CN115501205A - Radiotherapy sensitization nano particle and preparation method thereof - Google Patents
Radiotherapy sensitization nano particle and preparation method thereof Download PDFInfo
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- CN115501205A CN115501205A CN202211311214.1A CN202211311214A CN115501205A CN 115501205 A CN115501205 A CN 115501205A CN 202211311214 A CN202211311214 A CN 202211311214A CN 115501205 A CN115501205 A CN 115501205A
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Abstract
The invention provides a radiotherapy sensitization nano particle and a preparation method thereof, relating to the technical field of biomedical materials, wherein the preparation method comprises the following steps: performing polymerization reaction, namely performing reversible addition-fragmentation chain transfer polymerization reaction on a dipropylaminoethyl methacrylate monomer and a cinnamaldehyde monomer to form a dipropylaminoethyl methacrylate-poly-cinnamaldehyde diblock polymer; wherein, the cinnamaldehyde monomer has pH sensitivity and can be controllably released under the acidic condition of tumor tissues; oxidizing the dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer to form polyoxydipropylaminoethyl methacrylate-poly-cinnamaldehyde; and assembling the particles, namely self-assembling the poly (p-xylylene oxide) acrylic acid dipropyl aminoethyl-poly (cinnamic aldehyde) in an aqueous solution to form the nano particles. The nano-particle of the invention can induce cancer cell iron death and immunogenicity death, and enhance tumor radiosensitivity and tumor immunotherapy effect.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a radiotherapy sensitization nano particle and a preparation method thereof.
Background
In radiotherapy, it is an important research topic to improve the radiation sensitivity of a tumor by reducing the radiation resistance of the tumor by various auxiliary means. Until now, no ideal radiation sensitizer with low toxicity and high efficiency can be found for clinical practice. Overcoming the radiation resistance of the tumor, developing a tumor radiotherapy sensitizer and a new tumor treatment targeted drug have great significance, and have extremely important clinical and social benefits for improving the radiotherapy curative effect of tumor patients and prolonging the survival time of the tumor patients.
The Tumor Microenvironment (TME) supports tumor growth and forms various barriers to impair the therapeutic effect of the nanomedicine. It has been found that Glutathione (GSH) is one of the key factors in tumorigenesis, development and metastasis in these barriers; in addition, it is associated with resistance to treatments including iron death, platinum-based chemotherapy, photothermal therapy (PDT), or radiation therapy. Iron death is a new cell death mode different from apoptosis, necrosis and the like, discovered by D i xon et al in 2012, and mainly occurs through peroxidation of phospholipids (PUFAPLs) containing a plurality of unsaturated fatty acids in cell membranes under the condition of being rich in iron and Reactive Oxygen Species (ROS), lipid peroxides are generated, and excessive accumulation of the lipid peroxides in the cell membranes finally destroys the integrity of the cell membranes, so that the cells die.
Iron death occurs mainly through physiological processes such as Glutathione (GSH) anabolism, fatty acid metabolism, iron metabolism, etc., and Glutathione (GSH) abundant in tumors greatly weakens the effect, wherein a defense system centering on glutathione peroxidase 4 (GPX 4) has strong iron death resistance. To achieve effective tumor suppression, the delivered anticancer drugs need to remain in the blood for a sufficiently long time and be able to permeate into tumor tissues, however, the existing drugs cannot overcome a series of complex physiological and pathological obstacles, resulting in poor tumor suppression.
Disclosure of Invention
The invention aims to provide a radiosensitization nanoparticle and a preparation method thereof, and aims to solve the problems that the conventional anticancer drug cannot overcome a series of complex physiological and pathological barriers, cannot be kept in blood for a long time and can not permeate into tumor tissues, and the tumor inhibition effect is poor.
In order to solve the problems, the invention firstly provides a preparation method of radiotherapy sensitization nano particles, which comprises the following steps: performing polymerization reaction, namely performing reversible addition-fragmentation chain transfer polymerization reaction on a dipropylaminoethyl methacrylate monomer and a cinnamaldehyde monomer to form a dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer; wherein, the cinnamaldehyde monomer has pH sensitivity and can be controllably released under the acidic condition of tumor tissues; oxidizing dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer to form polyoxy dipropylaminoethyl methacrylate-poly-cinnamaldehyde; and assembling the particles, namely self-assembling the poly (p-dimethylaminoethyl methacrylate) -poly (cinnamic aldehyde) in an aqueous solution to form the nano particles.
Further, the polymerization reaction comprises a first polymerization reaction and a second polymerization reaction; the first polymerization reaction comprises: taking 2- [ dodecylthio (thiocarbonyl) thio ] -2-methylpropanoic acid as a chain transfer agent and azodiisobutyronitrile as an initiator, and carrying out reversible addition-fragmentation chain transfer polymerization reaction on a dipropylaminoethyl methacrylate monomer in a dimethylformamide solvent to obtain dipropylaminoethyl methacrylate; the second polymerization reaction comprises: mixing the poly dipropyl aminoethyl methacrylate and the cinnamaldehyde monomer, taking 2- [ dodecylthio (thiocarbonyl) thio ] -2-methylpropanoic acid as a chain transfer agent, taking azobisisobutyronitrile as an initiator, adding dimethylformamide, and performing reversible addition-fragmentation chain transfer polymerization to obtain the poly dipropyl aminoethyl methacrylate-poly-cinnamaldehyde two-block polymer.
Further, hydrogen peroxide is adopted in the oxidation reaction to oxidize the poly dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer.
Further, the cinnamaldehyde monomer is formed by acetalization of an aldehyde group of cinnamaldehyde.
Further, the particle assembly comprises an unloaded nanoparticle or an all-trans retinoic acid-loaded nanoparticle assembly, and the unloaded nanoparticle assembly step comprises: placing poly (p-butyl methacrylate) dipropyl aminoethyl methacrylate-poly (cinnamaldehyde) in an aqueous solution, and self-assembling under the hydrophilic-hydrophobic interaction to form no-load nano particles; the method for assembling the all-trans retinoic acid-loaded nanoparticles comprises the following steps of: mixing polyoxy-methyl acrylic acid dipropyl aminoethyl-polycyclocinnamic aldehyde and all-trans retinoic acid, adding tetrahydrofuran for dissolving, adding double distilled water, stirring until the tetrahydrofuran is completely volatilized, centrifuging and taking supernate to obtain the nano particles loaded with the all-trans retinoic acid.
Further, the concentration of the poly (p-dimethylaminoethyl methacrylate) -poly (cinnamic aldehyde) is 1-10mg/mL; and/or the concentration of the all-trans retinoic acid is 0.5-1mg/mL.
The invention also provides a radiotherapy sensitization nano particle which is prepared by the preparation method of the radiotherapy sensitization nano particle in the technical scheme, and the radiotherapy sensitization nano particle comprises an idle-load nano particle formed by self-assembling polymer polyoxy dipropyl aminoethyl methacrylate-poly cinnamic aldehyde or a nano particle loaded with all-trans retinoic acid, wherein the structural formula of the polyoxy dipropyl aminoethyl methacrylate-poly cinnamic aldehyde is shown in the specification
Furthermore, the particle size of the nano particles is 200-400nm.
Furthermore, the nano particles contain an alpha, beta-unsaturated ketone structure and can generate Michael addition reaction with glutathione.
Furthermore, the nano-particle loaded with the all-trans retinoic acid contains the all-trans retinoic acid, can reduce the expression of nuclear factor NF-E2 related factor 2 protein, and can reduce the transcription level of downstream cystine transporter system and glutathione peroxidase 4.
The radiotherapy sensitization nano particle and the preparation method thereof provided by the invention have the following technical advantages:
1. the preparation method adopted by the invention is simple and easy to operate, is formed by self-assembly by utilizing the interaction between hydrophilic and hydrophobic sections of the copolymer, does not relate to fussy chemical reaction and toxic organic chemical reagent, and is beneficial to production and clinical transformation;
2. the invention provides a new strategy for enhancing the generation of Reactive Oxygen Species (ROS) through endogenous and exogenous ways so as to improve the treatment effect of tumors. The in-vivo long-circulating no-load nanoparticles (PDPCA NPs for short) are prepared through reversible addition-fragmentation chain transfer polymerization (RAFT) reaction, and then the self-assembly technology is utilized to efficiently load the all-trans retinoic acid, so that the ROS synergistically amplified all-trans retinoic acid loaded nanoparticles (PDPCA @ ATRA NPs for short) are obtained, and the tumor radiosensitivity and the tumor immunotherapy effect can be enhanced;
3. the invention focuses on the important practical problem of tumor cell radiation resistance in tumor radiotherapy, mainly explores the molecular biological mechanism of PDPCA @ ATRA NPs in influencing the iron death and immunogenicity death of tumor cells, and further expands the application range of the radiotherapy in the radiation-resistant tumors;
4. the invention combines the subjects of tumor biology, nano medicine, radiation medicine, molecular imaging and the like, comprehensively applies various research means such as cell biology, molecular biology and the like, organically combines nano medicine, immunotherapy and radiation therapy, and provides experimental basis for early realizing medical transformation of nano medicine for treating tumors.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a reaction diagram of the synthesis of a dipropylaminoethyl polymethacrylate-poly-cinnamaldehyde diblock polymer (PDOPA-PCA for short) in example 1;
FIG. 2 is a NMR spectrum of a dipropylaminoethyl polymethacrylate-poly-cinnamaldehyde diblock polymer (PDOPA-PCA for short) in example 1;
FIG. 3 is a TEM image of all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs) of example 2;
FIG. 4 is a particle size distribution statistical chart obtained by light scattering of all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 2;
FIG. 5 is a statistical chart of the detection of active oxygen radical generating capacity of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) of example 3;
FIG. 6 is a statistical chart of the detection of glutathione-consuming capacity of the all-trans retinoic acid-loaded nanoparticles of example 4 (PDPCA @ ATRA NPs for short);
FIG. 7 is a graph showing the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) of example 5 on the morphology of A549 cell mitochondria;
FIG. 8 is a statistical chart of the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) and the iron death inhibitor of example 5 on the clonality of A549 cells;
FIG. 9 is a statistical graph of the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 5 on lipid peroxidation of A549 cells;
FIG. 10 is a statistical chart of the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 5 on the iron death marker gene PTGS2 in A549 cells;
FIG. 11 is a statistical chart of the detection of the immunogenic cell death-inducing ability of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) of example 6;
FIG. 12 is a graph showing the effect of all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 7 on radiotherapy sensitivity;
FIG. 13 is a graph showing the effect of all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 8 on nuclear factor NF-E2-associated factor 2 protein;
FIGS. 14 to 15 are statistical graphs showing the changes in radiosensitization and iron-death induction efficiency of the nanoparticle loaded with all-trans retinoic acid (PDPCA @ ATRA NPs for short) before and after the nuclear factor NF-E2-related factor 2 protein knockout in example 8;
FIGS. 16 to 17 are statistical graphs showing the change in the efficiency of the radiosensitizer iron death induction by the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) before and after the nuclear factor NF-E2-associated factor 2 protein anaplerosis of example 8;
FIGS. 18 to 19 are graphs showing the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) of example 8 on the nuclear expression of nuclear factor NF-E2-associated factor 2 protein;
FIGS. 20 to 22 are graphs showing the statistical effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) in example 8 on cystine transporter system/glutathione peroxidase 4 gene and protein expression;
FIGS. 23 to 24 are statistical graphs showing the variation of the efficiency of glutathione peroxidase 4 on radiosensitization and iron death induction before and after the deletion of the cystine transporter system of example 8;
FIGS. 25 to 26 are graphs showing statistics of the variation of the irradiation sensitization and the iron death induction efficiency of the nanoparticle loaded with all-trans retinoic acid (PDPCA @ ATRA NPs for short) before and after glutathione peroxidase knockout in example 8;
FIG. 27 is a statistical chart showing the effect of the all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short) of example 8 on the activity of glutathione peroxidase 4.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
As the occurrence of iron death mainly relates to physiological processes such as Glutathione (GSH) anabolism, fatty acid metabolism, iron metabolism and the like, the GSH abundant in tumors greatly weakens the effect of the iron death, and a defense system taking glutathione peroxidase 4 (GPX 4) as a center has strong iron death resistance. Therefore, depletion of intracellular GSH is an effective strategy to enhance its therapeutic effect on tumors.
Studies have shown that thiols play a central role in the antioxidant activity of GSH. Accordingly, blocking of thiols by maleimide can effectively enhance photothermal immunotherapy of breast cancer. Depletion of glutathione by maleimide is based on the michael addition reaction between thiol and α, β -unsaturated ketones. Similarly, cinnamaldehyde is a main component of cinnamon tree, and also contains an α, β -unsaturated ketone structure capable of depleting intracellular glutathione. Meanwhile, cinnamaldehyde is an amplifier of oxidative stress and can generate a large amount of reactive oxygen species (hereinafter, referred to as ROS). However, to achieve an effective tumor suppression effect, delivered anticancer drugs must overcome a complex series of physiological and pathological barriers, remain in the blood for a sufficiently long time and can penetrate into tumor tissues.
The inventor finds that the novel nano-drug delivery system can improve the effectiveness and bioavailability of the antitumor drug, and can improve the tumor treatment efficiency and overcome the resistance of the tumor to radiotherapy by combining with other treatment modes or medicaments to destroy the redox balance in tumor tissues. Here, the inventors propose a new strategy to enhance ROS production through both endogenous and exogenous pathways, thereby improving the therapeutic effect of tumors. The production of endogenous ROS is stimulated by CA, which can effectively inhibit the proliferation of tumor cells, amplify the oxidative stress in the cells, cause the rapid loss of the transmembrane potential of mitochondria, consume GSH in the cells and further induce the death of iron; in addition, the radiosensitizer all-trans retinoic acid (hereinafter referred to as RA) can further mediate a large amount of exogenous ROS generated under irradiation, promote explosive amplification of oxidative stress and immunogenic death of cancer cells, and induce anti-tumor immune response of organisms.
EXAMPLE 1 Synthesis of Polyoxymethyl (PdA) polyoxy (DMAEMA) -polycysteinaldehyde copolymer
The synthesis procedure of PDOPA-PCA is as follows (FIG. 1 is the preparation process):
(1) Dipropylaminoethyl methacrylate (hereinafter, abbreviated as DPA) is taken as a monomer, 2- [ dodecylthio (thiocarbonyl) thio ] -2-methylpropanoic acid (hereinafter, abbreviated as CTAm) is taken as a chain transfer agent, azobisisobutyronitrile (hereinafter, abbreviated as AIBN) is taken as an initiator, and the dipropylaminoethyl methacrylate (hereinafter, abbreviated as PDPA) is obtained by reversible addition-fragmentation chain transfer polymerization (hereinafter, abbreviated as RAFT) reaction in a dimethylformamide (hereinafter, abbreviated as DMF) solvent at the reaction temperature of 70 ℃;
(2) Preparing a pH-sensitive cinnamaldehyde monomer (CA) by aldehyde acetalization of cinnamaldehyde;
(3) Mixing PDPA and CA, taking CTAm as a chain transfer agent and AIBN as an initiator, and performing RAFT reaction again in a DMF solvent at the reaction temperature of 70 ℃ to obtain a dipropylaminoethyl polymethacrylate-poly-cinnamaldehyde diblock polymer (hereinafter, referred to as PDPA-PCA);
(4) The PDPA-PCA is oxidized by hydrogen peroxide to obtain poly (dipropylamino ethyl methacrylate) -poly (cinnamaldehyde) (hereinafter, the poly (p-propylene glycol) is abbreviated as PDOPA-PCA).
The chemical composition of PDOPA-PCA is analyzed by techniques such as nuclear magnetism, mass spectrum and the like, and FIG. 2 is a nuclear magnetic resonance spectrum of the PDOPA-PCA copolymer in example 1, and the successful synthesis of the copolymer can be seen from the FIG. 1.
Example 2 preparation of all-trans retinoic acid-loaded nanoparticles (PDPCA @ ATRA NPs for short)
PDPCA @ ATRA NPs were prepared as follows:
(1) 10mg of PDOPA-PCA and 5mg of all-trans retinoic acid (hereinafter, both referred to as RA) were simultaneously dissolved in 1mL of tetrahydrofuran;
(2) Dropwise adding the mixture into 10mM LLII-Q ultrapure water at the dropping rate of 100 mu L/min while stirring;
(3) Continuously stirring the solution for 48 hours until the tetrahydrofuran is completely volatilized;
(4) Centrifuging at 3000rpm for 5min to obtain PDPCA @ ATRA NPs nanoparticles.
Detecting the prepared PDPCA @ ATRA NPs nanoparticles:
diluting the nanoparticles into 1mg/mL solution with Milli-Q ultrapure water, taking 10-20 microliters of sample, dropwise adding the sample onto a 230-mesh copper net containing a carbon support membrane, and drying at constant temperature; 5 microliter of 1-2% uranyl acetate is stained for 5min, the staining solution is blotted on filter paper, and after drying at normal temperature, the sample morphology is observed by a projection electron microscope (TEM, FEI, tecnai G220S-TWIN,200 kV).
The nanoparticles were diluted with Milli-Q ultrapure water to a 1mg/mL solution and the particle size and polydispersity index (PDI) were measured by a laser particle sizer (DLS, malvern, UK, zetasizer NanoZS) at 25 deg.C, 90 deg.C and 633nm laser wavelength, equilibrated for 2min before each measurement, and each sample was tested three times and averaged.
Each detection map is shown in fig. 3-4; wherein, fig. 3 is a transmission electron microscope image of pdpca @ atra NPs in example 2, and it can be seen from fig. 3 that the pdpca @ atra NPs nanoparticles have a regular spherical structure, and the particle size is about 300 nm; FIG. 4 is a graph showing the light scattering particle size distribution of PDPCA @ ATRA NPs in example 2, in which the average particle size is 300nm and the polydispersity index is 0.3.
Example 3 detection of the ability of PDPCA @ ATRA NPs to generate reactive oxygen species (hereinafter referred to simply as ROS) free radicals
To detect intracellular ROS levels, the ROS sensitive probe DCFDA was used; the specific detection process is as follows:
(1) DCFDA was dissolved in DMSO to obtain a 10mM stock solution and further diluted before use;
(2) 1X 105A 549 cells were seeded in 6-well plates and PDPCA @ ATRA NPs were added 24h later, followed by 8Gy Cr administration 137 Gamma irradiation and addition of 5. Mu.M staining solution;
(3) Digesting the cells with 0.25% pancreatin EDTA solution after 24h, neutralizing with a culture medium, blowing and uniformly mixing the cells, and collecting the cells;
(4) Washing with PBS buffer solution for 3 times, discarding supernatant, and adding 500 μ LPBS buffer solution into cell precipitate;
(5) ROS expression levels were determined and analyzed by flow cytometry.
FIG. 5 is a measurement of the ability of PDPCA @ ATRA NPs to generate ROS radicals in example 3; as can be seen from this FIG. 5, the intracellular ROS levels are significantly elevated with the addition of the PDPCA @ ATRA NPs nanoparticle group, indicating that it can exacerbate the ROS free radicals generated by irradiation.
Example 4 detection of glutathione depleting Capacity of PDPCA @ ATRA NPs
Preparing a required reagent stock solution before an experiment; the detection process is specifically as follows:
(1) 2X 105A 549 cells were seeded in 6-well plates and PDPCA @ ATRA NPs were added in groups 24h later, followed by 8Gy of Cr 137 Irradiating by gamma rays, and collecting cells 24h after irradiation;
(2) Washing cells with PBS buffer solution, centrifuging to remove supernatant, adding 3 times of protein removal reagent M solution of cell sediment, fully whirling, performing 2 times of rapid freeze thawing and thawing with liquid nitrogen and 37 ℃ water bath, and standing at 4 ℃ for 5 minutes;
(3) Centrifuging at 10000g and 4 deg.C for 10min, collecting supernatant, and measuring total glutathione content;
(4) Sequentially adding the sample or the standard substance into a 96-well plate, adding 150 mu L of total glutathione detection solution, uniformly mixing, and incubating at room temperature for 5min; then 50 μ L of 0.5mg/mL NADPH solution is added and mixed evenly, A412 is measured immediately by a microplate reader once every 5 minutes for 25 minutes, and finally the glutathione content is calculated according to a standard curve.
FIG. 6 is the result of measuring the glutathione consumption ability of PDPCA @ ATRA NPs of example 4, and it can be seen from FIG. 6 that the glutathione content in the cells added with the PDPCA @ ATRA NPs nanoparticle group is significantly reduced, indicating that it can effectively remove glutathione in the cells.
Example 5 detection of iron-death-inducing ability of PDPCA @ ATRA NPs
(1) Observation experiment of cell submicrostructure
A549 cells are inoculated on a culture dish of 10cm and grouped, PDPCA @ ATRA NPs nano particles are added according to the grouping after 24 hours, and then 8Gy Cr is given 137 Irradiating with gamma rays, and collecting cells 24h after irradiation;
washing the cells with PBS buffer for three times, centrifuging to remove supernatant, and fixing the cells with 2.5% glutaraldehyde;
then ethanol, acetone and the like with different concentrations are used for dehydration treatment;
embedding, curing and slicing the sample; and finally, dyeing by using uranium acetate, and observing the shapes of cell nuclei and mitochondria by using a transmission electron microscope.
FIG. 7 shows the results of the effect of PDPCA @ ATRA NPs of example 5 on the cell sub-microstructure; the results in fig. 6 show that mitochondria in pdpca @ atra NPs combined irradiation group showed the most significant form of iron death: the mitochondrial cristae is reduced or disappeared, the number of mitochondrial inner vacuoles is increased, and the mitochondrial membrane density is increased. Suggesting the occurrence of more iron death events.
(2) Clone formation assay
A549 cells were seeded at a density of 1000/well in 6-well plates and grouped. Adding ferrostanin-1, incubating at 37 deg.C for 24h, pretreating cells with PDPCA @ ATRA NPs nanoparticles for 1h, and respectively adding 0, 2, 4 and 8Gy Cr 137 Gamma-ray irradiating the cells;
cells were cultured for 7 days, washed in 6-well plates after staining with 0.5% crystal violet, and cell colonies formed in each group were counted, cell survival curves were plotted using GraphPad Prism 6 according to the classical multi-target one-click model, with the equation (y =1- (1-exp (-k x)) < lambda > N), and then radiosensitization ratios (SERs) were determined for each group.
FIG. 8 shows the effect of PDPCA @ ATRA NPs of example 5 on cell colony formation; the result shows that PDPCA @ ATRA NPs effectively inhibit the clonogenic capacity of A549 cells by combined radiation, and the clonogenic capacity is recovered after the ferrodeath inhibitor ferrostatin-1 is added; it is demonstrated that PDPCA @ ATRA NPs inhibit A549 cell proliferation in a manner that increases iron death.
(3) Lipid peroxidation detection experiment
The cells were seeded in 6-well plates at 1X 105A 549 cells per well and grouped, PDPCA @ ATRA NPs were added 24h later, followed by 8Gy Cr administration 137 Gamma irradiation, after 24h 10. Mu.M BODII PY 581/591C11 dye per well and incubation continued for 30 min. The cells were collected by digestion for flow detection.
FIG. 9 shows the results of detection of lipid peroxidation in cells by PDPCA @ ATRA NPs of example 5; the results in figure 9 show that pdpca @ atra NPs combined with radiation group produced higher levels of lipid peroxidation than the single-shot group, indicating that this group had higher levels of iron death.
(4) Iron death marker gene detection experiment
Inoculating 2X 105A 549 cells per well in 6-well plate, grouping, adding PDPCa @ ATRA NPs after 24h, and then administering 8Gy Cr 137 Irradiating with gamma ray, and collecting cells after 24h to extract RNA. It was then reverse transcribed into cDNA and analyzed by PCR.
FIG. 10 shows the result of detecting the radiation-induced iron death marker gene by PDPCA @ ATRA NPs of example 5; as can be seen from the FIG. 10, PDPCA @ ATRA NPs increased the expression of the iron death marker gene PTGS2, indicating that PDPCA @ ATRA NPs significantly increased A549 iron death.
Example 6 detection of the ability of PDPCA @ ATRA NPs to induce immunogenic death
A549 cells are inoculated in a 6-well plate, PDPCA @ ATRA NPs are added after 24h, and then 6Gy Cr is added 137 Gamma-ray irradiation at a dose rate of 0.85 Gy/min;
after 24h, secretion of High Mobility Group Protein B1 (HMGB1) in the cell culture supernatant was detected by ELISA.
FIG. 11 shows the results of the detection of immunogenic death of tumor cells by PDPCA @ ATRA NPs of example 6; from the figure 11, it can be seen that the secretion of the high mobility group protein B1 (HMGB 1) by the cells added with the PDPCA @ ATRA NPs nanoparticle group is obviously increased, which indicates that the cells can effectively induce the immunogenic death of tumor cells.
Example 7 Effect of PDPCA @ ATRA NPs on cellular radiosensitivity
A549 cells were incubated at a cell density of 1000 cells per well for 24h beforeAdding PDPCA @ ATRA NPs at 1 hr, and respectively adding 2, 4, 6, 8Gy Cr 137 Gamma ray irradiation;
the cells were cultured for 8-10 consecutive days, and once colony formation was observed, the culture broth was discarded, the plate was washed twice with PBS, and then stained with 0.5% w/v crystal violet solution to observe the colony formation of each group.
FIG. 12 shows the results of the detection of the radiation sensitivity of PDPCA @ ATRA NPs of example 7 to tumor cells. As can be seen from this FIG. 12, the clone formation rate of the cells added with the PDPCA @ ATRA NPs nanoparticle group was significantly decreased, indicating that it could enhance the radiation sensitivity of the cells to gamma rays.
Example 8 PDPCA @ ATRA NPs radiosensitization mechanism study.
(1) The immunoblotting experiment explored the effect of PDPCA @ ATRA NPs on the Nuclear factor NF-E2-related factor 2 (Nuclear factor-extracellular 2-related factor 2, NRF2) protein
The immunoblotting experiment detects the protein expression level of NF-E2 related factor 2 (NRF 2 for short) of each group of antioxidant factor nuclear factor:
a549 cells (A549-NRF 2 ko) knocked out by NRF2 protein are constructed by adopting a Crisp-cas9 technology, and PDPCA @ ATRA NPs are detected and comparatively analyzed for radiation sensitization and iron death induction efficiency in A549 wild-type cells (A549 WT) and A549NRF2 knock-out cells (A549-NRF 2 ko);
constructing an NRF2 overexpression plasmid, performing NRF2 protein complementation in an A549-NRF2ko cell line, constructing an A549-NRF2Rescue cell line, and simultaneously detecting and comparatively analyzing the radiation sensitivity and iron death induction efficiency of PDPCA @ ATRA NPs in the A549-NRF2ko cell line and the A549-NRF2Rescue cell line.
FIGS. 13-17 are the mechanism by which PDPCA @ ATRA NPs of example 8 exert radiosensitization in a NRF2 protein-dependent manner; from these figures, it can be seen that pdpca @ atra NPs can effectively inhibit the expression of NRF2 protein, and that the efficiency of the sensitization of pdpca @ atra NPs decreases after NRF2 protein is knocked down as a target, while the sensitization of pdpca @ atra NPs resumes after NRF2 protein anaplerosis; it is demonstrated that PDPCA @ ATRA NPs are dependent on NRF2 protein for radiosensitization.
(2) Nuclear-cytoplasmic separation experiment for detecting expression condition of NRF2 protein in nucleus
A549 cells are inoculated in a culture dish and grouped, PDPCA @ ATRA NPs are added according to the grouping after 24 hours, and then 8Gy Cr is given 137 Irradiating with gamma rays, collecting cells 24h after irradiation, cleaning and centrifuging to remove supernatant;
adding pre-cooled cytoplasm Extraction Reagent 1 (Cytoplasmic Extraction Reagent I, CER I) into the dried cell sediment, incubating on ice for 10 minutes after vigorous vortex, and then adding pre-cooled cytoplasm Extraction Reagent 2 (Cytoplasmic Extraction Reagent II, CER II);
after continuing the vortex, the tube was centrifuged at maximum speed (-16,000 Xg) for 5 minutes, the supernatant was immediately transferred to a new tube and stored at-80 ℃;
the remaining insoluble (particulate) fraction was suspended in ice-cold Nuclear Extraction Reagent (NER), and the sample was placed on ice and vortexed for an additional 15 seconds every 10 minutes for a total of 40 minutes;
centrifugation at the highest speed (. About.16,000 Xg) for 10 minutes, immediately transferring the supernatant (nuclear extract) fraction to a clean pre-cooling tube and storing at-80 ℃;
ARE element plasmids with GFP fluorescent labels ARE constructed, cells ARE transfected, and NRF2 nuclear protein expression in each group of cells is verified through the combination principle of NRF2 in the cells and ARE elements.
FIGS. 18-19 are the mechanism explored by PDPCA @ ATRA NPs of example 8 to exert radiosensitization by affecting NRF2 nuclear expression; as can be seen from these figures, PDPCA @ ATRA NPs effectively inhibit the nuclear expression of NRF2 protein, suggesting that PDPCA @ ATRA NPs achieve radiosensitization by reducing the transcriptional function of NRF 2.
(3) Exploring the effects of PDPCA @ ATRA NPs on iron death-related proteins and genes downstream of NRF2
The cells were seeded and grouped in 6-well plates at 2X 105A 549 cells per well, PDPCA @ ATRA NPs were added 24h later, followed by 8GyCr administration 137 Gamma-ray irradiation, extracting protein and RNA of each group of cells, and detecting the protein of cystine transporter system (xCT)/glutathione peroxidase 4 (GPX 4) by immunoblotting experiment and PCR experiment respectivelyWhite blood expression and gene expression profiles. Then, xCT and GPX4 are knocked down respectively by the small interfering RNA technology, and the radiosensitization and iron death induction efficiency of PDPCA @ ATRA NPs before and after knocking down are compared and analyzed.
FIGS. 20-26 are the mechanism by which PDPCA @ ATRA NPs of example 8 exert radiosensitization by inhibiting the NRF2-GSH-GPX4 signal pathway; from these figures, it can be seen that PDPCA @ ATRA NPs effectively inhibit xCT/GPX4 expression, and when both are knocked down as targets, the sensitization efficiency of PDPCA @ ATRA NPs is decreased, indicating that PDPCA @ ATRA NPs exert radiosensitization action by inhibiting NRF2-GSH-GPX4 signal pathway.
(4) Glutathione peroxidase (hereinafter abbreviated as GPX) activity detection
Preparing required reagents before an experiment; a549 cells were inoculated in culture dishes and grouped, PDPCA @ ATRA NPs were added in groups after 24h, followed by 8GyCr administration 137 Irradiating with gamma ray, collecting cells 24h after irradiation, cleaning and centrifuging to remove supernatant;
cracking the cells according to the proportion that 100-200 microliter of lysis solution is added into every 100 ten thousand cells; subsequently, centrifugation was carried out at 12000g for 10 minutes at 4 ℃ to obtain a supernatant, which was used for the measurement of the enzyme activity;
and (3) adding a detection buffer solution, a sample to be detected and a GPX detection working solution into a 96-well plate in sequence, adding 40 mu L of the GPX detection working solution, mixing uniformly, and incubating for 15 minutes at room temperature. Adding 10 mu L of 30mM peroxide reagent solution into each hole, and uniformly mixing;
the a340 value was immediately measured using a microplate reader at room temperature, at which time the 0 minute reading was recorded. Recording A340 value every 1 minute, and continuously recording for at least 5 minutes to obtain data of 6 points; the GPX activity of each group was calculated from the data obtained.
FIG. 27 is a mechanism exploration of PDPCA @ ATRA NPs of example 8 to achieve radiosensitization by decreasing GPX4 activity; it can be seen from fig. 27 that pdpca @ atra NPs can effectively inhibit the activity of GPX, and surface pdpca @ atra NPs reduce the activity of GPX by consuming GSH, thereby achieving a radiosensitization effect.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be effected by one skilled in the art without departing from the spirit and scope of the invention, as defined in the appended claims.
Finally, it should also be noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrases "comprising a," "8230," "8230," or "comprising" does not exclude the presence of additional like elements in a process, method, article, or apparatus that comprises the element.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The preparation method of the radiotherapy sensitization nano particles is characterized by comprising the following steps:
performing polymerization reaction, namely performing reversible addition-fragmentation chain transfer polymerization reaction on a dipropylaminoethyl methacrylate monomer and a cinnamaldehyde monomer to form a dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer; wherein the cinnamaldehyde monomer has pH sensitivity and can be controllably released under the acidic condition of tumor tissues;
oxidizing the dipropylaminoethyl methacrylate-poly-cinnamaldehyde two-block polymer to form polyoxydipropylaminoethyl methacrylate-poly-cinnamaldehyde;
and particle assembly, namely self-assembling the poly (p-xylylene glycol) acrylic acid oxide dipropyl aminoethyl methacrylate-poly (cinnamaldehyde) in an aqueous solution to form the nano particles.
2. The method for preparing the radiosensibilization nanoparticle of claim 1, wherein the polymerization reaction comprises a first polymerization reaction and a second polymerization reaction;
the first polymerization reaction comprises: taking 2- [ dodecylthio (thiocarbonyl) thio ] -2-methylpropanoic acid as a chain transfer agent and azodiisobutyronitrile as an initiator, and carrying out reversible addition-fragmentation chain transfer polymerization reaction on the dipropylaminoethyl methacrylate monomer in a dimethylformamide solvent to obtain dipropylaminoethyl methacrylate;
the second polymerization reaction comprises: mixing the poly dipropyl aminoethyl methacrylate and the cinnamaldehyde monomer, taking the 2- [ dodecylthio (thiocarbonyl) thio ] -2-methylpropanoic acid as a chain transfer agent, taking the azobisisobutyronitrile as an initiator, adding the dimethylformamide, and performing reversible addition-fragmentation chain transfer polymerization to obtain the poly dipropyl aminoethyl methacrylate-poly-cinnamaldehyde two-block polymer.
3. The method for preparing the radiotherapy-sensitized nanoparticle according to claim 1, wherein the oxidation reaction is carried out by oxidizing the dipropylaminoethyl polymethacrylate-poly-cinnamaldehyde diblock polymer with hydrogen peroxide.
4. The method for preparing the radiotheraphy sensitizing nanoparticle according to claim 1, wherein the cinnamaldehyde monomer is formed by aldehyde-based acetalization of cinnamaldehyde.
5. The method for preparing the radiosensitization nanoparticles according to claim 1, wherein the particle assembly comprises the assembly of unloaded nanoparticles or nanoparticles loaded with all-trans retinoic acid,
the unloaded nanoparticle assembly step comprises: placing the polyoxy-methyl acrylic acid dipropyl aminoethyl ester-poly-cinnamaldehyde in aqueous solution, and self-assembling under the hydrophilic-hydrophobic interaction to form no-load nano particles;
the assembly step of the nano particle loaded with the all-trans retinoic acid comprises the following steps: mixing polyoxy-methyl acrylic acid dipropyl aminoethyl-polycysteinaldehyde and all-trans retinoic acid, adding tetrahydrofuran for dissolving, adding double distilled water, stirring until the tetrahydrofuran is completely volatilized, centrifuging and taking supernate to obtain the all-trans retinoic acid loaded nanoparticles.
6. The method for preparing the radiotherapeutic sensitization nano particles according to claim 2, wherein the concentration of the polyoxy-methacrylic acid dipropyl aminoethyl ester-poly-cinnamaldehyde is 1-10mg/mL; and/or the concentration of the all-trans retinoic acid is 0.5-1mg/mL.
7. A radiosensitizing nanoparticle, prepared by the method for preparing the radiosensitizing nanoparticle according to any one of claims 1 to 6, comprising an unloaded nanoparticle or a nanoparticle loaded with all-trans retinoic acid formed by self-assembly of a polymer polyoxy-dipropylamino-ethyl methacrylate-polycysteinaldehyde, wherein the structural formula of the polyoxy-dipropylamino-ethyl methacrylate-polycysteinaldehyde is shown in the specification
8. The radiosensitizing nanoparticle according to claim 7, wherein the nanoparticle has a particle size of 200-400nm.
9. The radiosensitizing nanoparticle according to claim 7, wherein the nanoparticle comprises an α, β -unsaturated ketone structure capable of undergoing a Michael addition reaction with glutathione.
10. The radiosensitizing nanoparticle according to claim 7, wherein the all-trans retinoic acid-loaded nanoparticle comprises all-trans retinoic acid and is capable of reducing the expression of a nuclear factor NF-E2-related factor 2 protein and reducing the transcription levels of a downstream cystine transporter system and glutathione peroxidase 4.
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