CN107281164B - Self-assembled nanoparticles based on low-generation PAMAM (polyamidoamine) dendrimer loaded anticancer drug and application of self-assembled nanoparticles in antitumor aspect - Google Patents
Self-assembled nanoparticles based on low-generation PAMAM (polyamidoamine) dendrimer loaded anticancer drug and application of self-assembled nanoparticles in antitumor aspect Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to preparation and anti-tumor application of a nano drug delivery system EL @ PAMAM/HA self-assembled nanoparticle. The invention is based on low-generation dendrimer PAMAM (G0/G1) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA), a solvent exchange method is adopted to prepare a targeted self-assembly nano drug delivery system EL @ PAMAM/HA NPs, the small-molecule self-assembly nano drug delivery system can entrap erlotinib which is an anti-tumor drug, HAs pH response, releases more drugs under acidic conditions, can target CD44 high-expression tumor cells, can specifically deliver more therapeutic drugs to tumor sites to play a drug effect, and HAs remarkable therapeutic advantages.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to preparation and anti-tumor application of a nano drug delivery system EL @ PAMAM/HA self-assembled nanoparticle.
Background
The general trade name of Erlotinib (Erlotinib) is named as Tarceva, and is an antitumor targeted therapeutic drug approved by the US FDA and listed in 2004, and is certified by the national food and drug administration (CFDA) in China, and is approved to enter the market of China in 2007. The chemical structural formula of erlotinib (EL for short) is
The chemical name of the derivative is N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinoline amine hydrochloride, and the derivative is a small molecule quinazoline derivative with high selectivity on Epidermal Growth Factor Receptor (EGFR). EL is used in a three-line treatment regimen for locally advanced or metastatic non-small cell lung cancer (NSCLC) following failure of two or more chemotherapies, and is also often used in combination with the anticancer drug gemcitabine to treat locally advanced or metastatic pancreatic cancer. Erlotinib is mainly cleared in the liver, and in vitro cytochrome enzyme P450 analysis shows that erlotinib is mainly metabolized by CYP3A4, and a small amount is metabolized by CYP1A2 and the extrahepatic isozyme CYP1A 1. The most common adverse reactions of oral EL are rash (75%) and diarrhea (54%), both of which are unexplained and mild and can be managed without discontinuation of medication.
A great deal of research shows that the anti-tumor effect of EL on EGFR mutant non-small cell lung cancer (NSCLC) is embodied in that the EL can inhibit phosphorylation of intracellular Tyrosine Kinase (TK) related to Epidermal Growth Factor Receptor (EGFR), and further block signal conduction of epidermal growth factor (HER 1), wherein TK is an important substance for tumor cell growth, and EL can inhibit tumor growth by inhibiting activity of TK. The invention takes human lung adenocarcinoma cells (A549) as a representative, and non-small cell lung cancer (NSCLC) cells verify that a self-assembly nano drug delivery system EL @ PAMAM/HA NPs with a targeting function is constructed on the basis of low-generation dendrimer PAMAM (G0/G1) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA).
The Polyamidoamine (PAMAM) dendrimer is a novel nano biomaterial which is symmetrically dispersed from the center to the outside and highly branched, and can form nanoparticles with proper size through molecular self-assembly due to the nanoscale, high water solubility, monodispersity and structural adjustability, so that the biocompatibility, bioavailability and targeting property of the medicament are improved, and the Polyamidoamine (PAMAM) dendrimer can be used as a delivery carrier of anticancer medicaments and imaging medicaments. At present, PAMAM is still mainly applied to a drug carrier, for example, in patent CN201410271351, a folic acid-PAMAM-ursolic acid nano drug with tumor targeting is disclosed, the adopted initial materials of the nano drug are G3 and G5 generation polyamidoamine dendrimer (PAMAM) with high toxicity, the amino group on the surface of PAMAM is required to be replaced by hydroxyl group to reduce the toxicity of the material, and then folic acid and ursolic acid react with the hydroxyl group on the surface of PAMAM to finally synthesize a target product. The low-generation PAMAM molecule (G0 is shown as formula I, G1 is shown as formula II), the number of surface amino groups is 4 and 8, the synthesis is simple, the toxicity is low, the price is low, the solubility of hydrophobic drugs can be improved, and the bioavailability is improved, so the low-generation PAMAM molecule is selected to be used as a nano delivery carrier.
Hyaluronic Acid (HA) is a natural linear glycosaminoglycan widely existing in living bodies and HAs a chemical structural formula
. The CD44 molecule as the specific receptor of hyaluronic acid is highly expressed on the cell surface of various malignant tumors, such as breast cancer, skin cancer, ovarian cancer and the like. HA is combined with CD44 molecules through a specific receptor-ligand mechanism, enters cytoplasm through endocytosis, can selectively enter tumor cells, and then is degraded under the action of enzymes such as hyaluronidase and acid hydrolase to realize targeted drug delivery, so hyaluronic acid is often used as a target of nano drugs.
The capillary endothelium in normal tissues has compact gaps and complete structure, nanoparticles are not easy to permeate, but the tumor microenvironment is complex, tumor vessels are rich, the gaps of vessel walls are wide, the structural integrity is poor, and lymphatic return is absent, so that a nano drug delivery system with the size of hundreds of nanometers can pass through, and therefore, the preparation of drugs into the nano drug delivery system has become a new trend in the field of tumor treatment and has wide application prospect. Self-assembly is a process in which non-covalent weak interactions, such as van der waals forces, hydrogen bonds, hydrophobic interactions, electrostatic interactions, pi-pi interactions, etc., occur between molecules under equilibrium conditions, spontaneously combine to form stable aggregates or supramolecules with certain structures and functions, can convert a disordered system into an ordered system, and is commonly used for preparing nanoparticles. The nanoparticles formed by molecular self-assembly generally have some characteristics, such as electrical, optical and biological characteristics, which a monomolecular or low-level molecular aggregate does not have, and meanwhile, the molecular self-assembly also has a structure amplification effect, and the amplification effect can endow the nanoparticles with some novel characteristics, such as characteristics of more compact and rich appearance and structure, and functions, intelligent response and the like, so that the application prospect of a self-assembly nano drug delivery system is increasingly wide due to the advantages. The invention constructs an EL @ PAMAM/HA nano drug delivery system by utilizing a self-assembly technology based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA).
The self-assembly nano drug-carrying system constructed by the invention can entrap erlotinib which is an anti-tumor drug and HAs pH response and CD44 receptor targeting, so that the nano drug-carrying system creatively utilizes the self-assembly technology to co-prepare low-generation PAMAM dendrimer, EL and HA, is simple and easy to operate, and provides a new research direction for erlotinib anti-tumor therapy.
Disclosure of Invention
The invention aims to prepare targeted self-assembly nano drug delivery system EL @ PAMAM/HA NPs by adopting a solvent exchange method based on low-generation dendrimer PAMAM (G0/G1) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA), so that the targeted self-assembly nano drug delivery system EL @ PAMAM/HA NPs can carry drugs to tumor parts in a targeted manner to exert curative effect.
The preparation method of the EL @ PAMAM/HA NPs comprises the following steps:
preparation of EL @ PAMAMEL (G0/G1)/HA
Dropwise adding 100 muL of EL good solvent solution into 700 muL of poor solvent at room temperature, then adding 100 muL of PAMAM (G0/G1) aqueous solution, oscillating for 1 minute, then adding 100 muL of HA aqueous solution, ultrasonically oscillating for 15 minutes, standing at room temperature, and obtaining the EL @ PAMAM (G0/G1)/HA self-assembled nano composite, wherein the good solvent and the poor solvent are respectively selected from absolute ethyl alcohol and water.
Particle size and potentiometric detection of EL @ PAMAM (G0/G1)/HA self-assembled nanocomposites
The low-generation PAMAM dendrimer is positively charged, HA is negatively charged, electrostatic adsorption can be generated in the self-assembly process, the morphology of the prepared nanoparticles is influenced, and a Malvern particle size analyzer is used for measuring the particle size distribution and the Zeta potential of the nano-composites prepared by different charge ratios.
TABLE 1 EL @ PAMAM (G0)/HA nanocomposite particle size distribution of different charge ratios
TABLE 2 EL @ PAMAM (G1)/HA nanocomposite particle size distribution of different charge ratios
The EL @ PAMAM (G0/G1)/HA is prepared by a solvent exchange method, the charge ratio is an important factor influencing the particle size of the EL @ PAMAM (G0/G1)/HA nanocomposite, the PDI value reflects the distribution of the particle size, the optimal charge ratio of the EL @ PAMAM (G0)/HA is 4:5, and the optimal charge ratio of the EL @ PAMAM (G1)/HA is 3: 5. When the positive and negative charge ratio is 4:5, the average particle size of the EL @ PAMAM (G0)/HA nanocomposite is 322.6 nm, the PDI is 0.286, and the potential is-5.72 mV; when the ratio of positive charges to negative charges is 3:5, the average particle size of the EL @ PAMAM (G1)/HA nano-composite is 146.1 nm, the PDI is 0.283, the potential is-6.92 mV, and in comparison, the EL @ PAMAM (G1)/HA nano-particles are smaller in particle size and more uniform in distribution.
3. Stability experiments of self-assembled nanocomposites
The particle size distribution of the nanoparticles is detected by using a Malvern laser particle sizer, and the result is shown in fig. 6, the particle size distribution of the EL @ PAMAM/HA nanocomposite does not change significantly in one continuous week, which indicates that the EL @ PAMAM/HA nanocomposite HAs good stability.
4. Determination of drug loading and encapsulation efficiency
And (3) obtaining unloaded free erlotinib and the nano-composite by using an ultrafiltration tube for centrifugation, freeze-drying and weighing the total mass of the nano-composite, measuring the ultraviolet absorbance of the free erlotinib by using an ultraviolet spectrophotometer, and calculating the corresponding concentration according to an erlotinib standard curve so as to calculate the drug loading rate and the encapsulation rate of the self-assembled nano-composite.
The drug loading and encapsulation efficiency of EL @ PAMAM (G0)/HA were 32.43%, 62.43%, respectively, when the positive-negative charge ratio was 4:5, as calculated from a standard curve of erlotinib; the drug loading and encapsulation efficiency of EL @ PAMAM (G1)/HA were 19.22% and 76.51% respectively when the positive to negative charge ratio was 3: 5.
5. Release of erlotinib at different pH conditions
The EL @ PAMAM (G0)/HA and EL @ PAMAM (G1)/HA nanocomposite solution is moved into a dialysis bag with the molecular weight of 1000, magnetic stirring is carried out in a dark place in dialysis media with different pH values at room temperature, the absorbance of a sample at each time point is measured by using an ultraviolet spectrophotometer, the cumulative release amount at each time point is calculated according to the standard curve of erlotinib, the release curve of erlotinib at different pH values along with the change of time is drawn, and the result is shown in figure 7, figure 8 and figure 9.
6. MTT method for detecting cytotoxicity
MTT method for detecting proliferation inhibition effect of EL-loaded nano drug delivery system on cervical cancer cell HeLa and non-small cell lung cancer cell A549
① A bottle of tumor cells in logarithmic growth phase is digested to 1 × 105Cell suspension in ml.
② transfer the cell suspension into 96-well plates at 100. mu.L/well, and put at 37 ℃ in 5% CO2Culturing in an incubator for 24 h.
③ removing culture medium, adding self-assembly nanometer composite according to concentration gradient, wherein each well is 100 μ L, and each is additionally provided with EL single drug group and PAMAM-G0/G1 group, removing drug-containing culture medium after 24 h, adding 100 μ L of serum-free and phenol-free culture medium into each well, adding 10 μ L of MTT solution, and continuing incubation for 24 h.
④ abandons the supernatant in the plate, each well is added with 100. mu.L DMSO, and the plate is placed on a shaker for 10min at a low speed, after the crystal is fully dissolved, the light absorption value (OD value) of each well is detected by using a microplate reader, and the proliferation inhibition rate of the cell is calculated, namely, the cell survival rate (%) = the average OD value of a drug group ÷ the average OD value of a blank control group x 100%, the data is processed by GraphPad Prism software, the light absorption value of each well is measured at OD 570 nm of an enzyme-linked immunosorbent assay detector, and the corresponding cell survival rate is calculated.
7. Cell uptake assay
The EL @ PAMAM (G1)/HA nano-delivery system was conjugated with FITC for characterizing the uptake of A549 cells into the nano-delivery system, and the results are shown in FIG. 14. In contrast to EL @ PAMAM NPs (G1)/HANPs, which are based on low-generation dendrimer PAMAM (G0/G1) and CD44 receptor targeting targeted Hyaluronic Acid (HA), which significantly increase the amount of drug entering cells, it is shown that they indeed have good targeting properties.
The invention has the advantages that:
1. the EL @ PAMAM (G0)/HA and the EL @ PAMAM (G1)/HA prepared by the method are prepared by a solvent exchange method, and the operation is simple and easy.
2. The micromolecule self-assembly nano drug delivery system constructed by the invention can entrap erlotinib which is an anti-tumor drug, has pH response, releases more drugs under an acidic condition, and is suitable for releasing drugs at tumor parts.
3. The micromolecule self-assembly nano drug delivery system constructed by the invention can entrap erlotinib which is an anti-tumor drug, can target CD44 high-expression tumor cells, can specifically deliver more therapeutic drugs to tumor parts to play a drug effect, and has remarkable treatment advantages.
4. The prepared EL @ PAMAM (G0)/HA and EL @ PAMAM (G1)/HA small molecule self-assembly nano drug delivery system can be used for targeted treatment of non-small cell lung cancer, not only can provide a new method for tumor treatment, but also provides a new idea for targeted drug delivery system research.
Drawings
FIG. 1 shows that a self-assembly nano drug delivery system EL @ PAMAM (G0)/HA nanocomposite with a targeting function, which is constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA), HAs a charge ratio of 4:5, and HAs a nano particle size;
FIG. 2 is a graph showing the potential of a nanometer when the charge ratio of a self-assembled nanometer drug delivery system EL @ PAMAM (G0)/HA nanocomposite with a targeting function, which is constructed on the basis of low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA), is 4: 5;
FIG. 3 shows that the self-assembly nano drug delivery system EL @ PAMAM (G1)/HA nanocomposite with the targeting function, which is constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA), HAs the charge ratio of 3:5, and the particle size is nano;
FIG. 4 shows that the self-assembly nano drug delivery system EL @ PAMAM (G1)/HA nanocomposite with the targeting function, which is constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA), HAs the charge ratio of 3:5 and the electric potential of a nano level;
FIG. 5 is an AFM image of nano-composite charge ratio of EL @ PAMAM (G1)/HA with a targeting function, constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA), at 3: 5;
FIG. 6 shows the stability detection of a self-assembled nano drug delivery system EL @ PAMAM/HA with a targeting function, which is constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA);
FIG. 7 Release curves of erlotinib at different pH conditions;
FIG. 8 shows the release curves of targeting self-assembled nano drug delivery system EL @ PAMAM-G1/HA NPs constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA) under different pH conditions;
FIG. 9 shows the release curves of targeting self-assembled nano drug delivery system EL @ PAMAM-G0/HA NPs constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA) under different pH conditions;
FIG. 10 shows the result of detecting HeLa cytotoxicity by MTT method based on low-generation dendrimer PAMAM (G0) and Hyaluronic Acid (HA) targeted by tumor cell CD44 receptor and having targeting function;
FIG. 11 shows the result of detecting HeLa cytotoxicity by MTT method based on low-generation dendrimer PAMAM (G1) and Hyaluronic Acid (HA) targeted by tumor cell CD44 receptor and having targeting function;
FIG. 12 shows the result of MTT method for detecting A549 cytotoxicity of self-assembled nano drug delivery system with targeting function, which is constructed based on low-generation dendrimer PAMAM (G0) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA);
FIG. 13 shows the result of MTT method for detecting A549 cytotoxicity of self-assembled nano drug delivery system with targeting function, which is constructed based on low-generation dendrimer PAMAM (G1) and tumor cell CD44 receptor-targeted Hyaluronic Acid (HA);
FIG. 14 is a cell uptake diagram of a self-assembled nano drug delivery system with a targeting function constructed based on low-generation dendrimer PAMAM (G0/G1 PAMAM) and tumor cell CD44 receptor targeted Hyaluronic Acid (HA).
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Preparation of EL @ PAMAM (G0)/HA
At 50 ℃, rapidly adding 100 muL of 25 muM erlotinib absolute ethanol solution into 700 muL of water in the process of oscillation (preparing 7 parts), then rapidly adding 100 muL of 25, 50, 75, 100, 125, 150, 175 and 200 muM PAMAM (G0) aqueous solution into the solution, oscillating for one minute, then adding 100 muL of 500 muM HA aqueous solution into the 7 parts of solution, and then carrying out oscillation treatment for 5 minutes. After the ultrasonic treatment is finished, the sample is subjected to ultrasonic treatment for 15 minutes and then is kept stand at room temperature, and the EL @ PAMAM (G0)/HA self-assembled nano composite with different charge ratios can be prepared.
Preparation of EL @ PAMAM (G1)/HA
At 50 ℃, 100 muL of 250 muM erlotinib absolute ethyl alcohol solution is rapidly added into 700 muL of water (7 prepared parts) in the process of oscillation, then 100 muL of 12.5, 25, 37.5, 50, 62.5, 75, 87.5 and 100 muM PAMAM (G1) aqueous solution is rapidly added into the solution, after oscillation for one minute, 100 muL of 500 muA aqueous solution is added into the 7 parts of solution, and then oscillation treatment is carried out for 5 minutes. After the ultrasonic treatment is finished, the sample is subjected to ultrasonic treatment for 15 minutes and then is kept stand at room temperature, and the EL @ PAMAM (G1)/HA self-assembled nano composite with different charge ratios can be prepared.
3. Determination of drug loading and encapsulation efficiency
And (3) obtaining unloaded free erlotinib and the nano-composite by using an ultrafiltration tube for centrifugation, freeze-drying and weighing the total mass of the nano-composite, measuring the ultraviolet absorbance of the free erlotinib by using an ultraviolet spectrophotometer, and calculating the corresponding concentration according to an erlotinib standard curve so as to calculate the drug loading rate and the encapsulation rate of the self-assembled nano-composite.
Calculating the formula:
drug loading rate (erlotinib total mass-free erlotinib mass)/total nano-mass 100%
Encapsulation efficiency ═ 100% (total erlotinib mass-free erlotinib mass)/total erlotinib mass%
4. Release profiles of erlotinib at different pH conditions
The erlotinib release experiments at different pH values were performed by transferring 1 mL of EL @ PAMAM (G0)/HA and EL @ PAMAM (G1)/HA nanocomposite solution into dialysis bags (MWCO = 1000) and then into dialysis media containing 49 mL PBS (pH 7.4/pH 5.5) with constant temperature magnetic stirring at 37 ℃. Sampling is carried out at preset time points (0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 h), 2mL of dialysate is taken each time, then 2mL of fresh dialysis medium is supplemented, then the absorbance of the sample at each time point is measured by using an ultraviolet spectrophotometer, the cumulative release amount at each time point is calculated according to a standard curve of erlotinib, and the release curve of erlotinib at different pH values along with the change of time is drawn.
The invention has breakthrough in applying the nano self-assembly technology to the anticancer drug erlotinib for tumor treatment, lays a theoretical foundation for targeted treatment of non-small cell lung cancer, and has certain reference significance for applying the nano technology to tumor treatment.
Claims (4)
1. A self-assembled nanoparticle based on low-generation PAMAM dendrimer loaded with anticancer drugs is characterized in that: based on low-generation dendrimer PAMAM and hyaluronic acid HA targeted by tumor cell CD44 receptor, the carried drug is erlotinib EL, and a solvent exchange method is adopted to prepare a targeted self-assembly nano drug delivery system EL @ PAMAM/HA; the preparation process of the solvent exchange method comprises the following steps: will be provided withDropwise adding a good solvent containing erlotinib into a poor solvent, then adding a PAMAM aqueous solution, oscillating, and then adding an HA aqueous solution to prepare an EL @ PAMAM/HA self-assembled nano composite; wherein the low-generation dendrimer PAMAM is low-generation dendrimer PAMAM G0 or low-generation dendrimer PAMAM G1, wherein the structural formula of G0 is
(ii) a G1 has a structural formula of
。
2. The self-assembled nanoparticle based on low-generation PAMAM dendrimer loaded with anticancer drugs according to claim 1, wherein: the preparation method comprises the following steps: at room temperature, dropwise adding 100 muL of good solvent solution containing erlotinib EL into 700 muL of poor solvent, then adding 100 muL of PAMAM aqueous solution, oscillating for 1 minute, then adding 100 muL of HA aqueous solution, ultrasonically oscillating for 15 minutes, standing at room temperature, and obtaining the EL @ PAMAM/HA self-assembled nano composite.
3. The self-assembled nanoparticle based on low-generation PAMAM dendrimer loaded with anticancer drugs according to claim 2, wherein: wherein the good solvent is absolute ethyl alcohol, and the poor solvent is water.
4. The use of the self-assembled nanoparticle of claim 1 for the preparation of an anti-tumor drug based on low generation PAMAM dendrimer loaded anticancer drug.
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