CN111643673B - Tumor-targeted nano-drug simultaneously encapsulating photosensitizer and protein and application thereof - Google Patents
Tumor-targeted nano-drug simultaneously encapsulating photosensitizer and protein and application thereof Download PDFInfo
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- CN111643673B CN111643673B CN202010653123.0A CN202010653123A CN111643673B CN 111643673 B CN111643673 B CN 111643673B CN 202010653123 A CN202010653123 A CN 202010653123A CN 111643673 B CN111643673 B CN 111643673B
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Abstract
The invention discloses a tumor-targeted nano-medicament simultaneously encapsulating a photosensitizer and protein and application thereof in preparing an anti-tumor medicament. The tumor targeted nano-drug has the characteristics of active targeting of tumor cells and drug release in response of tumor microenvironment, and can realize the cooperative treatment of photodynamic therapy and protein therapy while performing fluorescence imaging, thereby achieving good diagnosis and treatment effects.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a multifunctional nano-drug which has active targeting of tumor cells and responsiveness of tumor microenvironment and can be used for fluorescence imaging and realize the combination of photodynamic therapy and protein therapy, a synthesis method and application thereof.
Background
Cancer is one of the leading causes of morbidity and mortality worldwide, and the number of deaths due to cancer has increased rapidly over the past few decades. Small molecule anticancer drugs are one of the mainstream cancer treatments and one of the most commonly used. However, the free form of anticancer drugs may develop multidrug resistance. Thus, scientists have sought other therapeutic agents to circumvent the limitations described above.
Photodynamic therapy (PDT) with non-invasive clinical treatment and intrinsic fluorescence imaging properties has been a promising approach to cancer treatment since the beginning of the 21 st century. Compared to conventional therapies such as radiotherapy, surgery and chemotherapy, PDT has the advantages of repeatable administration, controllable light dose, rapid therapeutic effect and site-directed treatment by local irradiation. PDT is the excitation of Photosensitizers (PSs) with specific wavelength light irradiation to transfer energy to molecular oxygen (O) 2 ) Producing cytotoxic singlet oxygen: ( 1 O 2 ) Which in turn leads to apoptosis and/or necrosis of the tumor cells. However, the commonly used highly potent PSs are usually hydrophobic, resulting in their susceptibility to self-aggregation in aqueous solutions, which not only reduces their PDT efficacy, but also results in inefficient delivery of PSs molecules to the tumor site. In addition, the aggregation of the PSs molecules greatly reduces the PSs molecules and O 2 The chance of contact between the two parts is not good for the exertion of PDT efficacy.
Protein therapy is an emerging cancer treatment and has shown promise for highly effective treatment in preclinical and clinical trials. Compared with traditional chemotherapeutic agents, the protein used in protein therapy may activate apoptosis of tumor cells or block growth signals of tumors. For example, cytochrome c (cyt c) has been found to be involved in the initiation of the mitochondrial apoptotic pathway. In particular, high levels of Cyt c activate caspase and induce DNA fragmentation in the subsequent nucleus, and can also be used to circumvent chemotherapeutic resistance of tumors and improve therapeutic efficacy. However, clinical transformation of proteinaceous anticancer drugs has long been hampered by a series of problems. It is well known that free proteins are highly unstable in biologically relevant environments due to their sensitivity to chemicals, pH changes, temperature changes and enzymatic degradation, while denatured proteins can trigger immune responses and cause adverse health effects. Furthermore, the cellular uptake efficiency of proteins is unsatisfactory due to their size and surface charge.
Meanwhile, a single treatment method often has certain defects in the aspect of treatment effect, and complete treatment of tumors cannot be realized. The advent of nanotechnology opens up new avenues for the development of combined therapeutic modalities for photodynamic therapy and protein therapy. Researches show that the nano-carrier can efficiently deliver the hydrophobic photosensitizer and the protein, improve the uptake of the photosensitizer by tumors and protect the functional integrity of protein drugs in the delivery process, and simultaneously can use the surface engineering technology to increase the material stability and the uptake capacity of target cells. Therefore, the multifunctional nano-drug which has active targeting of tumor cells, response of tumor microenvironment, fluorescence imaging and combination of photodynamic therapy and protein therapy is developed, and has great application prospect in the aspect of improving tumor therapy.
Disclosure of Invention
The invention aims to provide a tumor targeting nano-drug simultaneously encapsulating a photosensitizer and protein and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
one of protection purposes of the invention is a tumor targeting nano-drug simultaneously encapsulating photosensitizer and protein, which is a nano-particle formed by using a metal organic framework material ZIF-8 as a carrier, simultaneously encapsulating a hydrophobic photosensitizer and a protein drug and modifying by using a modifier; the particle size of the nano-particles is 20-400 nm.
The hydrophobic photosensitizer is one or more of chlorin e6 (Ce 6), curcumin, hypericin, protoporphyrin (IX), tetraphenylporphyrin, zinc phthalocyanine and hypocrellin B.
The protein medicine is cytochrome c (Cyt c), carboxypeptidase G2, interferon alpha-2B, ribonuclease, interleukin-10, PD-1 antibody and granzyme B.
The modifier (SA) is one or more of Hyaluronic Acid (HA), polyethyleneimine, dextran, chitosan, fucose, albumin, gelatin, liposome, and polyvinylpyrrolidone.
The second protection purpose of the invention is the preparation method of the tumor targeting nano-drug, which is dimethyl imidazole (2-MIM) and Zn 2+ Self-assembling into a metal organic framework material ZIF-8, simultaneously synthesizing a hydrophobic photosensitizer and a protein drug in one step to prepare a pre-nano drug, and then utilizing carboxyl and Zn on a modifier 2+ The coordination function of the compound is used for synthesizing the tumor targeting nano-drug. The method comprises the following specific steps:
1) uniformly mixing a 2-MIM (metal-insulator-metal) aqueous solution, a Protein drug aqueous solution and a hydrophobic photosensitizer solution (dissolving the hydrophobic photosensitizer in N, N-dimethylformamide), stirring and dispersing for 5 min, then quickly dropwise adding an aqueous solution containing zinc acetate or zinc nitrate, stirring for 5-60 min (preferably 10 min) at 300-600 r/min (preferably 400 r/min), centrifuging for 5-60 min at 4 ℃ at 8000-14800 r/min, collecting lower-layer precipitates, and centrifuging and washing for multiple times by using water to obtain the front nano drug PS/Protein @ ZIF-8 encapsulated by the metal organic framework; wherein the weight ratio of the hydrophobic photosensitizer to the protein drug to the zinc acetate or the zinc nitrate is 1-20: 1-20: 100 (preferably 7.5: 8: 100), and a molar ratio of zinc acetate or zinc nitrate to 2-MIM of 1: 1 to 200 (preferably 1: 70);
2) dispersing the obtained PS/Protein @ ZIF-8 in water again, slowly dropwise adding a modifier solution under an ultrasonic condition, stirring for 2-6 h in the dark, adding anhydrous ethanol with the volume of 1/10 in a reaction system, centrifugally washing for 20-40 min at 8000-14800 r/min, centrifugally washing for multiple times with water to obtain the targeted nano-drug PS/Protein @ ZIF-8/SA, and storing in the dark at the temperature of 2-8 ℃; wherein the mass ratio of PS/Protein @ ZIF-8 to the modifier in the reaction system is 1: 0.1 to 10 (preferably 1: 1).
The tumor-targeted nano-drug can be targeted to tumor cells, and can be degraded and released in response to pH sensitivity in a tumor microenvironment to realize synergistic treatment of photodynamic therapy and protein therapy.
The invention has the following beneficial effects:
(1) the tumor targeting nano-drug has simple synthesis steps and mild conditions, and does not affect the activity of protein;
(2) the tumor-targeted nano-drug efficiently entraps the hydrophobic photosensitizer and the protein drug through non-covalent effects such as self-assembly, electrostatic effect and the like, so that the damage of covalent modification to the molecular structure of the drug is avoided;
(3) the tumor targeted nano-drug is modified by a modifier, so that the tumor targeted nano-drug can be degraded in response to a tumor micro-acid microenvironment, and the stability of the drug in a physiological environment and the efficient targeted release of the drug in a tumor are realized;
(4) the tumor targeting nano-drug has both photodynamic therapy capability and protein therapy capability, can realize the synergistic treatment of photodynamic therapy and protein therapy through the catalysis and/or treatment effect of protein, and enhances the combined killing capability on tumors.
In summary, the nano-drug can be used for fluorescence imaging at tumor sites and can also be used as a combined therapeutic agent for cancer.
Drawings
FIG. 1 is a transmission electron microscope (A) of nano-drug Ce6/Cyt C @ ZIF-8/HA, a particle size distribution diagram (B), a Zeta potential diagram (C), an ultraviolet-visible light absorption spectrum diagram (D), a fluorescence spectrum diagram (E) excited at Ce6 excitation wavelength, and a fluorescence spectrum diagram (F) excited at FITC excitation wavelength of different nano-drugs.
FIG. 2 is a graph showing the absorption of DPBF at 300-600 nm as a function of irradiation time under 670 nm laser irradiation (wherein A is Cyt C @ ZIF-8/HA, B is Ce6/Cyt C @ ZIF-8, and C is Ce6/Cyt C @ ZIF-8/HA), and a normalized change in absorption at 415 nm (D).
FIG. 3 shows the release of Ce6 (A) and Cyt c (B) as a function of time at different pH values of the nano-drug Ce6/Cyt c @ ZIF-8/HA.
FIG. 4 is a time variation graph (A) of the nano-drug Ce6/Cyt c @ ZIF-8/HA decomposed in the presence of hydrogen peroxide to generate oxygen and a comparison graph (B) of active oxygen generated under normal oxygen and hypoxic conditions.
FIG. 5 is a contrast graph of fluorescence imaging of nano-drug Ce6/Cyt c @ ZIF-8/HA taken up by cells.
FIG. 6 is a contrast chart of fluorescence imaging of different nano-drugs under light and no light conditions to generate reactive oxygen species in cells.
FIG. 7 is a comparison of PI staining fluorescence images of cells treated with different nano-drugs under light and no light.
FIG. 8 shows the results of quantitative cell viability measurements of different nanomedicines after cell treatment under light and no light conditions.
FIG. 9 shows the result of apoptosis detection of different nano-drugs after cell treatment under light and no light.
Detailed Description
In order to make the content of 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 of tumor-targeting Nanoparticulates
Respectively weighing 2.27 g of 2-MIM, 8 mg of Cyt c (serving as a protein medicament in the implementation) and 6 mg of Ce6 (serving as a photosensitizer in the implementation), respectively dissolving the materials in 8 mL of distilled water, 0.8 mL of distilled water and 0.6 mL of N, N-Dimethylformamide (DMF), and then stirring the materials at 400 r/min in dark for 5 min to fully and uniformly mix the three materials; weighing 86 mg of zinc acetate, dissolving in 0.8 mL of distilled water, quickly dripping the obtained zinc acetate solution into the reaction solution, stirring at 400 r/min in the dark for 10 min, collecting the reaction solution, centrifuging at 13300 r/min at 4 ℃ for 30 min, collecting the lower-layer precipitate, centrifuging and washing with distilled water for three times, and then suspending in the distilled water to prepare the front nano-drug Ce6/Cyt c @ ZIF-8 solution with the concentration of 2 mg/mL.
Adding an equal volume of 2 mg/mL HA (used as a modifier in the embodiment) aqueous solution into 2 mg/mL pre-nano-drug solution, performing ultrasonic sound and uniform mixing, oscillating for 3 hours in a dark place at 500 r/min, adding 1/10 volume of absolute ethyl alcohol into a reaction system, centrifuging for 20 minutes at 10000 r/min at 4 ℃, then centrifuging and washing for three times by using distilled water to obtain Ce6/Cyt c @ ZIF-8/HA, re-dispersing in the distilled water, and placing in a refrigerator for storage in a dark place at 4 ℃.
In addition, ZIF-8/HA (not loaded with photosensitizer and protein drug), Ce6@ ZIF-8/HA (not loaded with protein drug), Cyt c @ ZIF-8/HA (not loaded with photosensitizer), Ce6/Cyt c @ ZIF-8 (not using modifier), Ce6@ ZIF-8 (not loaded with protein drug and not using modifier) were synthesized separately according to the above-mentioned methods, and used as reference samples together with Ce6, Cyt c, and ZIF-8 for comparative studies.
Example 2:
1. the nano-drug synthesized in example 1 was characterized by tests such as Transmission Electron Microscopy (TEM), nano-particle size and Zeta potential analyzer (DLS, Zeta potential), ultraviolet-visible spectrophotometer (UV-Vis), fluorescence spectrometer, etc., and the results are shown in fig. 1.
As can be seen from figure 1, the size of the synthesized nano-drug Ce6/Cyt c @ ZIF-8/HA is about 110 nm (A); the size distribution of different nano-drug samples is concentrated, which shows that the synthesized sample is more uniform (B); and can be seen through Zeta potential diagram (C) and ultraviolet visible light absorption spectrogram (D), protein drug Cyt C and photosensitizer Ce6 are successfully encapsulated in the metal organic framework; as can be seen from fluorescence spectrograms (E) and (F), when the encapsulated photosensitizer and the protein drug labeled by fluorescence are available, a fluorescence peak of Ce6 at 660 nm and a fluorescence peak of FITC at 520 nm are respectively shown in the spectral line of the nano drug Ce6/Cyt c @ ZIF-8/HA, and further, the successful encapsulation of the photosensitizer and the protein in a metal organic framework is proved.
2. The ability of the nano-drug sample synthesized in example 1 to generate active oxygen under 670 nm laser irradiation was examined, i.e., 1, 3-Diphenylisobenzofuran (DPBF) was used as an active oxygen indicator probe, after different nano-drug samples were mixed with DPBF, laser irradiation was performed for different times, the change in absorbance within the range of 300-600 nm was tested, and the absorbance at 415 nm was taken for normalization treatment to prove the active oxygen generating ability of the metal-organic framework nano-drug, the results are shown in fig. 2.
As can be seen from fig. 2, the absorption value of the nano-drug sample with Ce6 entrapped at 415 nm decreases with the increase of the illumination time, while the sample without Ce6 entrapped has no obvious change, which indicates that the nano-drug with Ce6 entrapped can generate active oxygen under the illumination condition.
3. The ability of the nano-drug synthesized in example 1 to respond to release was examined by dissolving the nano-drug in PBS buffer solution of pH =5.0 and pH =7.4, respectively, and measuring the absorption, and the results were shown in fig. 3, in which the nano-drug released Ce6 and Cyt c.
As can be seen from fig. 3, in PBS buffer with pH =5.0, the nano-drug Ce6/Cyt c @ ZIF-8/HA was significantly degraded, almost completely releasing the entrapped Ce6 and Cyt c, demonstrating its acid-responsive release capability.
4. The ability of the nano-drug synthesized in example 1 to catalyze hydrogen peroxide to generate oxygen and to improve the photodynamic action was examined by reacting the nano-drug with 500 μ M hydrogen peroxide and measuring the change in dissolved oxygen by an oxygen electrode. Meanwhile, DPBF is used as a probe, and the capacity of the nano-drug for generating active oxygen is illuminated in the presence of hydrogen peroxide under the conditions of normal oxygen and anaerobic reaction. The results are shown in FIG. 4.
As can be seen from FIG. 4, Cyt c existing in the nano-drug can effectively catalyze the decomposition of hydrogen peroxide into oxygen (A) and improve the active oxygen generating capacity (B), thereby being beneficial to improving the photodynamic therapy effect.
Example 3:
1. a cervical cancer HeLa cell is taken as a model, and a confocal fluorescence microscope is utilized to test the capacity of carrying Ce6 and Cyt c and the tumor cell targeting capacity of HA of the nano-drug Ce6/Cyt c @ ZIF-8/HA at the cell level. Specifically, after incubating the nano-drug with L929 cells (mouse fibroblasts), HeLa cells and HA-blocked HeLa cells for 2 hours, fluorescence of Ce6 and FITC-Cyt c was detected by confocal fluorescence microscopy, and the results are shown in fig. 5.
As can be seen in FIG. 5, fluorescence images of Ce6 and FITC appear in HeLa cells, which proves that the nano-drug can successfully deliver Ce6 and Cyt c into the cells.
2. The ability of different nano-drugs to generate active oxygen in cells was investigated in combination with the active oxygen fluorescence indicator 2',7' -dichlorofluorescence yellow diacetate (DCFH-DA). The method specifically comprises the steps of incubating nano-drugs with HeLa cells for 4 hours respectively, washing off the nano-drugs, adding a fluorescence indicator DCFH-DA, incubating for 20 minutes, dividing the cells into two groups, wherein one group is used for irradiating the cells for 5 minutes at 670 nm, the other group is used for comparison without irradiation, and the results are shown in figure 6 after irradiation by using a fluorescence microscope.
As can be seen from figure 6, DCFH (DCFH) fluorescence is obvious in the nanometer medicine group containing Ce6 (Ce6@ ZIF-8/HA, Ce6/Cyt c @ ZIF-8/HA, HA + Ce6/Cyt c @ ZIF-8/HA), and the nanometer medicine containing Ce6 can generate active oxygen under illumination, so that the nanometer medicine can be used for cell photodynamic therapy.
3. The therapeutic effect of different nano-drugs under the condition of illumination and no illumination is investigated by combining a dead cell fluorescence indicator (propidium iodide, PI). The specific steps are that nano-drugs and HeLa cells are incubated for 4 hours respectively, then the nano-drugs are washed off, then the nano-drugs are divided into two groups respectively, wherein one group is used for irradiating the cells for 5 minutes under the condition of 670 nm, the other group is used for comparison without irradiation, after 24 hours, the cells are dyed with PI dye for 20 minutes, and then the detection is carried out by a fluorescence microscope, and the result is shown in figure 7.
As can be seen from fig. 7, in the absence of light, the killing effect of each nano-drug on cells is low; after illumination, compared with a test group (Control and Cyt c) without Ce6, the nano-drug group (Ce6@ ZIF-8/HA, Ce6/Cyt c @ ZIF-8/HA, HA + Ce6/Cyt c @ ZIF-8/HA) containing Ce6 HAs obviously improved killing capacity on cancer cells, and the result shows that the nano-drug group HAs a good photodynamic treatment effect. In addition, Ce6/Cyt c @ ZIF-8/HA is also improved to a certain extent compared with HA + Ce6/Cyt c @ ZIF-8/HA, because the effective uptake of the nano-drug by cells is reduced after HA blocking treatment, thereby reducing the effect of combined treatment.
4. And (3) quantitatively testing the treatment effect of the nano-medicament under the conditions of illumination and no illumination by using a cell viability quantitative detection kit (CCK-8 kit). Specifically, HeLa cells are cultured in a 96-well plate, different nano-drugs are respectively added for incubation for 4 hours, the nano-drugs are washed off, then the cells are divided into two groups, wherein one group is subjected to 670 nm illumination for 5 min, the other group is not subjected to illumination for comparison, after 24 hours, the detection is carried out according to the operation method of the cell viability quantitative detection kit, and the result is shown in figure 8.
As can be seen from fig. 8, in the absence of light, the killing effect of each nano-drug on cells is low; after illumination, compared with a nano-drug group (Ce6@ ZIF-8/HA, Ce6/Cyt c @ ZIF-8/HA, HA + Ce6/Cyt c @ ZIF-8/HA) without Ce6 group (Control and Cyt c), the killing capacity of the nano-drug group (Ce 6) to cancer cells is remarkably improved. In addition, compared with HA + Ce6/Cyt c @ ZIF-8/HA, the Ce6/Cyt c @ ZIF-8/HA is also improved to a certain extent, and the effective uptake of the nano-drugs by cells is reduced after HA blocking treatment, so that the combined treatment effect is reduced.
5. The treatment effect of the nano-drug under the conditions of illumination and no illumination is quantitatively tested by flow cytometry by using an apoptosis kit (annexin V-FITC/PI). Specifically, HeLa cells are cultured in a 6-pore plate, different nano-drugs are respectively added to the cells for incubation for 4 hours, the nano-drugs are washed off, then the cells are divided into two groups, one group of the cells are irradiated for 5 min at 670 nm, the other group of the cells are not irradiated for comparison, after 24 hours, the cells are detected by flow cytometry according to an apoptosis kit (annexin V-FITC/PI) operation method, and the result is shown in figure 9.
As can be seen from fig. 9, in the absence of light, the killing effect of each nano-drug on cells is low; after illumination, compared with a nano-drug group (Ce6@ ZIF-8/HA, Ce6/Cyt c @ ZIF-8/HA, HA + Ce6/Cyt c @ ZIF-8/HA) without Ce6 group (Control and Cyt c), the killing capacity of the nano-drug group (Ce 6) to cancer cells is remarkably improved. In addition, compared with HA + Ce6/Cyt c @ ZIF-8/HA, the Ce6/Cyt c @ ZIF-8/HA is also improved to a certain extent, and the effective uptake of the nano-drugs by cells is reduced after HA blocking treatment, so that the combined treatment effect is reduced.
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 (6)
1. A preparation method of a tumor-targeted nano-drug simultaneously encapsulating a photosensitizer and protein is characterized by comprising the following steps: the tumor targeting nano-drug is dimethyl imidazole and Zn 2+ The self-assembled metal organic framework material ZIF-8 is used as a carrier, simultaneously entraps a hydrophobic photosensitizer and a protein drug, and is modified by a modifier to form nano particles, and the preparation method specifically comprises the following steps:
1) uniformly mixing 2-methylimidazole, a Protein drug and a hydrophobic photosensitizer, stirring and dispersing for 5 min, then quickly dropwise adding an aqueous solution containing zinc acetate or zinc nitrate, stirring for 5-60 min, centrifuging for 5-60 min at 4 ℃ at 8000-14800 r/min, collecting lower-layer precipitates, and centrifuging and washing for multiple times by using water to obtain a front nano drug PS/Protein @ ZIF-8 encapsulated by a metal organic framework;
2) re-dispersing the obtained PS/Protein @ ZIF-8 in water, slowly dropwise adding a modifier SA solution under an ultrasonic condition, stirring for 2-6 hours in a dark place, adding absolute ethyl alcohol with the total volume of 1/10 in a reaction system, centrifugally washing for 20-40 minutes at 8000-14800 r/min, and centrifugally washing for multiple times with water to obtain the targeting nano-drug PS/Protein @ ZIF-8/SA;
the weight ratio of the hydrophobic photosensitizer and the protein medicine used in the step 1) to the zinc acetate or the zinc nitrate is 1-20: 1-20: 100; the molar ratio of the zinc acetate or the zinc nitrate to the 2-methylimidazole is 1: 1 to 200.
2. The preparation method of the tumor-targeted nano-drug according to claim 1, characterized in that: the hydrophobic photosensitizer is one or more of chlorin e6, curcumin, hypericin, protoporphyrin, tetraphenylporphyrin, zinc phthalocyanine and hypocrellin B.
3. The preparation method of the tumor-targeted nano-drug according to claim 1, characterized in that: the protein medicine is one or more of cytochrome c, carboxypeptidase G2, interferon alpha-2B, ribonuclease, interleukin-10, PD-1 antibody and granzyme B.
4. The preparation method of the tumor-targeted nano-drug according to claim 1, characterized in that: the modifier is one or more of hyaluronic acid, polyethyleneimine, dextran, chitosan, fucose, albumin, gelatin, liposome and polyvinylpyrrolidone.
5. The preparation method of the tumor-targeted nano-drug according to claim 1, characterized in that: the particle size of the nano-particles is 20-400 nm.
6. The preparation method of the tumor-targeted nano-drug according to claim 1, characterized in that: step 2) the mass ratio of PS/Protein @ ZIF-8 to the modifier in the reaction system is 1: 0.1 to 10.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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