CN115068608B - Phthalocyanine-artesunate oxygen-carrying liposome compound and application thereof in acoustic power - Google Patents
Phthalocyanine-artesunate oxygen-carrying liposome compound and application thereof in acoustic power Download PDFInfo
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- CN115068608B CN115068608B CN202210710761.0A CN202210710761A CN115068608B CN 115068608 B CN115068608 B CN 115068608B CN 202210710761 A CN202210710761 A CN 202210710761A CN 115068608 B CN115068608 B CN 115068608B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a phthalocyanine-artesunate oxygen-carrying liposome compound and application thereof in tumor sonodynamic therapy. The liposome compound contains oxygen carrier perfluoro tributylamine and zinc phthalocyanine-artesunate conjugate, and can generate high amount of singlet oxygen and obvious sound-sensitive activity through ultrasonic excitation under normal oxygen and anoxic conditions, so that the tumor anoxic microenvironment can be improved, the tumor anoxic microenvironment has high sound-dynamic anticancer activity, and the liposome compound has obvious application prospect in the treatment field of anoxic tumors.
Description
Technical Field
The invention belongs to the technical field of functional materials, and particularly relates to a phthalocyanine-artesunate oxygen-carrying liposome and application thereof in resisting tumors.
Background
Tumors are a world-wide high-grade disease and have become one of the main diseases threatening human lives. Traditional therapies such as surgical treatment, chemotherapy, radiotherapy, etc. are accompanied by significant side effects: easy infection and recurrence after operation; the treatment period is long, and the pain of the patient is not good; drug resistance can be generated by repeated administration. Therefore, the prevention and treatment of tumors have become a current urgent problem to be solved. With advances in technology and social development, a range of potential anticancer therapies, such as sonodynamic therapy (sonodynamic therapy, SDT), are emerging. SDT is a novel noninvasive and accurate anticancer therapy based on photodynamic therapy (Photodynamic therapy, PDT), and the action process is to activate a sonosensitizer in an oxygen environment to generate ROS with ultrasonic waves as an energy source, and form cavitation, bubbles and thermal therapy, which finally lead to death of tumor cells. SDT is a research hotspot due to its non-invasive, deep tissue penetration. The sonosensitizer is a key factor in determining the sound power effect. Therefore, it is important to design and construct a sound-sensitive agent system with excellent performance to improve sound-sensitive activity.
Tumor Microenvironment (TME) refers to a local, relatively steady state environment in which a tumor provides essential nutrients for its growth (development and progression), movement (including metastasis and invasion) during the course of growth, and is composed of tumor cells themselves, stromal cells, and other extracellular matrix. TME differs greatly from the normal internal environment of the human body in terms of its physicochemical properties. TME is characterized significantly by oxygen (O 2 ) Low content, low pH and high pressure, which are mainly caused by the reasons of rapid proliferation cycle of malignant tumor cells, abnormal damage of tumor vasculature and the like. Hypoxia is a common feature of most solid tumors that breaks the dynamic balance between oxygenation and oxygenation, allowing abnormally proliferating tumor cells near tumor vessels 70-150 μm to consume available O 2 Thereby limiting the diffusion of oxygen into the deep layer of the tumor, resulting in a decrease in normal oxygen tension of the tissue, resulting in hypoxia (i.e., partial pressure of oxygen (pO) in the tumor tissue region 2 ) Less than 2.5 mmHg. Thus improving the hypoxic tumor microenvironment is critical for cancer treatment.
Perfluorocarbons are a common compound containing multiple fluorine atoms, wherein all C-H bonds are replaced by C-F bonds, and have been widely used in industrial and medical applications, such as refrigerants, anesthesia, radiotherapy conditioning and vitreoretinal surgery, due to their low surface tension, viscosity and chemical inertness in biological systems. Several perfluorocarbons are approved by the U.S. Food and Drug Administration (FDA) for contrast-enhancing ultrasound imaging. In contrast to hemoglobin, oxygen molecules are internalized in perfluorocarbons by physical force-mediated adsorption. Thus, the amount of oxygen dissolved in perfluorocarbon increases linearly with oxygen tension and is inversely proportional to temperature. The solubility of oxygen in perfluorocarbon is about 40-50 milliliters of oxygen per 100 milliliters of liquid at 25 ℃ (1 atmosphere), which makes it very suitable for use as a blood substitute. Perfluorocarbons are potentially valuable oxygen regulators with great potential to supplement oxygen consumption and promote ROS production.
Disclosure of Invention
The invention aims to provide a phthalocyanine-artesunate oxygen-carrying liposome compound with sound sensitivity activity, and preparation and application thereof, which not only show excellent tumor targeting, but also can improve the tumor hypoxia microenvironment and have remarkable advantages in the sound power treatment of solid tumors.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a phthalocyanine-artesunate oxygen-carrying liposome compound is a microvesicle formed by encapsulating a zinc phthalocyanine-artesunate conjugate and an oxygen-carrying carrier perfluoro tributylamine (FC-43) in a lipid bilayer; the particle size of the composition is 100-200 nm, and the composition can improve the anoxic microenvironment of tumors and has sound-sensitive activity, so that the composition can be used for the sound-dynamic treatment of tumors.
The preparation of the phthalocyanine-artesunate oxygen-carrying liposome complex comprises the following steps:
1) Perfluoro tributylamine, dipalmitoyl phosphatidylcholine (DPPC), cholesterol, distearoyl phosphatidylethanolamine-polyethylene glycol 2000-folic acid (DSPE-PEG) 2k FA) and zinc phthalocyanine-artesunate conjugate are added into a mixed solvent of chloroform/ethyl acetate (7:3, v/v) according to a molar ratio of 135.3:18:9:5:1, and the ultrasonic treatment is carried out for 1 to 5 minutes to completely dissolve and disperse all the raw materials;
2) After ultrasonic treatment, the solution is decompressed and spin-steamed to the bottom of a bottle to form a layer of film, and deionized water (DI) is added for ultrasonic treatment, so that the liposome suspension is formed after the wall of the solution is removed;
3) And (3) ultrasonically treating the obtained liposome suspension for 15-20 minutes at 0-20 ℃ by adopting an ultrasonic cell crusher, filtering and extruding by using a microporous filter head with the diameter of 0.22 mu m to remove unencapsulated macromolecular drugs, and dialyzing with deionized water (the molecular weight of a regenerated cellulose dialysis bag used is 3000) at 4-25 ℃ for 36-48 hours to remove free zinc phthalocyanine-artesunate conjugate, thereby obtaining the liposome nano-composite.
The phthalocyanine-artesunate oxygen-carrying liposome compound can be used for preparing a tumor sonodynamic therapy sensitizer after being oxygenated (an oxygen machine is used for oxygenating for 20 min) so as to realize the treatment of tumors. The acoustic effect conditions used were ultrasonic waves with an intensity of 1.5W/cm 2 The duty cycle is 100% and the frequency is 2 MHz.
The beneficial effects and outstanding advantages of the invention are as follows:
(1) The invention adopts perfluoro tributylamine as oxygen carrier, which has strong oxygen molecule adsorption capacity, certain polarity and high compatibility with zinc phthalocyanine-artesunate conjugate in the same system, thus obtaining nano oxygen carrying-sound sensitive liposome with high encapsulation efficiency.
(2) In the phthalocyanine-artesunate oxygen-carrying liposome compound provided by the invention, the phthalocyanine zinc-artesunate conjugate mainly exists in an aggregate form, and has a unique aggregation enhanced sound power effect.
(3) The phthalocyanine-artesunate oxygen-carrying liposome compound provided by the invention has excellent tumor targeting, can generate a large amount of active oxygen under ultrasonic excitation to have good sound-sensitive activity, and the oxygen-carrying carrier in the liposome can also play a role in supplementing oxygen to a certain extent, so that the phthalocyanine-artesunate oxygen-carrying liposome compound has good effect on improving the tumor hypoxia environment, and can be used as a novel anti-tumor drug for acoustic power treatment.
Drawings
FIG. 1 shows the stability of nanoliposome complexes in water in example 3.
FIG. 2 shows the stability of nanoliposome complexes in 10% FBS solution in example 3.
FIG. 3 shows the change in DCFH fluorescence spectrum of the nanoliposome complex of example 4 in the absence/presence of oxygen for 5 min.
FIG. 4 is a graph showing comparison of fluorescence intensity of cells under anaerobic conditions for nanoliposome complexes of example 5 (ROS-ID Hypoxia as an anaerobic probe).
Detailed Description
In order to make the contents of the present invention more easily understood, the technical scheme of the present invention will be further described with reference to the specific embodiments, but the present invention is not limited thereto.
The zinc phthalocyanine-artesunate conjugate used in the examples has the following chemical structural formula and is prepared according to the previously disclosed patent (CN 113788848A) of the subject group.
EXAMPLE 1 preparation of Liposome Complex comprising Zinc phthalocyanine-artesunate and oxygen carrier
Perfluoro tributylamine, dipalmitoyl phosphatidylcholine (DPPC), cholesterol, distearoyl phosphatidylethanolamine-polyethylene glycol 2000-folic acid (DSPE-PEG) 2k FA) and zinc phthalocyanine-artesunate conjugate are added into a 100 mL single-necked bottle according to a molar ratio of 135.3:18:9:5:1, mixed solvent of chloroform/ethyl acetate (7:3, v/v) is added, and ultrasonic treatment is carried out for 1-5 min to completely dissolve all raw materials; after ultrasonic treatment, the solution is decompressed and spin-steamed to the bottom of a bottle to form a layer of film, and then deionized water (DI) is used for ultrasonic wall stripping to form liposome suspension; and (3) filtering and extruding the liposome suspension for 15-20 minutes at 0-20 ℃ by adopting an ultrasonic cell crusher, removing unencapsulated macromolecular drugs by using a microporous filter head with the diameter of 0.22 mu m, and dialyzing with deionized water (the molecular weight of a regenerated cellulose dialysis bag used is 3000) at 4-25 ℃ for 36-48 hours to remove free zinc phthalocyanine-artesunate conjugate, thereby obtaining the nano liposome composite T1A@FNPs.
The particle size of the obtained nano liposome complex in the aqueous solution is between 100 and 200 and nm as measured by a nano particle size analyzer. The obtained nano liposome compound has better particle size distribution, and is favorable for preservation and use after preparation.
EXAMPLE 2 calculation of drug concentration and encapsulation efficiency in Phthalocyanine-artesunate oxygen-carrying Liposome Complex
Drawing a standard curve:
accurately weighing zinc phthalocyanine-artesunate conjugate, and dissolving the conjugate in DMF solution to prepare medicine mother liquor with the concentration of 2 mM; different volumes of drug mother liquor are sucked and added into 2 mL of DMF to prepare a diluent with the concentration of 1-6 mu M, and the electron absorption spectrum of the diluent at a specific wavelength is measured, so that a standard curve of the concentration of the drug in DMF is obtained.
Taking 20 mu L of the nano liposome complex prepared in the example 1, adding the nano liposome complex into DMF and fixing the volume to 2 mL so that the nano liposome complex is destroyed by a large amount of DMF, releasing the loaded drug into the solution, then measuring the electron absorption spectrum of the solution, and calculating the concentration C of the zinc phthalocyanine-artesunate conjugate in the solution according to a standard curve at a corresponding wavelength 1 Encapsulation efficiency EE (%) and drug concentration in the nanoliposome complex were then further calculated as follows:
EE(%)=(M 0 /M 1 )×100%，
C 0 ×V 0 =C 1 ×V 1 ，
wherein M is 0 Representing the mass of drug encapsulated in nanoliposome complexes, M 1 Indicating the dosage of the drug. C (C) 0 Indicating the concentration of mother liquor, V 0 20 mu L, C 1 Represents the concentration of diluted zinc phthalocyanine-artesunate coupling, V 1 2 mL.
The result shows that the concentration of the zinc phthalocyanine-artesunate conjugate in the nano liposome compound is 252.53 mu M, and the encapsulation rate is 90.77%, which indicates that the prepared nano liposome compound realizes better encapsulation rate. In contrast, liposome complexes prepared by replacing the perfluorotributylamine used with perfluorohexane, perfluoropropane or perfluoropentane have lower encapsulation efficiency (less than 30%).
EXAMPLE 3 stability test of Phthalocyanine-artesunate oxygen-carrying Liposome Complex in Water/10% FBS
The nanoliposome complex prepared in example 1 was taken at 20 μl, diluted into 1 mL ultrapure water and its stability was measured with a particle sizer for 30 days. The results show that the prepared nano liposome nano complex has better stability within 30 days (as shown in figure 1).
20. Mu.L of nanoliposome complex was diluted into 1 mL of 10% FBS solution in the same manner and its stability was measured. The results show that the prepared nano liposome compound has good stability in 24 hours (as shown in figure 2), and is predicted to have better delivery capacity in vivo, thereby being beneficial to clinical transformation.
EXAMPLE 4 test of the ability of the oxygen carrying Liposome Complex of Phthalocyanine-artesunate to acoustically kinetically generate active oxygen
The 2',7' -dichlorofluorescein diacetate (DCFH-DA) hydrolysate 2',7' -dichlorofluorescein Diacetate (DCFH) is used as a probe of active oxygen (the excitation wavelength of the probe is 488-nm, the emission wavelength detection range is 500-600 nm, and the preparation is carried out by referring to the prior paper J. Immunol Methods 1993, 159 (1-2) and 131-138). The ability of the sample to acoustically sensitize to ROS was determined by observing the change in fluorescence of DCFH in the solution containing the sample to be tested as a function of the time of ultrasonic excitation. The specific measurement method comprises the steps of sucking the nano liposome compound in deionized water by a pipette to make the final concentration of the nano liposome compound be 4 mu M, then adding 100 mu L of 2',7' -dichlorofluorescein diacetate (the final concentration of the 2',7' -dichlorofluorescein diacetate is 10 mu M), and performing ultrasonic treatment (the ultrasonic intensity is 1.5W/cm) 2 The fluorescence intensity at 500-600 nm is tested every 1 min under the conditions of the duty ratio of 100% and the frequency of 2 MHz), and the sound sensitization performance of the nanoliposome complex is determined according to the ability of the fluorescence intensity to generate active oxygen (taking nonoxygenated nanoliposome as a control). The stronger the fluorescence intensity generated by DCFH, the stronger the ROS generating ability, the higher the sonosensitization activity.
The results showed that oxygenated nanoliposomes (tia@f NPs (O 2 ) More ROS can be produced with a fluorescence quantum yield 1.5 times that of unoxygenated nanoliposomes (tia@f NPs) (see fig. 3).
EXAMPLE 5 ultrasonic activation of Phthalocyanine-artesunate oxygen-carrying Liposome Complex in tumor cells to active oxygen production assay
ROS-ID Hypoxia is used as an anoxic probe, and the improvement condition of the oxygen-carrying liposome complex of the phthalocyanine-artesunate on the anoxic environment of tumor cells after entering the cells is researched, so that the oxygen release capacity of the oxygen-carrying liposome complex of the phthalocyanine-artesunate in the tumor cells is analyzed. The stronger the fluorescent intensity of the ROS-ID Hypoxia probe in a hypoxic environment.
Hypoxia group: hepG2 liver cancer cell in logarithmic growth phase was cultured at 5X 10 4 Cell density/mL was inoculated into a confocal plate in DMEM medium containing 10% calf serum under anaerobic conditions (37 ℃ C., 5% CO) 2 、5%O 2 ) Incubate overnight. The next day, the old medium was discarded, 400 μl of medium containing drug (oxygenated or unoxylated nanoliposomes, each with a drug concentration of 4 μm) was added, and the culture was continued for 1.5 hours. After 1.5 hours, 100 μl of ROS-ID hypoxia probe was added and the sample was sonicated (ultrasound intensity 1.5W/cm 2 Duty cycle of 20%, frequency of 2 MHz) or under non-ultrasonic conditions for 0.5 hours. The drug-containing medium was then discarded, gently washed 2-3 times with PBS, and finally covered with 400 μl PBS for fluorescence copolymerization Jiao Paizhao (i.e., co-drug-free, oxygenated liposomes+ultrasound; unoxygenated liposomes+ultrasound, and oxygenated liposomes+ultrasound-ultrasound-free groups were compared). Three different positions were selected for each confocal plate for photographing with 532 nm laser excitation, and after photographing, image processing was performed with SPE ROI fluorescence analysis software, with at least 10 cells per plate of average fluorescence intensity. The histogram is plotted using Origin plotting software with drug name on the abscissa and relative fluorescence intensity on the ordinate. The results are shown in FIG. 4.
The experimental results showed that the relative fluorescence intensities of the oxygenated liposomes (oxygenated-NO US) and the non-oxygenated liposomes (non-oxygenated-NO US) did not change significantly in the absence of sonication, relative to the drug-free Control (CT), indicating that sonication is required for liposome disruption to release oxygen. Meanwhile, compared with a control group (CT), the unoxygenated liposome does not improve the degree of hypoxia under the condition of hypoxia, and the fluorescence intensity of the unoxygenated liposome after the ultrasonic treatment (oxygenation-US) is reduced by 12.28 times compared with that of the control group, so that the liposome can be proved to be capable of effectively releasing oxygen and improving the hypoxia condition.
In conclusion, the oxygenated liposome compound can release a large amount of oxygen after ultrasonic disruption, and has the characteristic of better improving the anoxic environment of tumors.
The foregoing description is only of the preferred embodiments of the invention, and all changes and modifications that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (7)
1. An oxygen carrying liposome compound of phthalocyanine-artesunate with sound sensitivity activity, which is characterized in that: the liposome compound is a microvesicle formed by encapsulating zinc phthalocyanine-artesunate conjugate and oxygen carrier perfluoro tributylamine in a lipid bilayer.
2. The phthalocyanine-artesunate oxygen-carrying liposome complex of claim 1, wherein: the particle size of the liposome complex is 100-200 nm.
3. The phthalocyanine-artesunate oxygen-carrying liposome complex of claim 1, wherein: the preparation method comprises the following steps:
1) Adding dipalmitoyl phosphatidylcholine, distearoyl phosphatidylethanolamine-polyethylene glycol 2000-folic acid, cholesterol, zinc phthalocyanine-artesunate conjugate and perfluoro tributylamine into a mixed solvent of chloroform/ethyl acetate according to a proportion, and carrying out ultrasonic treatment for 1-5 min to completely dissolve and disperse all raw materials;
2) After ultrasonic treatment, the solution is decompressed and spin-steamed to the bottom of the bottle to form a layer of film, and then deionized water is added for ultrasonic treatment, so that the liposome suspension is formed after the wall of the solution is removed;
3) And carrying out ultrasonic treatment on the obtained liposome suspension for 15-20 minutes at the temperature of 0-20 ℃, then filtering and extruding by using a microporous filter head with the diameter of 0.22 mu m, and dialyzing by using deionized water at the temperature of 4-25 ℃ for 36-48 hours to obtain the liposome nano-composite.
4. The phthalocyanine-artesunate oxygen-carrying liposome complex of claim 3, wherein: the molar ratio of perfluoro tributylamine, dipalmitoyl phosphatidylcholine, cholesterol, distearoyl phosphatidylethanolamine-polyethylene glycol 2000-folic acid and zinc phthalocyanine-artesunate conjugate used in step 1) was 135.3:18:9:5:1.
5. The phthalocyanine-artesunate oxygen-carrying liposome complex of claim 3, wherein: the volume ratio of chloroform to ethyl acetate in the mixed solvent in the step 1) is 7:3.
6. The phthalocyanine-artesunate oxygen-carrying liposome complex of claim 3, wherein: and 3) dialyzing by using a regenerated cellulose dialysis bag with a molecular weight of 3000.
7. Use of the phthalocyanine-artesunate oxygen-carrying liposome complex of claim 1 in the preparation of a sensitizer for acoustic power treatment of tumors.
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| CN105561306A (en) * | 2015-01-16 | 2016-05-11 | 南京大学 | Composition containing singlet oxygen protective agent and preparation method thereof |
| CN111388669A (en) * | 2020-03-19 | 2020-07-10 | 中南大学湘雅二医院 | Oxygen supply nano platform and preparation method and application thereof |
| CN113788848A (en) * | 2021-10-18 | 2021-12-14 | 福州大学 | Phthalocyanine-artemisinin conjugate used as acoustic power/optical power sensitizer and preparation method and application thereof |
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| CN105561306A (en) * | 2015-01-16 | 2016-05-11 | 南京大学 | Composition containing singlet oxygen protective agent and preparation method thereof |
| CN111388669A (en) * | 2020-03-19 | 2020-07-10 | 中南大学湘雅二医院 | Oxygen supply nano platform and preparation method and application thereof |
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