CN109498818B - pH sensitive liposome for generating NO and preparation method thereof - Google Patents
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Abstract
The invention discloses a pH sensitive liposome for generating NO and a preparation method thereof, wherein a pH sensitive polymer PEG-PLL-DMA is coated on the surface of the liposome through electrostatic action, a hydrophilic NO donor is loaded in a water phase in the liposome, and a hydrophobic anti-tumor drug is loaded by a phospholipid bilayer to construct the liposome which has the microenvironment pH sensitivity of tumor tissues and can generate NO in tumor cells.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a pH sensitive liposome for generating NO and a preparation method thereof.
Background
The development of multidrug resistance in tumor cells is an important reason for the failure of tumor therapy. With respect to the mechanism of drug resistance in tumor cells, the current more prevalent view is the P-glycoprotein (P-gp) mediated drug efflux. NO is a gaseous molecular messenger that plays a key role in various physiological processes. More importantly, NO can down regulate the expression level of P-gp, thereby playing a role in reversing the multidrug resistance of the tumor. The NO donor can generate NO through stimulation of enzyme, acidity, oxidation reduction, light and the like in tumor cells, but the NO donor has the problems of poor physiological stability, lack of targeting property and tissue specificity, short action time of a medicament and the like, so that the application of the NO donor as a P-gp inhibitor is limited.
The liposome is a vesicle with a bilayer structure consisting of phospholipids, has good biocompatibility and bioavailability, and can simultaneously entrap liposoluble and water-soluble drug micromolecules. The pH sensitive liposome can promote the release of the drug under the acidic pH condition of tumor tissues or tumor cells. The invention combines the characteristics that the polymer PEG-PLL-DMA with the tumor microenvironment (pH = 6.5) pH sensitivity and the NO donor can spontaneously generate NO to construct the pH sensitive liposome capable of generating NO, so that the pH sensitive liposome has the characteristics that the charge reversal can occur in the tumor tissue microenvironment and the NO can be spontaneously generated, and the curative effect is improved.
Disclosure of Invention
The invention aims to provide a pH-sensitive liposome capable of generating NO, which can perform charge reversal in a tumor tissue microenvironment to promote the uptake of tumor cells into the liposome and can generate NO simultaneously to inhibit P-gp mediated drug efflux and reverse tumor multidrug resistance.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pH sensitive liposome for generating NO comprises cholesterol (Chol), hydrogenated soybean lecithin (HSPC), 1, 2-distearic acid-3-phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG) in phospholipid layer2000) The liposome comprises (2, 3-dioleoyl-propyl) -trimethylamine (DOTAP) and a hydrophobic anti-tumor drug, wherein a hydrophilic NO donor is loaded in an inner water phase, and a pH-sensitive polymer polyethylene glycol-polylysine-dimethylmaleic anhydride (PEG-PLL-DMA) is coated on the surface of the liposome through electrostatic action.
Wherein, HSPC, Chol, DSPE-PEG2000The molar ratio of the DOTAP to the hydrophobic anti-tumor drug is 12:1:1 (0.3-10) to (0.1-5). The hydrophobic antitumor drug is any one of paclitaxel, docetaxel, camptothecin and vincristine.
HSPC, DOTAP and DSPE-PEG2000The ratio of the sum of the masses of (a) to the mass of the hydrophilic NO donor used is 10:1 to 120: 1. The hydrophilic NO donor is any one of diethylenetriamine NO nucleophilic complex (DETA NONONONOate), polyazelaine dianhydride NO nucleophile (PAPA NONONOate) and Spermine nitrogen oxide adduct (Spermine NONONOate).
HSPC, DOTAP and DSPE-PEG2000The ratio of the sum of the mass of (a) to the mass of the PEG-PLL-DMA to be used is 1:1 to 1: 30.
The preparation method of the pH-sensitive liposome for generating NO comprises the following steps:
(1) mixing HSPC, Chol, DSPE-PEG2000Dissolving DOTAP and hydrophobic antitumor drug in chloroform solution;
(2) removing the chloroform solution by rotary evaporation to obtain a uniform film-like material;
(3) eluting with PBS buffer solution with pH =8.0 and containing 0.5-3 mM hydrophilic NO donor, and performing ultrasonic treatment for 5-20 min by using an ultrasonic cell disruption instrument under the condition of power of 100-400W to form liposome containing the NO donor and the antitumor drug;
(4) and adding PEG-PLL-DMA, and stirring at room temperature for 5 min-8 h to obtain the pH sensitive liposome generating NO.
The invention has the following remarkable advantages: the invention adopts the pH sensitive polymer PEG-PLL-DMA to coat the cationic liposome which is carried with the antitumor drug and the NO donor together, so that the obtained pH sensitive liposome can generate charge reversal in the microenvironment of tumor tissues, thereby being beneficial to the uptake of tumor cells to the liposome; after reaching tumor cells, the NO donor encapsulated in the water phase in the liposome can spontaneously generate NO, so that the P-gp mediated drug efflux can be inhibited, the permeability of a liposome membrane can be improved, the enrichment of an antitumor drug encapsulated between liposome phospholipid bimolecular layers in the tumor cells can be enhanced, and the curative effect can be improved.
Drawings
FIG. 1 is a potential diagram of NO-producing pH sensitive liposomes prepared in example 1 in PBS at various pH values.
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.
Example 1: preparation method of pH sensitive liposome for generating NO
(1) Chol 2.01 mg, HSPC 47.03 mg, DSPE-PEG2000 13.75 mg, DOTAP 7.0 mg and taxol 4.05 mg dissolved in 30 mL chloroform solution;
(2) performing rotary evaporation for 4 h at the room temperature at the rotating speed of 100 r/min by using a rotary evaporator to obtain a uniform film-shaped material;
(3) after elution with 6.78 mL of PBS buffer solution containing 2.2 mM DETA NONOate at pH =8.0, sonication was performed for 10 min at 300W using a sonicator to form liposomes encapsulating NO donors and antitumor drugs;
(4) using HSPC, DOTAP and DSPE-PEG2000Adding PEG-PLL-DMA into the mixture at a mass ratio of the sum of the mass of the PEG-PLL-DMA to the mass of the PEG-PLL-DMA of 1:6, and stirring the mixture for 1 hour at room temperature to obtain the pH sensitive liposome generating NO.
Example 2: preparation method of pH sensitive liposome for generating NO
(1) Chol 2.01 mg, HSPC 47.03 mg, DSPE-PEG2000 13.75 mg, DOTAP 15.05 mg and taxol 4.05 mg dissolved in 30 mL of chloroform solution;
(2) performing rotary evaporation for 4 h at the room temperature at the rotating speed of 100 r/min by using a rotary evaporator to obtain a uniform film-shaped material;
(3) after elution with 7.58 mL of PBS buffer solution containing 1.375 mM DETA NONOate at pH =8.0, sonication was performed with a sonicator at 300W for 10 min to form liposomes encapsulating the NO donor and the antitumor drug;
(4) using HSPC, DOTAP and DSPE-PEG2000Adding PEG-PLL-DMA into the mixture at a mass ratio of the sum of the mass of the PEG-PLL-DMA to the mass of the PEG-PLL-DMA of 1:30, and stirring the mixture for 1 hour at room temperature to obtain the pH sensitive liposome generating NO.
Example 3: potentiometric assay of NO-producing pH-sensitive liposomes
The NO-producing pH sensitive liposomes prepared in example 1 were diluted to a concentration of 400 μ g/mL using PBS solutions of pH =7.4, 6.5 and 5.0, respectively, and Zeta potential thereof was measured with a malvern laser granulometer, and the results thereof are shown in fig. 1.
As can be seen from fig. 1, in the PBS solution with pH =7.4, the Zeta potential of the liposome is negative; in PBS solutions at pH =6.5 and 5.0, the liposomes turned charge to positive charge, indicating that the liposomes prepared were pH sensitive.
Example 4: in vitro release assay for pH sensitive liposomes producing NO
275 mL of the liposome prepared in example 1 was diluted to 1 mL with a PBS solution of pH =8.0, then immersed in 40 mL of PBS solutions of pH =7.4, 6.5, and 5.0, respectively, and released at 37 ℃ at 100 r/min, while satisfying the sink conditions; 0.5 mL of the release solution was withdrawn at predetermined time points (1, 2, 4, 8, 12, 24, 48, 72, 96, 120 h) while an equal amount of fresh PBS solution was replenished; and diluting the taken release liquid with a proper amount of acetonitrile, detecting the release amount of the drug at a wavelength of 227 nm by using HPLC, and calculating the cumulative release rate of the paclitaxel.
The experimental result shows that the release amount of paclitaxel in the pH sensitive liposome generating NO and the liposome without entrapped NO is about 30% in the solution with pH =7.4 when 120 h is released; in the solution with pH =6.5, the release amount of paclitaxel in the NO-producing pH sensitive liposomes increased to 70%, while the release amount of paclitaxel in the NO-unencapsulated liposomes was still less than 53%; in the solution with pH =5.0, the release amount of paclitaxel in pH sensitive liposome generating NO is up to 90%, and the release amount of paclitaxel in liposome without entrapped NO is about 70%, and the above results further prove that NO generated by NO donor entrapped in liposome under acidic condition can obviously promote the release of paclitaxel in liposome.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (4)
1. A preparation method of pH sensitive liposome for generating NO is characterized in that the liposome is composed of a phospholipid layer containing hydrophobic antitumor drugs, an internal water phase containing hydrophilic NO donors and a pH sensitive polymer PEG-PLL-DMA coated on the surface of the liposome;
the preparation method comprises the following steps:
(1) mixing HSPC, Chol, DSPE-PEG2000Dissolving DOTAP and hydrophobic antitumor drug in chloroform solution;
(2) removing the chloroform solution by rotary evaporation to obtain a uniform film-like material;
(3) eluting with PBS buffer solution with pH =8.0 and containing hydrophilic NO donor, and performing ultrasonic treatment with ultrasonic cell disruptor for 5-20 min;
(4) adding PEG-PLL-DMA, and stirring at room temperature for 5 min-8 h to obtain the pH sensitive liposome generating NO;
HSPC, Chol and DSPE-PEG used in the step (1)2000The molar ratio of the DOTAP to the hydrophobic anti-tumor medicine is 12:1:1 (0.3-10) to (0.1-5);
the concentration of the hydrophilic NO donor in the step (3) is 0.5-3 mM; the ultrasonic power is 100-400W;
the amount of PEG-PLL-DMA used in step (4) is determined by HSPC, DOTAP and DSPE-PEG2000The ratio of the sum of the mass of (A) to the mass of PEG-PLL-DMA is 1:1 to 1: 30.
2. The method of preparing NO producing pH sensitive liposomes according to claim 1 wherein: the hydrophobic antitumor drug is any one of paclitaxel, docetaxel, camptothecin and vincristine.
3. The method of preparing NO producing pH sensitive liposomes according to claim 1 wherein: HSPC, DSPE-PEG2000And the ratio of the sum of the mass of DOTAP and the mass of the hydrophilic NO donor is 10:1 to 120: 1.
4. The method of preparing NO producing pH sensitive liposomes according to claim 1 wherein: the hydrophilic NO donor is any one of DETA NONONOate, PAPA NONONOate and Spermine NONOate.
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| CN101001623A (en) * | 2004-06-10 | 2007-07-18 | 日本化药株式会社 | Anticancer effect enhancer |
| CN101766570A (en) * | 2010-01-18 | 2010-07-07 | 武汉大学 | PH-sensitive precursor cation nanometer liposome of target tumour cell and preparation method thereof |
| CN106177987A (en) * | 2016-08-17 | 2016-12-07 | 上海交通大学 | Little molecule macromolecule conjugates self assembly drug-loading nanoparticles and preparation method thereof |
| CN107049953A (en) * | 2017-06-05 | 2017-08-18 | 福州大学 | A kind of pH/ near infrared lights response bubble liposome and preparation method thereof |
| CN107260676A (en) * | 2017-06-05 | 2017-10-20 | 福州大学 | A kind of application of pH/ near infrared lights response bubble liposome |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001623A (en) * | 2004-06-10 | 2007-07-18 | 日本化药株式会社 | Anticancer effect enhancer |
| CN101766570A (en) * | 2010-01-18 | 2010-07-07 | 武汉大学 | PH-sensitive precursor cation nanometer liposome of target tumour cell and preparation method thereof |
| CN106177987A (en) * | 2016-08-17 | 2016-12-07 | 上海交通大学 | Little molecule macromolecule conjugates self assembly drug-loading nanoparticles and preparation method thereof |
| CN107049953A (en) * | 2017-06-05 | 2017-08-18 | 福州大学 | A kind of pH/ near infrared lights response bubble liposome and preparation method thereof |
| CN107260676A (en) * | 2017-06-05 | 2017-10-20 | 福州大学 | A kind of application of pH/ near infrared lights response bubble liposome |
Non-Patent Citations (2)
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| Multifunction Enveloped Mesoporous Silica Nanoparticles for Subcellular Co-delivery of Drug and Therapeutic Peptide;Guo-Feng Luo,et al.;《SCIENTIFIC REPORTS》;20140814;第4卷(第6064期);1-10 * |
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