum oxide layer; and after the treatment function is exerted on the disease part, the biological safe ions and molecules are easily degraded, and the long-term side effect is reduced. Meanwhile, LDH is used as a nano-drug carrier, which has some defects, on one hand, LDH has positive charges under physiological conditions, although the LDH has high affinity to cancer cell membranes, the LDH is easy to perform nonspecific interaction with plasma proteins and is rapidly eliminated, and the LDH is not beneficial to the enrichment of LDH at tumor sites, which easily causes the positively charged nanoparticles to enter normal cells to cause adverse reactions; on the other hand, if the LDH surface is modified and then the coating with negative charges can greatly weaken the binding capacity of the nano-carrier and the tumor cell membrane, the absorption of the cancer cells to the drugs carried by the nano-carrier is not facilitated, and the treatment effect is obviously reduced.
Therefore, there is a need to develop a drug based on LDH nanoparticles co-loaded with salinomycin and albumin paclitaxel, which solves the above problems.
Disclosure of Invention
In view of the above, the invention provides a nano-drug based on LDH nanoparticles loaded with salinomycin and albumin paclitaxel, which solves the problem of limited therapeutic effect of a single drug.
On one hand, the invention adopts a nano-drug based on LDH nano-particles to carry salinomycin and albumin paclitaxel, which comprises 0.65-3.62% of salinomycin, 0.76-3.71% of albumin paclitaxel and 3.81-15.0% of LDH nano-carrier.
Preferably, the medicament also comprises 81.97-91.60% by mass of serum albumin.
Preferably, the medicament comprises 0.76% of salinomycin, 0.89% of albumin paclitaxel, 8.94% of LDH layered nanoparticles and 89.41% of bovine serum albumin in percentage by mass.
In another aspect, a method for loading salinomycin and albumin paclitaxel on the basis of LDH nanoparticles comprises the following steps:
(1) loading salinomycin on the LDH nano particles by using a high-temperature coprecipitation ion exchange method to obtain Sal/LDH nano particles;
(2) continuously adding the Sal/LDH nano particle suspension into a mixed solution of serum albumin and albumin paclitaxel dropwise, stirring at a high speed, continuously adding the serum albumin solution into the reaction solution dropwise to prepare a Sal/LDH @ Nab-PTX nano particle solution, and freeze-drying to obtain the drug based on LDH layered nano particle co-loaded salinomycin and albumin paclitaxel.
Preferably, the mass ratio of the salinomycin in the step (1) to the LDH carrier is 0.1:1-1: 1.
Preferably, in the step (1), the salinomycin encapsulation rate of the Sal/LDH nano particles is 95.66-98.69%, and the uploading rate is 8.46-48.50%.
Preferably, in step (2), 1mL of Sal/LDH with a concentration of 2mg/mL is aspirated, 0.5mL of a mixed solution mixed with 2mg/mL of serum albumin and 0.4-2mg/mL of albumin paclitaxel is added, and 0.5mL of a serum albumin solution with a concentration of 8-46mg/mL is continuously and dropwise added to the mixed solution.
In addition, the application of the drug based on the LDH nano-particle co-loaded salinomycin and albumin paclitaxel in treating breast cancer is further provided, and the drug releases salinomycin in an explosive manner in an environment with the pH value of 6.
By adopting the method based on LDH nano-particles for loading salinomycin and albumin paclitaxel together, the salinomycin for inhibiting breast cancer stem cells is successfully inserted into Mg by using an ion exchange method3An Al-LDH interlayer with high encapsulation efficiency; then adhering the Nab-PTX and the BSA to the surface of the LDH nano-particles through electrostatic interaction between Sal/LDH with positive charges on the surface and Nab-PTX with negative charges and BSA respectively; the Sal/LDH @ Nab-PTX anticancer nano-drug loaded with salinomycin and albumin paclitaxel is successfully constructed, the preparation method is simple, the cost is low, and the popularization is easy;
further, the Sal/LDH @ Nab-PTX nano-drug has pH responsiveness and releases salinomycin in an explosive manner at the pH value of 6.0; meanwhile, the LED nano-carrier is coated by the serum albumin, so that the alcoholysis polymerization of the serum albumin and the albumin taxus on the surface of the nano-carrier is facilitated to be separated off under the weak-acid tumor microenvironment condition, the LDH with positive charges is gradually exposed, tumor cells are promoted to phagocytose the taxol and salinomycin drugs carried by the LDH, and the synergistic curative effect of the two drugs is improved.
Furthermore, the Sal/LDH @ Nab-PTX nano-drug has good biocompatibility, and can transmit the antitumor drug into cytoplasm to induce apoptosis of tumor cells; the Sal/LDH @ Nab-PTX nano-drug with the same low dose is used for treating the breast cancer 4T1 cells, the mutual synergistic effect is remarkable, the limitation of single-drug treatment is overcome, the side effect is small, the curative effect is remarkable, and compared with the mixed administration of free salinomycin and albumin paclitaxel, the drug use amount is greatly reduced.
Furthermore, the Sal/LDH @ Nab-PTX nano-drug not only has the function of obviously inhibiting the growth of breast tumors, but also reduces the probability of breast tumor metastasis.
Drawings
FIG. 1 is a chart of the infrared spectra of LDH, Sal/LDH, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX nanoparticles;
FIG. 2 is an XRD pattern of LDH, Sal/LDH, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX nanoparticles;
FIG. 3 is a DLS particle size distribution plot from left to right for LDH, Sal/LDH @ BSA, LDH @ Nab-PTX, and Sal/LDH @ Nab-PTX nanoparticles;
FIG. 4 is a graph of zeta potential distributions from left to right for LDH, Sal/LDH @ BSA, LDH @ Nab-PTX, and Sal/LDH @ Nab-PTX nanoparticles;
FIG. 5 is a graph of salinomycin release profiles of Sal/LDH @ BSA nanoparticles in buffers of varying pH formulated with citric acid monohydrate and dipotassium hydrogen phosphate;
FIG. 6 is a confocal laser microscopy image after 4T1 cells were treated with FITC/LDH @ BSA at 37 ℃ for 4 h;
FIG. 7 is a graph showing the change in cell viability after treatment of 4T1 cells with Sal/LDH @ BSA, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX nanopharmaceuticals (left to right), respectively;
FIG. 8 is a graph of mean tumor volume change following treatment of breast cancer tumor-bearing mice with different groups of drugs;
FIG. 9 is a graph of mean tumor weight change after different groups of drug treatment of breast cancer tumor-bearing mice;
FIG. 10 is a photograph of tumors excised at 28 days post-sacrifice after treatment of breast cancer tumor-bearing mice with different groups of drugs (group A: PBS; group B: Sal/LDH @ BSA; group C: Sal + Nab-PTX; group D: Sal/LDH @ Nab-PTX; group E: LDH @ Nab-PTX);
FIG. 11 shows the results of histological and immunofluorescence analysis of different groups of drug-treated breast cancer-bearing mice;
FIG. 12 is a histopathological analysis of major organs (heart, liver, spleen and kidney) after the end of treatment with different groups of drug administration.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The first embodiment is as follows: the method for loading salinomycin and albumin paclitaxel on the basis of LDH nanoparticles specifically comprises the following steps:
(1) preparation of LDH nanoparticles
a. Weighing 610mg of magnesium chloride hexahydrate and 241.4mg of aluminum chloride hexahydrate according to the weight ratio of 3: adding 1 mol ratio (0.6/0.2M) into a centrifuge tube filled with 5mL of deionized water, and completely dissolving by ultrasonic assistance to prepare solution A;
b. weighing 320mg of sodium hydroxide, adding the sodium hydroxide into a glass bottle filled with 20mL of deionized water (4 ℃) and stirring at a constant speed, and reacting at room temperature for 10min under the protection of argon to obtain a solution B;
c. quickly dripping the solution A into the completely dissolved solution B, and continuously stirring for 20min to prepare Mg3Al-LDH mixed solution;
d. mixing Mg3Transferring the Al-LDH mixed solution into a 50mL centrifuge tube, placing the centrifuge tube in a high-speed refrigerated centrifuge for centrifugation for 5min, removing supernatant, and collecting Mg3Al-LDH precipitates;
e. will contain Mg3Adding 20mL of deionized water into a container of the Al-LDH precipitate, repeatedly blowing and beating, fully and uniformly mixing, centrifugally washing, removing supernatant, collecting the precipitate, re-suspending the precipitate in 20mL of deionized water, and blowing, uniformly mixing to obtain milky Mg3Al-LDH suspension.
f. Mixing Mg3The Al-LDH suspension was transferred to an autoclave and LDH nanoparticles were obtained after heat sterilization for 16h in an oven at 100 ℃.
(2) Preparation of Sal/LDH nanoparticles loaded with salinomycin
Quickly dripping 0.1mL of salinomycin solution with the mass concentration of 7.51mg/mL into 1mL of pre-prepared B solution (16mg/mL of sodium hydroxide solution) and continuously and violently stirring for about 10min, then dropwise adding 0.25mL of A solution (the magnesium-aluminum salt solution in the step (1)), stirring at a high speed for 1h at room temperature, centrifuging at a high speed for 5min to remove supernatant, dispersing and centrifuging for 15min by using 1mL of deionized water, and repeating for 2 times to obtain Sal/LDH nano particles; residual Sal in the supernatant was detected using a UV-2900 UV spectrophotometer at the 226nm peak and calculated to have an encapsulation efficiency of 95.66% Sal and an upload efficiency of 8.46%.
(3) Preparation of Sal/LDH @ Nab-PTX nanoparticles loaded with salinomycin and albumin paclitaxel Nab-PTX
Sucking 1mL of Sal/LDH with the concentration of 2mg/mL and continuously adding the solution dropwise into 0.5mL of Sal/LDH mixed with 2mg/mL BSA-1 and 0.4mg/mL Nab-PTX solution, stirring the solution at a high speed for 30min, then continuously adding 0.5mL of bovine serum albumin BSA-2 solution with the concentration of 38mg/mL dropwise into the solution to prepare Sal/LDH @ Nab-PTX nano particle solution containing Sal/LDH with the concentration of 1mg/mL, Nab-PTX with the concentration of 0.1mg/mL and 10mg/mL BSA, and freeze-drying to obtain medicinal powder based on LDH layered nano particle co-loaded salinomycin and albumin taxol, wherein nano drugs are loaded with 0.76 mass percent of salinomycin, 0.89 percent of albumin taxol, 8.94 percent of LDH and 89.41 percent of bovine serum albumin.
Example two: the difference between the second example and the first example is that the input mass ratio of the salinomycin and the LDH in the step (2) is 0.1: 1; 0.5: 1 and 1:1, as shown in the results of Table 1, the encapsulation rate of salinomycin reaches 95.66-98.69%, the uploading rate is 8.46-48.50%, on one hand, the salinomycin is easy to insert among LDH carrier layers, and the preparation method is simple; on the other hand, the utilization rate of salinomycin can be improved, the waste of salinomycin medicaments in the preparation process is reduced, and the production cost is reduced.
TABLE 1 Effect of input mass ratio of different salinomycin and LDH vectors on Sal/LDH nanoparticles
Figure BDA0003068788600000061
Wherein the encapsulation efficiency (EE%) is represented by EE ═ 1-Cf/Ct) X 100%, wherein CfAmount of free drug; ctThe total amount of the drug in the nanoparticle suspension;
the loading rate (DL%) refers to the drug loaded/(total amount of nanocarrier and drug);
LDH has the structural formula of Mg3Al(OH)8(Cl,1/2CO3)·2H2O。
Example three: the difference between the third example and the first example is that the Sal/LDH nanoparticles, the albumin paclitaxel Nab-PTX and the bovine serum albumin are added in different amounts.
TABLE 2 Effect of different component addition on Sal/LDH @ Nab-PTX Nanoparticles
Figure BDA0003068788600000062
Figure BDA0003068788600000071
In the examples in table 2, different Sal/LDH @ Nab-PTX nano-drug components are prepared by changing the input amount of raw materials, which directly affects the uniformity and potential of nano-particle size, thereby affecting the drug administration effect, such as the Sal/LDH @ Nab-PTX (Sal ═ 2.35%, Nab-PTX ═ 2.78%, LDH ═ 25.43%, BSA ═ 69.44%) nano-drug is easy to agglomerate and disperse unevenly when the input amount of serum albumin is insufficient, thereby affecting the subsequent drug administration. Therefore, the Sal/LDH @ Nab-PTX component content ratio which is optimized through a large amount of experiments is as follows: 0.65-3.62% of salinomycin, 0.76-3.71% of albumin taxol, 3.81-15.00% of LDH and 81.97-91.60% of serum albumin. And when Sal is 0.76%;
Nab-PTX ═ 0.89%; LDH is 8.94%; when the BSA is 89.41%, the Sal/LDH @ Nab-PTX nano-drug has proper size, strong targeting effect and optimal synergistic curative effect.
Comparative example one: preparation of Sal/LDH @ BSA
Sucking 1mL of 2mg/mLSal-LDH suspension, dropwise adding the suspension into 1mL of BSA solution containing 20mg/mL, stirring at a high speed for 30min to prepare Sal/LDH @ BSA nanoparticle solution containing Sal/LDH and BSA at the concentrations of 1mg/mL and 10mg/mL, and freeze-drying to obtain the Sal/LDH @ BSA nano-drug.
Comparative example two: preparation of LDH @ Nab-PTX
Sucking 1mL of LDH nano particles with the concentration of 2mg/mL and dropwise adding the LDH nano particles into 0.5mL of a solution mixed with 2mg/mL of BSA and 0.4mg/mL of Nab-PTX, stirring at a high speed for 30min, then dropwise adding 0.5mL of a solution of BSA with the concentration of 38mg/mL into the solution to prepare an LDH @ Nab-PTX nano particle solution containing 1mg/mL of LDH, 0.1mg/mL of Nab-PTX and 10mg/mL of BSA, and freeze-drying to obtain the LDH @ Nab-PTX nano drug.
Example four: the Sal/LDH @ Nab-PTX nano-drug prepared in the first embodiment is characterized and tested
(1) Infrared characterization of the LDH, Sal/LDH, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX samples of example one was performed using an FT-IR spectrometer, the FT-IR spectroscopy (see FIG. 1) showed LDH at 3479cm-1Shows a broad band ascribed to H absorbed in LDH2O-H stretching of the O molecules and OH groups indicates stretching vibration of the active hydroxyl groups or physically adsorbed water molecules in the LDH in the brucite-like layer. 510-800cm-1Strong adsorption peaks in the range are ascribed to M-O vibration and M-O-M bending (M ═ Mg or Al) in the LDH bulk layer. 2960cm of BSA was clearly observed in LDH @ Nab-PTX nano-hybrids-1、1655cm-1And 1544cm-1Three peaks at (a) which are assigned to tensile oscillations of C-H, C ═ O and N-H bonds, respectively. The characteristic band of Sal/LDH is 2964cm-1A strong peak at is determined as-CH3Indicating that Sal was successfully embedded in the LDH interlayer. Characteristic band of Sal is 1715cm-1And 1565cm-1Two strong peaks are attributed to the stretching vibration of C ═ O and C ═ N bonds, and the vibration is 1712cm-1And 1569cm-1The Sal/LDH nano hybrid is obviously seen, and the LDH nano particle interlayer is proved to be successfully loaded with ionized salinomycin, namely, the LDH, Sal/LDH, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX nano particles are proved to be successfully prepared.
(2) The results of testing LDH, Sal/LDH, LDH @ Nab-PTX and the Sal/LDH @ Nab-PTX lyophilized powder of example one (see FIG. 2) with an X-ray diffractometer show characteristic reflections corresponding to planes (003) and (006) of LDH, indicating that the layered structure of LDH crystals is not affected after loading Sal intercalation; it was confirmed that Sal molecules were randomly inserted into the LDH interlayer, resulting in a broader XRD peak for Sal/LDH, while the interlayer spacing of LDH and Sal/LDH nanoparticles was similar as the Sal loading was increased, further indicating that Sal was deposited in the interlayer.
(3) The four nanoparticles Sal/LDH, Sal/LDH @ BSA, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX of example one were tested using DLS and the results (as shown in FIG. 3 and Table 2) showed that the average particle sizes of Sal/LDH (92.78nm), Sal/LDH @ BSA (122.76nm), LDH @ Nab-PTX (143.24nm) and Sal/LDH @ Nab-PTX (155.45nm) increased gradually, not only indirectly indicating successful preparation of the final product Sal/LDH @ Nab-PTX; the medicine has uniform particle size, proper size and PDI value of about 0.1, and has obvious advantages in targeting administration.
(4) The four nanoparticles Sal/LDH, Sal/LDH @ BSA, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX of example one were tested using a potentiometric tester, and the results (FIG. 4 and Table 3) showed that Sal/LDH was positively charged and the charge was 45.54 mV; the Sal/LDH @ BSA, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX after being coated by the serum albumin are all negatively charged, and the electric quantity is-19.85 mV, -21.90mV and-23.56 mV respectively, so that the Sal/LDH @ Nab-PTX nano-drug disclosed by the embodiment presents negative charges, the circulation time of the nano-drug in blood is prolonged, the accumulation of the nano-drug at a tumor site is increased, the positively charged Sal/LDH can be released after the nano-drug reaches a weak acid environment around a tumor, the Sal/LDH has strong binding capacity with a tumor cell membrane, and the nano-carrier-drug can be absorbed by cancer cells.
TABLE 3 particle size and potential of Sal/LDH, Sal/LDH @ BSA, LDH @ Nab-PTX, and Sal/LDH @ Nab-PTX nanoparticles
Figure BDA0003068788600000091
(4) Stability test of Sal/LDH @ Nab-PTX nano particles shows that the medicine can keep good stability in deionized water, PBS and a culture medium containing 10% FBS for 24 hours; the in vitro release experiment result (as shown in fig. 5) also shows that the drug release is good, the drug is released explosively in a buffer solution with the pH value of 6.0, and the drug release amount is up to 63% compared with the drug release amount in the environment with the pH value of 7.4, which indicates that the Sal/LDH @ Nab-PTX nano-drug has pH responsiveness and is advantageous to release the drug in the tumor environment with subacid in vivo.
Example five: in vitro experiment of tumor-bearing mouse breast cancer cell 4T1 was performed on Sal/LDH @ Nab-PTX nano-drug of the first example
(1) The results of the uptake of the first drug FITC/LDH @ Nab-PTX nano-drug of this example by 4T1 breast cancer cells (see FIG. 6) were studied by flow cytometry (FACS) and confocal scanning microscopy (CLSM), and the FACS results showed that most of 4T1 cells internalize FITC/LDH @ BSA after 2h incubation and more LDH nano-particles were gradually absorbed by the cells as the incubation time increased; the CLSM images also confirmed that a green fluorescent signal of FITC/LDH @ BSA could be observed inside the cells after 4h of culture, and that the signal was mainly located in the cytoplasm, indicating that the 4T1 cells had the highest uptake rate of the Sal/LDH @ Nab-PTX drug of example one.
(2) Various concentrations of Sal and Nab-PTX, Sal/LDH @ BSA, LDH @ Nab-PTX, and Sal/LDH @ Nab-PTX nanomedicine solutions were evaluated for toxicity in treating breast cancer 4T1 cells using a cell counting kit-8 (CCK-8).
The method comprises the steps of firstly treating 4T1 cells by using FITC/LDH @ BSA at 37 ℃ for 4h, wherein the results show that when the concentration of LDH nano particles is as high as 400 mu g/mL, the activity of the breast cancer 4T1 cells treated by the LDH @ BSA is still higher than 90%, and the LDH nano carrier has good biocompatibility. After 4T1 cells were treated with different concentrations of Sal/LDH @ BSA, LDH @ Nab-PTX and Sal/LDH @ Nab-PTX, the results of cell viability change indicated that the Sal/LDH @ Nab-PTX nanopharmaceutical had a lower inhibitory concentration (IC50 ═ 0.26. mu.g/mL) which was much lower than that of free Sal and Nab-PTX.
(3) The results of the combination therapy with equivalent amounts of Sal (0.47-7.5. mu.g/mL) and Nab-PTX (0.47-7.5. mu.g/mL) selected showed significant reduction in 4T1 cell viability, only 44.8-16.6%, with significant synergy (combination index from 1.74-1.98) following Sal/LDH @ BSA and LDH @ Nab-PTX nanopharmaceutical treatment relative to treatment with Sal/LDH @ PTX alone (Table 4 and FIG. 7).
TABLE 4 synergistic effects of Sal/LDH @ Nab-PTX (CT) vs. Sal/LDH @ BSA (CT1) and LDH @ Nab-PTX (CT2)
Figure BDA0003068788600000111
Example six: EXAMPLE I Effect of the Nanoparticulate Sal/LDH @ Nab-PTX for in vivo Targeted therapy of Breast cancer and metastatic cancer
(1) By constructing a tumor model of breast cancer cells 4T1-Luc of tumor-bearing mice, grouping the mice, treating the mice with drugs under different conditions, recording the general conditions, the weight and the tumor size change of experimental mice, the tumor metastasis conditions of important organs and lymph node tissues, comparing and analyzing the recorded conditions, and specifically inoculating 2 × 10 subcutaneous tissue on the right flank of each Balb/c female mouse (6-8 weeks old)64T1 breast cancer cells, mice were randomly divided into five groups (5 mice per group), group a: PBS buffer solution; group B: Sal/LDH @ BSA; group C: a mixture of free Sal and Nab-PTX (mass ratio 1: 1); group D: Sal/LDH @ Nab-PTX; group E: LDH @ Nab-PTX.
Wherein 100. mu.L of the corresponding preparation was injected into each mouse via the tail vein 1 time for 5 times on days 0, 4, 8, 12 and 16, respectively, and the dose was 3mg/kg per group. During the treatment period, the change in body weight and tumor size were monitored and recorded every other day, and a growth curve of tumor volume as a function of time was plotted, while the body weight of the mice was recorded. Tumor volume (V) was calculated by the following equation: v ═ L × W2) 2, L: the longest dimension of the tumor. W: the shortest size of the tumor. Mice were sacrificed 28 days after treatment and the major tissues of each group, including tumor tissue, heart, liver, spleen, lung and kidney of mice were collected for further immunofluorescence and histological examination.
Experiment knotThe results showed that the tumors in the mice in the PBS group grew rapidly and reached 1472.5mm after day 28 of the first inoculation3The inhibition effect of Sal/LDH @ BSA group on tumors is not obvious (882.7 mm)3) Free Sal and Nab-PTX cocktail groups have some inhibitory effect on tumor growth (72.9 mm)3) LDH @ Nab-PTX showed some inhibition of tumor growth (310.4 mm)3) While the low dose of Sal/LDH @ Nab-PTX showed the most significant inhibition of tumor growth (30.8 mm)3) It is demonstrated that the Sal/LDH @ Nab-PTX of example one has the advantages of efficient delivery of LDH nanoparticles to tumor tissue and drug release on demand, and has pH responsiveness, facilitating the uptake of drugs by cells in acidic tumor microenvironment. (as shown in fig. 8-10).
(2) Hematoxylin and eosin (H & E) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis were performed on (1) post-treatment tumor sections. H & E staining showed that most of the tumor cells in the Sal/LDH @ Nab-PTX group lost cell membrane integrity and nuclear density was significantly reduced. TUNEL staining of tumor tissues also showed that the Sal/LDH @ Nab-PTX treated group significantly induced apoptosis and inhibited proliferation of tumor cells in vivo (as shown in fig. 11), with significant efficacy.
In conclusion, the method for loading salinomycin and albumin paclitaxel together based on LDH nanoparticles provided by the invention successfully inserts salinomycin inhibiting breast cancer stem cells into Mg by using an ion exchange method3The Al-LDH interlayer, Sal/LDH with positive charge on the back surface respectively and Nab-PTX with negative charge and BSA adhere to the surface of LDH nano-particles through electrostatic interaction; successfully constructs the Sal/LDH @ Nab-PTX anticancer nano-drug with pH response;
furthermore, in vitro cell experiments show that the nano-drug has good biocompatibility and can transmit the anti-tumor drug into cytoplasm to induce tumor cell apoptosis; the Sal/LDH @ Nab-PTX nano-drug with the same low dose is used for treating the breast cancer 4T1 cells, has obvious mutual synergistic effect, overcomes the limitation of single-drug treatment, and reduces the side effect.
Furthermore, the results of drug therapy using a tumor model of tumor-bearing mouse breast cancer 4T1-Luc cells show that the Sal/LDH @ Nab-PTX nano-drug has the effect of significantly inhibiting the growth of breast tumors, can effectively deliver LDH nano-particles to tumor tissues, promote cellular uptake and explosive drug release in a tumor acidic (pH 6) microenvironment, and the results of fig. 12 also show that the Sal/LDH @ Nab-PTX nano-drug can reduce the probability of tumor metastasis to other tissues such as lung and liver.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (9)

1. The drug based on the LDH nano-particle co-loaded salinomycin and albumin paclitaxel is characterized by comprising 0.65-3.62% of salinomycin, 0.76-3.71% of albumin paclitaxel and 3.81-15.0% of LDH nano-carrier.
2. The LDH nanoparticle co-loaded salinomycin and albumin paclitaxel based drug according to claim 1, further comprising 81.97-91.60% by weight of serum albumin.
3. The LDH nanoparticle co-loaded salinomycin and albumin paclitaxel based drug according to claim 2, wherein the drug comprises 0.76% of salinomycin, 0.89% of albumin paclitaxel, 8.94% of LDH layered nanoparticles and 89.41% of bovine serum albumin by mass percentage.
4. A method for loading salinomycin and albumin paclitaxel based on LDH nano particles is characterized by comprising the following steps:
(1) loading salinomycin on the LDH nano particles by using a high-temperature coprecipitation ion exchange method to obtain Sal/LDH nano particles;
(2) continuously adding the Sal/LDH nano particle suspension dropwise into a mixed solution of serum albumin and albumin paclitaxel, continuously adding the serum albumin solution dropwise into the reaction solution after stirring at a high speed to prepare a Sal/LDH @ Nab-PTX nano particle solution, and freeze-drying to obtain the LDH layered nano particle co-loading salinomycin and albumin paclitaxel based drug disclosed in any one of claims 1 to 3.
5. The method for loading salinomycin and albumin paclitaxel on the basis of LDH nanoparticles as claimed in claim 4, wherein the mass ratio of salinomycin to LDH nanoparticles in step (1) is 0.1:1-1: 1.
6. The LDH nanoparticle-based salinomycin and albumin paclitaxel method according to claim 5, wherein in step (1), the salinomycin encapsulation rate of said Sal/LDH nanocarrier is 95.66-98.69%, and the uploading rate is 8.46-48.50%.
7. The LDH nanoparticle-based salinomycin and albumin paclitaxel co-loading method according to claim 4, wherein in step (2), 1mL of Sal/LDH suspension with concentration of 2mg/mL is sucked and added dropwise into 0.5mL of mixed solution mixed with 2mg/mL of serum albumin and 0.2-2mg/mL of albumin paclitaxel, and after stirring at high speed, 0.5mL of serum albumin with concentration of 8-46mg/mL is added dropwise into the mixed solution.
8. Use of an LDH-nanoparticle-based drug co-loaded with salinomycin and albumin paclitaxel according to any one of claims 1 to 3 in the treatment of breast cancer.
9. Use of an LDH nanoparticle-based salinomycin and albumin paclitaxel for the treatment of breast cancer as claimed in any one of claims 1 to 3, wherein the drug releases salinomycin in an explosive manner at pH 6.
CN202110533463.4A 2021-05-17 2021-05-17 LDH (layered double hydroxide) nanoparticle-based drug for loading salinomycin and albumin paclitaxel together as well as preparation method and application thereof Pending CN113521301A (en)

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