CN112451680A - ROS sensitive nano reagent with synergistic induction of photodynamic therapy and iron death and preparation method thereof - Google Patents
ROS sensitive nano reagent with synergistic induction of photodynamic therapy and iron death and preparation method thereof Download PDFInfo
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Abstract
An ROS sensitive nano reagent with cooperative induction of photodynamic therapy and iron death and a preparation method thereof belong to the technical field of biological medicine. The nanometer reagent is constructed by a photosensitizer-modified ROS-sensitive amphiphilic block polymer, and comprises an amphiphilic biodegradable polymer, a photosensitizer group connected at the tail end, and a ROS-sensitive monomer which is modified by a side chain and can induce iron death; the amphiphilic polymer can self-assemble into an ROS sensitive nanoagent with synergistic induction of photodynamic therapy and iron death, wherein the hydrophobic part self-assembles into a hydrophobic core and the hydrophilic part becomes a hydrophilic shell. Finally, a film dispersion method is utilized to drive the ROS sensitive amphiphilic block polymer modified by the photosensitizer to self-assemble into the ROS sensitive nano reagent which can synergistically induce photodynamic therapy and iron death, so that the ROS sensitive nano reagent can achieve the effect of inhibiting tumor growth under the synergistic action of the photodynamic therapy and the iron death therapy under the action of a tumor microenvironment.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an ROS (Reactive Oxygen Species) sensitive nano reagent with the synergistic effect of inducing photodynamic therapy and iron death and a preparation method thereof.
Background
Cancer is the host of human health in China and even worldwide, and the incidence of cancer is increasing. Recent survey results show that in 2019, new cancer cases in the world reach more than 2000 cases, and more than ten million deaths occur. Among them, the number of cancer diseases and cancer deaths in China is the first to live in the world. At present, the conventional cancer treatment method cannot provide a satisfactory treatment effect and has the defects of low specificity, strong toxic and side effects, high recurrence rate and the like. Early cancer is difficult to find, and tumor cells are easy to metastasize and spread through such pathways as lymph vessels, and the like, so that the cure rate of the cancer is not ideal. Current clinical cancer therapies are surgery, radiation and chemotherapy. However, surgical treatment has the disadvantages of high risk, large wound area and easy recurrence; radiotherapy and chemotherapy can kill tumor cells and damage normal cells of the body, resulting in impaired normal physiological functions and multi-drug resistance. Therefore, there is a need to develop new cancer treatment regimens and drugs to overcome this problem.
Photodynamic therapy is an effective cancer treatment method emerging in recent years, and can generate cytotoxic singlet oxygen under the irradiation of light with specific wavelength, selectively remove tumor cells without damaging healthy tissues and organs, so that the photodynamic therapy has attracted wide attention in tumor treatment as an imaging probe for cancer diagnosis and can also be used for guiding cancer treatment. However, the low efficiency of photosensitizer delivery and the insensitivity to diagnosis severely limit its use in the clinic. Several approaches have been developed to utilize nano-drug carriers that are responsive to the tumor microenvironment. The nano-drug carrier has excellent cell penetration capability, can improve the effect of the drug, and controls the release and targeting of the drug to tumor cells. Thereby reducing the dosage and side effects of the drug. The method is an effective way for improving the photodynamic treatment effect by improving the tumor targeting aggregation capability of the nano-carrier and activating the photosensitizer in cells.
However, with the continuous development of medical technology, the drug resistance of some tumor cells is also revealed, and a single treatment system cannot meet the requirements of the current cancer treatment, so that a brand-new nano-drug preparation needs to be developed by combining a plurality of treatment means. In recent years, a completely new form of cell death, iron death (Ferroptosis), has emerged. Iron death is an iron-dependent, novel programmed cell death pattern that is distinguished from apoptosis, cell necrosis, and autophagy. The main mechanism of iron death is that under the action of ferrous iron, unsaturated fatty acids are catalyzed to undergo lipid peroxidation, so that lipid peroxides are accumulated to induce cell death.
Disclosure of Invention
The invention aims to overcome the existing problems and provide an ROS (Reactive Oxygen Species) sensitive nano reagent with the function of synergistically inducing photodynamic therapy and iron death and a preparation method thereof.
The invention relates to an ROS sensitive nano reagent with the function of synergistically inducing photodynamic therapy and iron death, which is characterized in that: the nanometer reagent is constructed by a photosensitizer-modified ROS-sensitive amphiphilic block polymer, wherein the photosensitizer-modified ROS-sensitive amphiphilic polymer comprises an amphiphilic biodegradable polymer (namely, a polymer main skeleton formed by initiating ring-opening polymerization of cyclic amino acid monomers in one step by taking methoxy polyethylene glycol amine containing terminal amino groups as a macroinitiator), a tail end connected photosensitizer group and a side chain-modified ROS-sensitive monomer capable of inducing iron death; the photosensitizer-modified ROS-sensitive amphiphilic polymer can be self-assembled into an ROS-sensitive nano reagent with the function of synergistically inducing photodynamic therapy and iron death, wherein a hydrophobic part is self-assembled into a hydrophobic core, and a hydrophilic part is a hydrophilic shell. Finally, a film dispersion method is utilized to drive the ROS sensitive amphiphilic block polymer modified by the photosensitizer to self-assemble into the ROS sensitive nano reagent which can synergistically induce photodynamic therapy and iron death, so that the ROS sensitive nano reagent can achieve the effect of inhibiting tumor growth under the synergistic action of the photodynamic therapy and the iron death therapy under the action of a tumor microenvironment.
The invention relates to a preparation method of an ROS sensitive nano reagent with the functions of synergistically inducing photodynamic therapy and iron death, which comprises the following steps:
(1) methoxy polyethylene glycol amine (mPEG-NH) as hydrophilic chain segment2) Mixing a macroinitiator and a cyclic amino acid monomer, then placing the mixture in an organic solvent 1, stirring the mixture for 70 to 72 hours at the temperature of 30 to 35 ℃ under nitrogen, then pouring the mixture into a separation solvent, and stirring, settling, filtering and drying the mixture in vacuum to obtain a main polyamino acid skeleton (mPEG-b-PBLG);
(2) mixing a photosensitizer containing carboxyl groups and a compound for activating the carboxyl groups in the photosensitizer, placing the mixture in an anhydrous solvent, and stirring the mixture for 2 to 3 hours at the temperature of 30 to 35 ℃ in a dark place under nitrogen to obtain a reaction system A; then, dissolving the main skeleton (mPEG-B-PBLG) of the polyamino acid obtained in the step (1) in an anhydrous solvent to obtain a reaction system B; then adding the reaction system B into the reaction system A, and stirring for 24-28 hours at 30-35 ℃ in a dark place under nitrogen; finally dialyzing under the condition of keeping out of the sun, and freeze-drying to obtain a photosensitizer modified polyamino acid main skeleton (mPEG-b-PBLG-Ce 6);
(3) mixing the photosensitizer modified polyamino acid main skeleton obtained in the step (2), a chain protective agent and a micromolecule compound containing double-end amino groups, placing the mixture in an anhydrous solvent, stirring the mixture for 70-72 hours at the temperature of 50-55 ℃ in a dark place, then dialyzing the mixture in hydrochloric acid and deionized water in sequence, and freeze-drying the mixture to obtain a polyamino acid main skeleton (mPEG-b-P (ED) LG-Ce6) with a side chain containing free amino groups;
(4) mixing an ROS sensitive monomer capable of inducing iron death and a carboxyl group compound in an activated sensitive monomer, placing the mixture in an anhydrous solvent, and stirring the mixture for 2 to 3 hours in a dark place at 30 to 35 ℃ under nitrogen to obtain a reaction system C; dissolving the polyamino acid main skeleton with the side chain provided with the free amino group obtained in the step (3) in an anhydrous solvent, adding the solution into a reaction system C, stirring the solution for 24 to 28 hours at the temperature of 30 to 35 ℃ in the dark, dialyzing, and freeze-drying the solution to obtain a photosensitizer-modified ROS-sensitive amphiphilic block polymer (mPEG-b-P (ED-AA) LG-Ce 6);
(5) preparing the photosensitizer modified ROS sensitive amphiphilic block polymer (mPEG-b-P (ED-AA) LG-Ce6) obtained in the step (4) into nanoparticles by a film dispersion method, and specifically comprising the following steps: the film dispersion method comprises the steps of dissolving the ROS sensitive amphiphilic block polymer modified by the photosensitizer into an organic solvent 2, then placing the solution into a round-bottom flask, carrying out rotary evaporation in a vacuum state until a layer of dry film is formed on the inner wall of the flask, then adding deionized water into the flask, carrying out ultrasonic treatment for 5-10 minutes until the film is completely dispersed, dialyzing, and carrying out freeze drying to obtain the ROS sensitive nano reagent (PPA @ Ce 6).
Preferably, the hydrophilic segment methoxy polyethylene glycol amine (mPEG-NH) in the step (1)2) The macromolecular initiator has an average molecular mass of 1000-5000.
Preferably, the cyclic amino acid monomer in step (1) is poly benzyl glutamate carboxylic anhydride (BLG-NCA) or benzyl aspartate internal cyclic anhydride monomer (BLA-NCA).
Preferably, the molar ratio of the macroinitiator to the cyclic amino acid monomers in the step (1) is 1: 20 to 40.
Preferably, the organic solvent 1 in step (1) is one of anhydrous chloroform, anhydrous dichloromethane or anhydrous dimethylformamide.
Preferably, the solvent used for separating the polymer in the step (1) is diethyl ether.
Preferably, the photosensitizer having a carboxyl group in step (2) is one of chlorin e6(Ce6), m-tetrakis (4-carboxyphenyl) porphyrin or pheophorbide a.
Preferably, the compound for activating the carboxyl group in the photosensitizer in the step (2) is one of a condensation agent of Dicyclohexylcarbodiimide (DCC) in combination with N-hydroxysuccinimide (NHS) or N' N-Carbonyldiimidazole (CDI).
Preferably, the molar ratio of the photosensitizer in the step (2) to the compound activating the carboxyl group in the photosensitizer is 1: 1 to 1.1.
Preferably, the dialysis conditions in step (2) are: the interception component of the dialysis bag is 1000-3500 Da, the dialysis time is 48-72 hours, and the dialysate is deionized water.
Preferably, the small molecule compound containing a double-terminal amino group in step (3) is one of ethylenediamine, diethylenetriamine, triethylenetetramine, and tetraethylenepentamine.
Preferably, the chain protecting agent in step (3) is 2-hydroxypyridine, which is used for preventing the main chain of the polyamino acid from being broken.
Preferably, the mole ratio of the photosensitizer modified polyamino acid main skeleton (mPEG-b-PBLG-Ce6) in the step (3) to the small molecule compound containing double-end amino groups is 1: 20-30, wherein the molar ratio of the main skeleton of the photosensitizer-modified polyamino acid (mPEG-b-PBLG-Ce6) to the chain protective agent is 1: 5 to 10.
Preferably, the dialysis conditions in step (3) are: the cut-off amount of the dialysis bag is 1000-3500 Da, and the dialysis bag is dialyzed in 0.05-0.1 mol/L hydrochloric acid for 48-72 hours and then in deionized water for 24-48 hours;
preferably, the ROS-sensitive monomer capable of inducing iron death in step (4) is one of Arachidonic Acid (AA), docosatetraenoic acid, or docosahexaenoic acid (DHA).
Preferably, the molar ratio of the ROS-sensitive monomer capable of inducing iron death in the step (4) to the main skeleton of the polyamino acid with free amino groups on the side chains is 0.8-1: 1.
preferably, the carboxyl group compound in the activated and sensitive monomer in the step (4) is one of a condensation agent of Dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) or N' N-Carbonyldiimidazole (CDI).
Preferably, the molar ratio of the carboxyl group compound in the ROS-sensitive monomer capable of inducing iron death and the activation-sensitive monomer in step (4) is 1: 1 to 1.1.
Preferably, the anhydrous solvent in step (2), step (3) and step (4) is anhydrous dimethyl sulfoxide (DMSO).
Preferably, the dialysis conditions in step (4) are: the interception component of the dialysis bag is 1000-3500 Da, the dialysis time is 48-72 hours, and the dialysate adopts deionized water.
Preferably, the organic solvent 2 in the step (5) is anhydrous chloroform.
Preferably, the dialysis conditions in step (5) are: the interception component of the dialysis bag is 30000-50000 Da, the dialysis time is 12-24 hours, and the dialysate adopts deionized water.
Preferably, the rotary evaporation temperature in the step (5) is 35-40 ℃.
Preferably, the temperature range of the freeze-drying in the step (2), the step (3), the step (4) and the step (5) is-40 ℃ to-60 ℃.
Preferably, the particle size of the ROS sensitive nano reagent prepared in the step (5) is 40-60 nm, so that the ROS sensitive nano reagent is favorably and effectively gathered at a tumor position through passive targeting.
Compared with the prior art, the invention has the following advantages:
(1) the invention provides a simple and effective preparation method of a multifunctional nano therapeutic agent, which selects methoxy polyethylene glycol amine as a macroinitiator, prepares a main skeleton of polyamino acid through one-step ring-opening polymerization, and then obtains a target polymer by modifying a photosensitizer at the tail end and grafting an arachidonic acid monomer on a side chain. Finally, a simple thin film dispersion method was used to prepare ROS sensitive nanoreagents. The preparation strategy has the advantages of adjustability, simple mode, flexibility, strong repeatability and the like.
(2) The prepared ROS sensitive nano reagent has good biocompatibility and biodegradability.
(3) The prepared ROS sensitive nano reagent has smaller size, and is beneficial to the effective aggregation of nano particles at a tumor part.
(4) The prepared ROS sensitive nano reagent can stimulate hydrophobic arachidonic acid to be released and converted into hydrophilic lipid peroxide to activate photodynamic therapy in tumor cells through endogenous active oxygen, and can enhance the iron death effect through the combined action of generated singlet oxygen and the lipid peroxide, thereby effectively improving the cancer treatment efficiency.
Drawings
FIG. 1 shows the prepared mPEG-b-P (ED-AA) LG-Ce6 hydrogen nuclear magnetic spectrum.
FIG. 2 is a UV absorption spectrum of prepared mPEG-b-P (ED-AA) LG-Ce 6.
FIG. 3 is a transmission electron microscope image of the ROS sensitive nanoreagent (PPA @ Ce6) obtained by the preparation method
FIG. 4 is a diagram showing the singlet oxygen generation detection of the prepared ROS sensitive nano reagent under the action of hydroxyl radicals.
FIG. 5 is a graph showing the consumption of glutathione in tumor cells of the prepared ROS-sensitive nanoreagent without 660nm laser radiation.
FIG. 6 is a graph showing the consumption of glutathione in tumor cells by the prepared ROS-sensitive nano reagent under 660nm laser radiation.
FIG. 7 is a graph showing the activity of the prepared ROS-sensitive nanoreagent on GPX4 in tumor cells in the presence and absence of 660nm laser radiation.
FIG. 8 is a cytotoxicity test chart of the prepared ROS sensitive nano reagent under the condition of no 660nm laser radiation.
FIG. 9 is a cytotoxicity test chart of the prepared ROS sensitive nano reagent under 660nm laser radiation.
FIG. 10 is a graph of in vivo and in vitro fluorescence imaging of the prepared ROS-sensitive nanoreagents.
FIG. 11 is a graph showing the tumor growth inhibition effect of the prepared ROS-sensitive nanoagents under different conditions.
FIG. 12 is a graph of separated tumor mass for the inhibition of tumor growth under different conditions for the prepared ROS-sensitive nanoreagents.
FIG. 13 is a graph showing the H & E and TUNEL staining of tumor tissues under different conditions for tumor growth inhibition by the prepared ROS-sensitive nanoagents.
FIG. 14 is a toxicological profile of the prepared ROS-sensitive nanoreagent staining in vivo tissues (Heart: Heart; Liver: Liver; Spleen: Spleen; Lung: Lung; Kidney: Kidney; tumor: tumor) H & E and TUNEL.
Detailed Description
The following detailed description of the invention is given in conjunction with the accompanying drawings and specific examples, which are included to aid the understanding of the invention and are not to be construed as limiting the scope of the invention.
On closer inspection, the steps of the examples must correspond to the steps described in the summary; the raw material in the examples must be one of the raw materials described in the summary of the invention; the process parameters such as raw material dosage, time and temperature in the examples must be within the data range described in the summary of the invention!
Preparation of mPEG-b-P (ED-AA) LG-Ce6
(1) The synthesis process of mPEG-b-P (ED-AA) LG-Ce6 is shown as formula (I). First, 1g of methoxypolyethyleneglycoamine (mPEG-NH)2Average molecular weight of 5000) and 1.0532g of BLG-NCA were mixed and dissolved in 30mL of anhydrous dimethylformamide, and the reaction solution was stirred at 30 ℃ for 72 hours under nitrogen protection. After the reaction is finished, the solution is poured into 300mL of ether solution, and the main skeleton of the polyamino acid (mPEG-b-PBLG) is obtained by stirring, sedimentation, filtration and vacuum drying.
(2) 264mg of Dicyclohexylcarbodiimide (DCC) and 147mg of N-hydroxysuccinimide (NHS) were mixed with 636mg of Ce6, and the mixture was dissolved in 10mL of anhydrous Dimethylsulfoxide (DMSO), and the reaction solution was stirred under nitrogen at 30 ℃ for 2 hours in the absence of light to obtain reaction system A. 1g of polyamino acid backbone (mPEG-b-PBLG) was dissolved in 10mL of anhydrous DMSO and added dropwise to the reaction system A, and the mixture was stirred at 30 ℃ for 24 hours in the dark. Finally, dialyzing in deionized water (adopting a dialysis membrane with a molecular weight cut-off of 3500) for 72h under the condition of keeping out of the light, and freeze-drying at-50 ℃ to obtain the photosensitizer modified polyamino acid main skeleton (mPEG-b-PBLG-Ce 6).
(3) 0.5g of mPEG-b-PBLG-Ce6 and 0.4774g of 2-hydroxypyridine were dissolved together in 10mL of anhydrous DMSO, followed by addition of 2.013mL of ethylenediamine, and the mixture was stirred under nitrogen at 50 ℃ for 72 hours in the absence of light. After the reaction is finished, dialyzing (dialysis membrane with molecular weight cutoff of 3500) in 0.05mol/L hydrochloric acid solution for 72 hours, then dialyzing in deionized water for 48 hours, and freeze-drying at-50 ℃ to obtain mPEG-b-P (ED) LG-Ce 6.
(4) 58mg of N' -N-Carbonyldiimidazole (CDI) and 108mg of Arachidonic Acid (AA) were dissolved together in 6mL of anhydrous DMSO, and the mixture was stirred under nitrogen at 30 ℃ for 2 hours in the dark to obtain reaction system C. 200mg of mPEG-b-P (ED) LG-Ce6 was dissolved in 5mL of anhydrous DMSO, and the solution was poured into reaction system C and stirred under nitrogen at 30 ℃ for 24 hours under dark conditions. Dialyzing (with dialysis membrane with molecular weight cutoff of 1000) in deionized water for 72h, and freeze-drying at-50 deg.C to obtain final product mPEG-b-P (ED-AA) LG-Ce 6.
Chemical structure identification was performed using nuclear magnetic hydrogen spectroscopy (see FIG. 1), and the results demonstrated that the characteristic peaks at 3.41ppm and 3.58ppm belonged to mPEG, the characteristic peaks at 2.01ppm, 2.41ppm and 2.92ppm belonged to PBLG backbone, and the characteristic peaks at 7.32ppm and 5.45ppm belonged to AA, which demonstrated successful synthesis of mPEG-b-P (ED-AA) LG-Ce 6. The photosensitizer Ce6 load was identified by UV absorption spectroscopy (see FIG. 2), and as shown, the absorption peaks of mPEG-b-P (ED-AA) LG-Ce6 at 400nm, 500nm and 660nm were completely consistent with that of free Ce6, which indicates that Ce6 was successfully grafted onto mPEG-b-P (ED-AA) LG-Ce 6.
(II) preparation of ROS sensitive Nanometric reagent (PPA @ Ce6)
20mg of mPEG-b-P (ED-AA) LG-Ce6 was placed in a round bottom flask, followed by 10mL of anhydrous chloroform and stirred until all dissolved. The resulting mixed solution was subjected to vacuum at 40 ℃ to remove chloroform by rotary evaporation until a dry film was formed on the inner wall of the bottle. Then, deionized water (20mL) was added to the flask and sonicated for 5 minutes to fully disperse. After 24 hours of dialysis in deionized water (dialysis membrane with molecular weight cutoff 30000), ROS sensitive nanoagents were obtained by freeze drying at-50 ℃.
The shape and the particle size of the nano reagent are measured by a high-definition transmission electron microscope, and the result indicates that the prepared nano reagent is uniform and granular, shows that the particle size is about 50nm, and proves that the ROS sensitive nano reagent is successfully prepared (see figure 3).
(III) evaluating the performance of the ROS sensitive nano reagent in generating singlet oxygen under the action of hydroxyl free radical (. OH)
Dispersing the prepared ROS sensitive nano reagent in a medium containing and not containing ferrous chloride (FeCl)2) And hydrogen peroxide (H)2O2) In a solution of deionized water (in the presence of FeCl)2And H2O2In solution of FeCl2And H2O2All at 100. mu.M, and all at 1mg/mL) by FeCl2And H2O2Hydroxyl free radicals generated by Fenton reaction are used for simulating ROS in an intracellular environment, and after a singlet oxygen green fluorescent probe (SOSG, 1 mu M) is added, a 660nm laser is selected for irradiation (power: 50mW/cm2) The fluorescence intensity was then measured at 525nm using a fluorescence spectrophotometer. The results show that the prepared ROS sensitive nano reagent can enhance the generation of singlet oxygen in the solution containing hydroxyl radicals, and the prepared nano reagent can activate the photosensitizer to generate more singlet oxygen in the presence of active oxygen (see FIG. 4).
(IV) evaluation of ability of ROS-sensitive Nanometric reagents to eliminate GSH in tumor cells
HepG2 tumor cells at 1X 104One cell/well was seeded in a 96-well plate, and after the cells were completely stretched and incubated with ROS-sensitive nanoreagents for 4 hours, the cells were washed with PBS and then irradiated with 660nm of Laser for 15 minutes (power: 100 mW/cm)2) Finally, the cells were incubated for 1 hour, 2 hours and 4 hours, respectively, and the cells were treated with no nanoagents as a reference group and without laser irradiation as a control group, followed by harvesting the cells, and suspended in a PBS solution and sonicated. The GSH content was then determined at various time points according to the instructions for use of the GSH detection reagent. The results show that under the condition of no light irradiation, the concentration of GSH is slightly reduced, which indicates that AA can be oxidized into lipid peroxide by hydroxyl radical to become a new active oxygen to consume GSH; compared with the GSH content obviously reduced under the laser irradiation condition, the generated singlet oxygen can better eliminate the GSH. And the GSH content is obviously lower than that of the control group after 4 hours, which indicates that the ROS sensitive nano reagent has stronger capability of eliminating GSH in tumor cells (see figures 5 and 6).
(V) evaluating the inhibition ability of the ROS sensitive nano reagent on GPX4 activity in tumor cells
HepG2 tumor cells at 1X 104One cell/well was seeded in a 96-well plate, and after the cells were completely stretched and incubated with ROS-sensitive nanoreagents for 4 hours, the cells were washed with PBS and then irradiated with 660nm of Laser for 10 minutes (power: 100 mW/cm)2) The control group was incubated for 12 hours without laser irradiation, and then the cells were harvested, suspended in PBS solution, and sonicated. The activity of GPX4 was then determined according to the instructions of the glutathione peroxide assay kit. The results show that the ROS sensitive nano reagent can inhibit the activity of GPX4 more obviously under the irradiation of light (see figure 7).
(VI) evaluating the inhibition ability of the ROS sensitive nano reagent on GPX4 activity in tumor cells
HepG2 tumor cells at 1X 104One/well was seeded in a 96-well plate, and after 24 hours of incubation, cells were treated with ROS sensitive nanoagents and free Ce6(FreeCe6) (Ce6 concentration set at 0.5, 1, 2, 4 and 8 μ g/mL), respectively, and after 4 hours of incubation, cell culture was changed,ultrasonic treatment, irradiation with 660nm Laser for 20 minutes (power: 100 mW/cm)2) No laser irradiation was used as a control group. After a further 24 hours of incubation. Cytotoxicity was measured with CCK-8, and the results showed that there was no significant cytotoxicity of ROS-sensitive nanoreagents without laser irradiation, whereas ROS-sensitive nanoreagents after irradiation showed significant cytotoxicity, and cytotoxicity increased with increasing concentration of Ce6 (see fig. 8 and 9).
(VII) evaluation of tumor aggregation Capacity of ROS-sensitive Nanometric reagents
5 BABL/c female nude mice with the weight of about 25g are taken and inoculated with HepG2 tumor cells subcutaneously, and when the tumor grows to 100mm3On the left and right, ROS sensitive nano reagent (Ce 6: 2mg/kg) was injected via tail vein, then fluorescence imaging conditions in mice at different time points were detected by using fluorescence system in mice, after 24 hours of imaging, mice were sacrificed, tumors and other major organs (Heart: Heart, Liver: Liver, Spleen: Spleen, Lung: Lung, Kidney: Kidney) were exfoliated and analyzed by fluorescence imaging. The results showed that ROS sensitive nanoagents could efficiently aggregate to tumor cells by passive targeting (see FIG. 10)
(VIII) evaluation of tumor suppression Effect and biosafety evaluation of ROS-sensitive Nanometric reagents
25 BABL/c female nude mice with the weight of about 25g are taken and inoculated with HepG2 tumor cells subcutaneously, and when the tumor grows to 100mm3On the left and right, groups were randomly divided into 5 (salene as control, free Ce6+ laser, free AA, ROS sensitive nanoreagent (PPA @ Ce6) and PPA @ Ce6+ laser, respectively). FreeCE6, FreeAA, and PPA @ Ce6 were each injected via the tail vein (Ce 6: 5mg/kg), and 24 hours after injection, the FreeCE6 and PPA @ Ce6 groups were irradiated with a laser for 30 minutes (power: 0.25W/cm)2) Tumor volumes of mice were measured with a vernier caliper every 3 days, after 21 days of treatment, mice were sacrificed, in vivo fluorescence imaging conditions of mice at different time points were detected by an in vivo fluorescence system, after 24 hours of imaging, mice were sacrificed, tumors and other major organs were isolated (heart: heart, liver: liver, spleen: spleen, lung: lung, kidney: kidney) and isolated tumors were weighed, while tumor tissue was subjected to H&E and TUNEL staining. KnotROS-sensitive nanoagents were shown to be highly effective in inhibiting tumor growth (see fig. 11, 12 and 13). In addition, H was performed on other major organs&E and TUNEL staining to evaluate the biological safety, and the result is shown in figure 14, and the ROS sensitive nano reagent does not cause obvious toxic or side effect on other main organ tissues and shows good biological safety.
Claims (10)
1. A method for preparing ROS sensitive nano reagent with synergistic induction of photodynamic therapy and iron death comprises the following steps:
(1) mixing a methoxy polyethylene glycol amine macroinitiator serving as a hydrophilic chain segment and a cyclic amino acid monomer, then placing the mixture in an organic solvent 1, stirring the mixture for 70 to 72 hours at the temperature of 30 to 35 ℃ under nitrogen, then pouring the mixture into a separation solvent, and stirring, settling, filtering and drying the mixture in vacuum to obtain a polyamino acid main skeleton;
(2) mixing a photosensitizer containing carboxyl groups and a compound for activating the carboxyl groups in the photosensitizer, placing the mixture in an anhydrous solvent, and stirring the mixture for 2 to 3 hours at the temperature of 30 to 35 ℃ in a dark place under nitrogen to obtain a reaction system A; then, dissolving the main skeleton of the polyamino acid obtained in the step (1) in an anhydrous solvent to obtain a reaction system B; then adding the reaction system B into the reaction system A, and stirring for 24-28 hours at 30-35 ℃ in a dark place under nitrogen; finally dialyzing under the condition of keeping out of the sun, and freeze-drying to obtain the photosensitizer modified polyamino acid main skeleton;
(3) mixing the main skeleton of the polyamino acid modified by the photosensitizer obtained in the step (2), a chain protective agent and a micromolecule compound containing double-end amino groups, placing the mixture in an anhydrous solvent, stirring the mixture for 70-72 hours at the temperature of 50-55 ℃ in a dark place, dialyzing the mixture in a hydrochloric acid solution and deionized water in sequence, and freeze-drying the mixture to obtain the main skeleton of the polyamino acid with free amino groups on side chains;
(4) mixing an ROS sensitive monomer capable of inducing iron death and a carboxyl group compound in an activated sensitive monomer, placing the mixture in an anhydrous solvent, and stirring the mixture for 2 to 3 hours in a dark place at 30 to 35 ℃ under nitrogen to obtain a reaction system C; dissolving the polyamino acid main skeleton with the side chain provided with the free amino group obtained in the step (3) in an anhydrous solvent, adding the solution into a reaction system C, stirring the solution for 24 to 28 hours at the temperature of 30 to 35 ℃ in the dark, dialyzing, and freeze-drying the solution to obtain a photosensitizer-modified ROS-sensitive amphiphilic block polymer;
(5) preparing the nano particles from the photosensitizer modified ROS sensitive amphiphilic block polymer obtained in the step (4) by a film dispersion method, which specifically comprises the following steps: the film dispersion method comprises the steps of dissolving the ROS sensitive amphiphilic block polymer modified by the photosensitizer in an organic solvent 2, then placing the solution in a round-bottom flask, rotationally evaporating the solution in a vacuum state until a layer of dry film is formed on the inner wall of the flask, then adding deionized water into the flask, carrying out ultrasonic treatment for 5-10 minutes until the film is completely dispersed, dialyzing, and carrying out freeze drying to obtain the ROS sensitive nano reagent.
2. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the hydrophilic chain segment methoxy polyethylene glycol amine macroinitiator in the step (1) has the average molecular mass of 1000-5000; the cyclic amino acid monomer is polyglutamic acid benzyl ester carboxylic anhydride or aspartic acid benzyl ester internal cyclic anhydride monomer, and the molar ratio of the macroinitiator to the cyclic amino acid monomer is 1: 20-40 parts of; the organic solvent 1 is one of anhydrous trichloromethane, anhydrous dichloromethane or anhydrous dimethylformamide; the solvent used to isolate the polymer was diethyl ether.
3. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the photosensitizer containing carboxyl groups in the step (2) is one of chlorin e6, m-tetra (4-carboxyphenyl) porphyrin or pheophorbide A, and the compound for activating the carboxyl groups in the photosensitizer is one of a condensing agent formed by combining dicyclohexylcarbodiimide and N-hydroxysuccinimide or N' N-carbonyldiimidazole; the molar ratio of the photosensitizer to the compound activating the carboxyl groups in the photosensitizer is 1: 1 to 1.1; the interception component of the dialysis bag is 1000-3500 Da, the dialysis time is 48-72 hours, and the dialysate is deionized water.
4. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the small molecular compound containing double-end amino groups in the step (3) is one of ethylenediamine, diethylenetriamine, triethylenetetramine or tetraethylenepentamine; the chain protective agent is 2-hydroxypyridine; the mole ratio of the main skeleton of the photosensitizer modified polyamino acid to the micromolecule compound containing double-end amino groups is 1: 20-30, wherein the molar ratio of the main skeleton of the photosensitizer-modified polyamino acid to the chain protective agent is 1: 5-10; the cut-off amount of the dialysis bag is 1000-3500 Da, and the dialysis bag is firstly dialyzed in 0.05-0.1 mol/L hydrochloric acid for 48-72 hours and then dialyzed in deionized water for 24-48 hours.
5. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the ROS sensitive monomer capable of inducing iron death in the step (4) is one of arachidonic acid, docosatetraenoic acid or docosahexaenoic acid; the molar ratio of the ROS sensitive monomer capable of inducing iron death to the polyamino acid main skeleton with free amino groups on side chains is 0.8-1: 1; the carboxyl group compound in the activated sensitive monomer is one of a condensation agent formed by combining dicyclohexylcarbodiimide and N-hydroxysuccinimide or N' N-carbonyldiimidazole, and the molar ratio of the carboxyl group compound in the ROS sensitive monomer capable of inducing iron death to the carboxyl group compound in the activated sensitive monomer is 1: 1 to 1.1; the interception component of the dialysis bag is 1000-3500 Da, the dialysis time is 48-72 hours, and the dialysate adopts deionized water.
6. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the anhydrous solvent in the step (2), the step (3) and the step (4) is anhydrous dimethyl sulfoxide.
7. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the organic solvent 2 in the step (5) is anhydrous chloroform; the interception component of the dialysis bag is 30000-50000 Da, the dialysis time is 12-24 hours, and the dialysate adopts deionized water; the rotary evaporation temperature is 35-40 ℃.
8. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the temperature range of the freeze drying in the step (2), the step (3), the step (4) and the step (5) is-40 ℃ to-60 ℃.
9. The method of claim 1, wherein the ROS sensitive nanoagents synergistically induce photodynamic therapy and iron death are prepared by: the particle size of the ROS sensitive nano reagent prepared in the step (5) is 40-60 nm.
10. An ROS sensitive nanoreagent with synergistic induction of photodynamic therapy and iron death, comprising: is prepared by the method of any one of claims 1 to 9.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113069431A (en) * | 2021-04-02 | 2021-07-06 | 天津大学 | Nanometer diagnosis and treatment agent with variable particle size and preparation method thereof |
| CN114075127A (en) * | 2021-09-13 | 2022-02-22 | 广州汇元医药科技有限公司 | Di-carboxyl crosslinking monomer containing thioketal bond and preparation method and application thereof |
| CN114404364A (en) * | 2022-01-18 | 2022-04-29 | 广西大学 | Construction of photosensitive nano-micelle capable of inducing polarization of tumor-associated macrophage M1 type and anti-tumor application thereof |
| CN114904014A (en) * | 2022-04-21 | 2022-08-16 | 山东大学 | Self-oxygen-generating bionic photodynamic/iron death/immunosuppression microenvironment regulation nano platform and preparation and application thereof |
| CN115177737A (en) * | 2022-07-19 | 2022-10-14 | 沈阳药科大学 | Carrier-free lipid peroxidation nano amplifier for synergistically inducing iron death and preparation method and application thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011090333A2 (en) * | 2010-01-20 | 2011-07-28 | 주식회사 진코스 | Chlorine derivative/unsaturated fatty acid conjugates, photosensitizers comprising same, and cancer treatment compositions to be used in photodynamic therapy comprising same |
| KR20150097032A (en) * | 2014-02-17 | 2015-08-26 | 대구가톨릭대학교산학협력단 | The high density photosensitizer using spherical macromolecules for photodyn amic therapy and method of manufacturing thereof |
| CN108473869A (en) * | 2016-01-14 | 2018-08-31 | Omya国际股份公司 | Remove O2CaCO3Processing |
| CN109498548A (en) * | 2018-12-11 | 2019-03-22 | 吉林化工学院 | A kind of protein and photosensitizer transmit pH responsiveness polyaminoacid nanogel and preparation method thereof altogether |
| CN110314136A (en) * | 2019-04-29 | 2019-10-11 | 华南师范大学 | A kind of preparation and its application of the tumor-targeting drug based on unsaturated fatty acid nanoparticle |
| CN110898007A (en) * | 2019-11-13 | 2020-03-24 | 中国药科大学 | Preparation of targeting antitumor uronic acid carboxyl free polysaccharide derivative micelle |
-
2020
- 2020-11-24 CN CN202011327233.4A patent/CN112451680B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011090333A2 (en) * | 2010-01-20 | 2011-07-28 | 주식회사 진코스 | Chlorine derivative/unsaturated fatty acid conjugates, photosensitizers comprising same, and cancer treatment compositions to be used in photodynamic therapy comprising same |
| KR20150097032A (en) * | 2014-02-17 | 2015-08-26 | 대구가톨릭대학교산학협력단 | The high density photosensitizer using spherical macromolecules for photodyn amic therapy and method of manufacturing thereof |
| CN108473869A (en) * | 2016-01-14 | 2018-08-31 | Omya国际股份公司 | Remove O2CaCO3Processing |
| CN109498548A (en) * | 2018-12-11 | 2019-03-22 | 吉林化工学院 | A kind of protein and photosensitizer transmit pH responsiveness polyaminoacid nanogel and preparation method thereof altogether |
| CN110314136A (en) * | 2019-04-29 | 2019-10-11 | 华南师范大学 | A kind of preparation and its application of the tumor-targeting drug based on unsaturated fatty acid nanoparticle |
| CN110898007A (en) * | 2019-11-13 | 2020-03-24 | 中国药科大学 | Preparation of targeting antitumor uronic acid carboxyl free polysaccharide derivative micelle |
Non-Patent Citations (5)
| Title |
|---|
| FU, Y (FU, YAN)等: "Dual activatable self-assembled nanotheranostics for bioimaging and photodynamic therapy", 《JOURNAL OF CONTROLLED RELEASE》 * |
| RUIHUA LI等: "Transcriptome Investigation and In Vitro Verification of Curcumin-Induced HO-1 as a Feature of Ferroptosis in Breast Cancer Cells", 《OXIDATIVE MEDICINE AND CELLULAR LONGEVITY》 * |
| YANG, HY: "Hierarchical tumor acidity-responsive self-assembled magnetic nanotheranostics for bimodal bioimaging and photodynamic therapy", 《JOURNAL OF CONTROLLED RELEASE》 * |
| YANG, HY等: "Polymer ligand-assisted fabrication of multifunctional and redox-responsive self-assembled magnetic nanoclusters for bimodal imaging and cancer treatment", 《JOURNAL OF MATERIALS CHEMISTRY B》 * |
| 辛科霆: "花生四烯酸多肽胶束用于癌症光动力学治疗的研究", 《中国优秀硕士学位论文全文数据库（电子期刊）》 * |
Cited By (10)
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|---|---|---|---|---|
| CN113069431A (en) * | 2021-04-02 | 2021-07-06 | 天津大学 | Nanometer diagnosis and treatment agent with variable particle size and preparation method thereof |
| CN113069431B (en) * | 2021-04-02 | 2022-07-01 | 天津大学 | Nanometer diagnosis and treatment agent with variable particle size and preparation method thereof |
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| CN114404364A (en) * | 2022-01-18 | 2022-04-29 | 广西大学 | Construction of photosensitive nano-micelle capable of inducing polarization of tumor-associated macrophage M1 type and anti-tumor application thereof |
| CN114904014A (en) * | 2022-04-21 | 2022-08-16 | 山东大学 | Self-oxygen-generating bionic photodynamic/iron death/immunosuppression microenvironment regulation nano platform and preparation and application thereof |
| CN114904014B (en) * | 2022-04-21 | 2023-06-02 | 山东大学 | Self-oxygen-generating bionic photodynamic/iron death/immunosuppression microenvironment regulation nano platform and preparation and application thereof |
| CN115177737A (en) * | 2022-07-19 | 2022-10-14 | 沈阳药科大学 | Carrier-free lipid peroxidation nano amplifier for synergistically inducing iron death and preparation method and application thereof |
| CN115177737B (en) * | 2022-07-19 | 2024-03-29 | 沈阳药科大学 | Carrier-free lipid peroxidation nano amplifier for synergistically inducing iron death and preparation method and application thereof |
| CN116585622A (en) * | 2023-07-12 | 2023-08-15 | 四川省肿瘤医院 | Photodynamic tablet and preparation method thereof, and anti-tumor model construction method and system |
| CN116585622B (en) * | 2023-07-12 | 2023-10-10 | 四川省肿瘤医院 | Photodynamic tablet and preparation method thereof, and anti-tumor model construction method and system |
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