CN111700862A - Bispecific nano micelle based on folic acid targeting and Cherenkov radiation response and preparation method and application thereof - Google Patents
Bispecific nano micelle based on folic acid targeting and Cherenkov radiation response and preparation method and application thereof Download PDFInfo
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- CN111700862A CN111700862A CN202010456188.6A CN202010456188A CN111700862A CN 111700862 A CN111700862 A CN 111700862A CN 202010456188 A CN202010456188 A CN 202010456188A CN 111700862 A CN111700862 A CN 111700862A
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Abstract
The invention discloses a bispecific nano micelle based on folic acid targeting and Cherenkov radiation response, a preparation method and application thereof, and belongs to the technical field of nano material manufacturing and application. According to the invention, a photosensitive group nitrobenzyl is coupled with a hexadecyl DOX derivative (with enhanced hydrophobicity), and the derivative is embedded in a folic acid modified amphiphilic polymer (FA-PEG-PCL) to prepare nano micelle NM/DOC, the NM/DOC can target tumor cells by folic acid, and further in the process of X-ray local radiotherapy, the generated Cherenkov radiation breaks the photosensitive group-nitrobenzyl to increase the hydrophilicity of DOX, trigger the release of a drug, organically integrate radiotherapy and chemotherapy, and enhance the specificity of the effect of the chemotherapy drug by the active targeting and response of NM/DOC, so that the toxic and side effects on organisms are greatly reduced.
Description
Technical Field
The invention belongs to the technical field of nano material manufacture and application, and particularly relates to a nano micelle for folic acid targeting and responding to Cherenkov radiation to release chemotherapeutic drugs, which is used for coordinating the radiotherapy synergy of X rays.
Background
Currently, radiotherapy and chemotherapy are still the standard treatment strategies for many cancer patients in clinical application, which can realize effective control of local lesions and prolong the life of the patients. And chemotherapy is synchronously performed in the radiotherapy process, so that the traditional Chinese medicine composition has a good prognosis effect on treating cancers such as late-stage rectal cancer, cervical cancer, non-small cell lung cancer, head and neck cancer and the like. However, the treatment mode of the cooperation of radiotherapy and chemotherapy still has obvious systemic toxicity, which is mainly because the common chemotherapeutic drugs lack the target enrichment capacity and will inevitably cause damage to normal tissues and organs of the organism. In the process of clinically making a treatment scheme, not only the expected killing effect on tumor cells is achieved, but also the toxic and side effects of treatment means on normal tissues are considered. Therefore, how to organically integrate radiotherapy and chemotherapy, enhance the specific killing of chemotherapeutic drugs on tumor cells and reduce the toxic and side effects of organisms is also a key problem to be solved.
In recent years, extensive research of nano-carriers in the biomedical field provides a good platform for effective delivery of chemotherapeutic drugs. Firstly, the nano-carrier can target receptor molecules expressed at a high level at a tumor part by covalent coupling or electrostatic adsorption of ligand molecules, such as folic acid, hyaluronic acid, Epidermal Growth Factor (EGF) and the like, so that the targeted delivery of chemotherapeutic drugs is realized, the drug concentration in tumors is improved, the nonspecific enrichment of the drugs in other tissues and organs is reduced, and the toxic and side effects of organisms are reduced. And secondly, the nano-carrier can specifically respond to exogenous and endogenous stimulation through the design of a molecular layer, regularly and fixedly release the embedded chemotherapeutic drugs, enhance the specificity of the drug action, reduce the drug release of non-target sites and also reduce the toxic and side effects of organisms. The light is used as exogenous stimulation, has high resolution and strong controllability, can remotely and accurately control the release of the medicine, is noninvasive and harmless to the body, is an ideal stimulation source, but has limited tissue penetration depth, and becomes a main obstacle for the development of the light-controlled nano carrier.
X-rays are a commonly used source of radiotherapy radiation in clinical settings, are not limited by tissue penetration depth, and produce a short-wavelength blue glow, cerenkov radiation, upon irradiation. Doxorubicin (DOX) is a widely used chemotherapeutic drug that can be used to treat a number of different types of cancer, but overuse of DOX can cause significant cardiotoxicity. The common chemotherapy drugs such as adriamycin (DOX), paclitaxel and cisplatin have stronger hydrophobicity, limit the effective delivery in vivo and have low bioavailability. In addition, lack of specificity to tumor cells, simple intraperitoneal or intravenous injection of chemotherapeutic drugs can cause strong toxic and side effects to the body.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a bispecific nano-micelle based on folate targeting and Cerenkov radiation response, and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:
the invention discloses a bispecific nano micelle based on folic acid targeting and Cherenkov radiation response, which is characterized in that a folic acid modified amphiphilic block polymer FA-PEG-PCL is used as a nano carrier, and DOC (o-nitrobenzyl coupled hexadecyl DOX derivative) capable of responding to Cherenkov radiation is self-assembled and encapsulated to obtain nano micelle NM/DOC.
Preferably, the bispecific nano micelle has a regular shape, the average particle size is about 181nm, and the particles are uniformly distributed.
The invention also discloses a preparation method of the bispecific nano-micelle based on folic acid targeting and Cherenkov radiation response, which comprises the following steps:
1) dissolving DOC in dimethyl sulfoxide;
2) dissolving an amphiphilic block polymer FA-PEG-PCL solution in tetrahydrofuran;
3) uniformly stirring and mixing the two solutions, dropwise adding the two solutions into continuously stirred ultrapure water, and fully stirring until tetrahydrofuran in a mixed solution system is volatilized to obtain a mixed solution;
4) filtering the mixed solution by using an ultrafiltration membrane, and performing ultrafiltration washing to prepare the bispecific nano micelle NM/DOC.
Preferably, in the step 1), the feed-liquid ratio of DOC to dimethyl sulfoxide is 1 mg: (200-500) mu L.
Preferably, in the step 2), the feed-liquid ratio of the amphiphilic block polymer FA-PEG-PCL to tetrahydrofuran is 10 mg: (1-2) mL.
Preferably, in the step 3), the dosage ratio of the added ultrapure water to the DOC is (10-15) mL: 1 mg.
Preferably, in the step 3), a magnetic stirrer is adopted for full stirring, and the rotating speed is 2000-8000 rpm/min.
Preferably, in the step 4), the ultrafiltration membrane adopts an ultrafiltration membrane with a filter head of 0.45 μm; the ultrafiltration washing is carried out for three times by adopting an ultrafiltration membrane with the molecular weight cutoff of 10000.
The invention also discloses application of the bispecific nano micelle based on folic acid targeting and Cherenkov radiation response as a drug-carrying agent of an anti-tumor drug.
The invention also discloses application of the bispecific nano micelle based on folic acid targeting and Cherenkov radiation response as a synergist of an antitumor drug.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, a photosensitive group nitrobenzyl is coupled with a hexadecyl DOX derivative (with enhanced hydrophobicity), and the derivative is embedded in a folic acid modified amphiphilic polymer (FA-PEG-PCL) to prepare nano micelle NM/DOC, wherein the NM/DOC can target tumor cells by folic acid, and further in the process of X-ray local radiotherapy, the generated Cherenkov radiation breaks the photosensitive group-nitrobenzyl, so that the hydrophilicity of DOX is increased, and the release of a drug is triggered. The Cerenkov radiation is used as an optical stimulus for releasing the nano-carrier drug, so that the problem of limited penetration depth of a common light source can be overcome, effective cooperation of radiotherapy and chemotherapy can be realized, the specificity of the effect of the chemotherapeutic drug is enhanced through active targeting and response drug release of NM/DOC, and the toxic and side effects on organisms are greatly reduced.
The bispecific nano micelle NM/DOC prepared by the invention has the following characteristics:
(1) the NM/DOC nano micelle has higher stability under physiological conditions, and can ensure that the entrapped DOX cannot be released early and non-specifically in the blood circulation process in vivo;
(2) the NM/DOC nano micelle can actively target a tumor part by means of surface-modified folic acid molecules, so that the nonspecific enrichment of normal tissues and organs of an organism is reduced;
(3) in the process of X-ray local radiotherapy, the NM/DOC nano micelle can specifically respond to Cherenkov radiation, releases DOX at a target spot and carries out fixed-point chemotherapy at the same time of radiotherapy.
Drawings
FIG. 1 is an electron micrograph of NM/DOC nanomicelle of the present invention;
FIG. 2 is a graph showing a distribution of the NM/DOC nanomicelle particle size according to the present invention;
FIG. 3 is the particle size variation of NM/DOC nanomicelle of the present invention in PBS at different time points;
FIG. 4-1 is the fluorescence spectra of DOX in dialysate at different time points for NM/DOC nanomicelle (X-ray treatment);
FIG. 4-2 is fluorescence spectra of DOX in dialysate at different time points for NM/DOC nanomicelles (X-ray untreated);
FIG. 4-3 cumulative drug release of NM/DOC nanomicelle;
FIG. 5 is a confocal micrograph of Hela cells co-incubated with NM/DOC nanomicelles, with or without X-ray treatment;
FIG. 6 shows the killing effect of NM/DOC nano-micelle on Hela cells in vitro in cooperation with X-rays;
FIG. 7 shows the enrichment of NM/ICG nanomicelles in vivo by fluorescence imaging of ICG;
FIG. 8 is a graph showing tumor growth curves of various groups of mice;
fig. 9 shows survival rates of the respective groups of mice.
Detailed Description
In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be noted that the terms "first," "second," and the like in the description and claims of the present invention and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in sequences other than those illustrated or described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention is described in further detail below with reference to the accompanying drawings:
the invention takes folic acid modified amphiphilic block polymer FA-PEG-PCL as a nano carrier, self-assembles and entraps DOC capable of responding to Cherenkov radiation, and prepares NM/DOC nano micelle. The NM/DOC nano micelle has regular appearance and uniform particle size, has good stability in a phosphate buffer solution, can actively target tumors, responds to Cherenkov radiation generated during X-ray radiotherapy, releases chemotherapeutic drugs DOX, and achieves the purposes of synergistic effect of radiotherapy and chemotherapy and reduction of toxic and side effects of organisms.
The DOC used in the invention is a DOX derivative of o-nitrobenzyl coupled hexadecyl, and the DOC is prepared by the following references: photo-responsive Nanovehicle for Two-way Independent wavelet Light-TriggerledSequential Release of P-gp shRNA and Doxorubicin to optize and enhanced synergistic Therapy of Multi-drug-resistant Cancer, a synthetic method disclosed.
The structural formula of DOC is as follows:
the synthesis route of DOC is as follows:
the specific synthesis method of the DOC comprises the following steps:
step 1: 5-hydroxy-2-nitrobenzol (2mmol) and 733mg of bromohexadecane were dissolved thoroughly in 20mL of DMF, followed by 424mg of sodium carbonate (Na)2 CO 34 mmol). Placing the above mixed solution in an oil bath, reacting at 80 deg.C for 24 hr, vacuum distilling to remove DMF, dissolving the obtained mixture in a mixed solution of double distilled water and ethyl acetate, washing the oil phase (ethyl acetate layer) with double distilled water twice, and adding appropriate amount of anhydrous sodium sulfate (Na) into the oil phase2SO4) And dried overnight. Next, ethyl acetate was removed by rotary evaporation to give a crude product, which was finally purified by column chromatography using ethyl acetate/petroleum ether as eluent to give compound 1 as a pale yellow solid.
Step 2: 4-Nitrophenyl chloroformate (148mg, 0.73mmol) was dissolved in 5mL of Tetrahydrofuran (THF), and added to 2mL of chloroform containing Compound 1(148mg, 0.7mmol) and N, N-diisopropylethylamine (DIPEA, 256. mu.L, 1.47mmol), and after mixing well, the mixture was placed in a containerThe reaction was carried out at room temperature for 24 h. Thereafter, the reacted product was concentrated and redissolved in 50mL of ethyl acetate, and then the ethyl acetate in which the reaction product was dissolved was treated with 1M phosphoric acid (H)3PO4) The solution was washed 3 times with sodium bicarbonate (NaHCO)3) Washing with the solution for 2 times, and adding anhydrous Na2SO4Drying overnight and finally rotary evaporation to remove the solvent to give the crude product. The crude product was purified by column chromatography using ethyl acetate/petroleum ether as eluent to give compound 2, compound 2 as a white solid.
And step 3: adriamycin hydrochloride (50mg, 0.086mmol) was dissolved in 6mL of DMF, followed by addition of 36. mu.L triethylamine (Et)3N, 0.258mmol) and 49mg of compound 2(0.086mmol) were sufficiently dissolved, and the mixture was left to react at room temperature for 36 hours, after which the reaction solvent was removed by vacuum distillation to obtain a crude product. And finally, using silica gel as a stationary phase, using methanol/chloroform (1: 100-5: 100, V/V) as an eluent, and purifying the crude product by column chromatography to obtain the red solid DOC.
1. Preparation of NM/DOC nano micelle
Weighing DOC 1mg, and dissolving in 200 μ L dimethyl sulfoxide (DMSO); weighing 10mg of FA-PEG-PCL polymer, and dissolving in 1mL of Tetrahydrofuran (THF); the two solutions are uniformly mixed by stirring (the specific stirring time is not specially required, and the two solutions are uniformly mixed), 10mL of continuously stirred ultrapure water is dropwise added, then the solution is continuously placed on a magnetic stirrer (2000rpm/min) to be stirred for 24h, and THF in the mixed solution is volatilized. Then, the mixed solution was filtered with a 0.45 μm filter head and washed three times with an ultrafiltration membrane (MWCO: 10000) by ultrafiltration, and the prepared nano-micelle was collected and stored in a refrigerator at 4 ℃ for later use.
The nano-micelle prepared by the method is observed by a transmission electron microscope, and is regular in appearance and good in dispersibility, as shown in figure 1. Dynamic light scattering detection (as shown in FIG. 2) can obtain the average particle diameter of about 181nm and uniform particle distribution. As shown in FIG. 3, the particle size of NM/DOC nano-micelle in PBS has not changed significantly after continuous particle size monitoring for many days, indicating that the stability is better. The NM/DOC nano micelle can respond to Cherenkov radiation generated by X-rays and release chemotherapeutic drugs DOX. In the research, NM/DOC nano-micelle treated by X-ray is placed in a dialysis bag (MWCO, 3500) for dialysis, samples are taken at different time points, PBS with the same volume is supplemented, and finally the fluorescence spectrum of DOX in the collected samples is detected by a fluorescence spectrometer. Fig. 4-1 shows the X-ray treated experimental group, while fig. 4-2 shows the untreated control group, in which strong DOX fluorescence can be detected at different time points, while the fluorescence spectrum of the control group has no significant change, which shows that X-rays (cheenkov radiation) can trigger NM/DOC nano-micelles to rapidly release loaded DOX. Further, the cumulative release curves of the drugs of the experimental group and the control group are calculated and drawn by the fluorescence intensity of DOX (as shown in figure 4-3), after X-ray irradiation, the cumulative release amount of the DOX of NM/DOC reaches about 40% after 96h, while the cumulative release amount of the DOX of the control group is only less than 10%.
Released DOX was able to rapidly enter the nucleus, as shown in FIG. 5, NM/DOC was co-incubated with Hela cells, after 4h the cells were irradiated with 8Gy of X-rays, followed by further incubation for 4 h. Then, after washing, fixing and staining, the cells are placed under a confocal microscope for observation, in the cells treated by X-rays, a part of red fluorescence of DOX is obviously overlapped with blue fluorescence of cell nuclei, and the red fluorescence of DOX hardly appears in the cell nuclei (blue fluorescence) of a control group, which shows that NM/DOC nano-micelles have stronger specificity, can effectively release loaded DOX only under the condition of triggering of X-rays (Cerenkov), and only free DOX can rapidly enter the cell nuclei.
2. In vitro, cell and animal experiments prove that NM/DOC can actively target tumors
The prepared NM/DOC can actively target tumors through in-vitro, cell and animal experiments, and most importantly, the prepared NM/DOC can specifically release drugs due to the generation of Cerenkov light under X-ray radiotherapy, so that the effective synergy of radiotherapy and chemotherapy is realized, and the toxic and side effects on organisms are reduced.
2.1 NM/DOC can cooperate with radiotherapy to enhance the killing effect on tumor cells after triggering and releasing chemotherapeutic drugs by X-rays (Cherenkov radiation)
In the study, NM/DOC nano-micelles are incubated with Hela cells, the cells are irradiated with X-rays at different doses (0, 2, 4, 6, 8 and 10Gy) after 4h, and then the incubation is continued for 72h, and then the survival rate of the cells is detected and counted by using a CCK8 kit. As shown in FIG. 6, the survival rate of Hela cells is continuously decreased with the increase of X-ray radiation dose, and the cell survival rate of NM/DOC nano-micelle incubated at the same time is lower under the same X-ray radiation dose, which indicates that NM/DOC nano-micelle can cooperate with the radiation effect of X-ray to enhance the killing of tumor cells after the release of drug by stimulation.
2.2 NM/DOC nanomicelle capable of actively targeting tumor by folic acid
In the research, an animal model is firstly established, and for the convenience of in vivo tracking, ICG is embedded in FA-PEG-PCL instead of DOC to prepare NM/ICG nano-micelles (the same as the NM/DOC preparation steps). Tail vein injecting ICG or NM/ICG nano micelle, and monitoring the distribution of the medicine in vivo by using a small animal living body imaging system. As shown in figure 7, the drug was mainly distributed in the liver after ICG1 h injection in mice, and was essentially cleared by the body metabolism after 24h, while for NM/ICG nanomicelle injection mice, the drug was effectively enriched in the tumor site, and the fluorescence intensity in the tumor was increased with time, and reached the maximum after 48h, and the strong ICG fluorescence remained in the tumor after 72 h. The results show that the micromolecule drug is easy to be metabolized and eliminated by organisms, and the drug entrapped in the nanometer micelle has the function of folic acid targeting and can be efficiently enriched on tumor parts.
2.3 NM/DOC nano micelle can effectively cooperate with X-ray radiotherapy, and the radiotherapy can specifically trigger the chemotherapy effect at the same time, thereby enhancing the inhibition effect on tumors
The tumor body is about 150mm in the research3The tumor-bearing mice were randomly divided into four groups: (1) a PBS group; (2) PBS + X-ray group; (3) NM/DOC group; (4) NM/DOC + X-ray group. The DOC injection dose is 5mg/kg, the X-ray irradiation dose is 8Gy, and the size change condition and the survival period of the mouse tumor are measured and counted in the treatment process. As shown in FIG. 8, the injection of NM/DOC alone did not effectively stimulate the release of DOX, so that NM/DOC group had no significant anti-tumor effect, as compared with PBS group, while PBS + X-ray group had no significant anti-tumor effect due to X-rayThe radiotherapy effect of the radiation inhibits the rapid growth of the tumor to a certain extent. The growth rate of the mouse tumor in NM/DOC + X-ray group is the slowest, which proves that the tumor inhibition effect of X-ray radiotherapy and NM/DOC specific chemotherapy is the most obvious. From the survival of each group of mice (as shown in FIG. 9), the mice in NM/DOC + X-ray group still had 80% survival rate after 47 days of treatment, which also demonstrates that the combination of X-ray radiotherapy in combination with NM/DOC-specific chemotherapy is most effective and can greatly prolong the survival of the mice.
In conclusion, the targeted delivery and the responsive release of the drug by means of the nano-carrier are an effective strategy for improving the bioavailability and the specificity of the drug. Folic acid is a commonly used targeted modification molecule in the nano field, and can be combined with a folate receptor highly expressed on the surface of a tumor cell to realize targeted transportation of a drug. The light is a common external stimulus source of the responsive nano-carrier, has strong controllability, can effectively trigger the release of the embedded drugs in the carrier, but has limited penetration depth of the light and can not reach the focus deep in the tissue. X-rays are not limited by the depth of penetration and are associated with the generation of cerenkov radiation during radiation therapy. Therefore, the Cerenkov radiation generated by the X-ray is utilized to stimulate the nano-carrier to release the drug, so that the problem of limited light penetration depth can be overcome, and in addition, the radiotherapy effect of the X-ray can be cooperated to enhance the inhibition effect on tumor cells. Based on the method, the nano micelle NM/DOC is prepared by coupling a photosensitive group nitrobenzyl with a hexadecyl DOX derivative (with enhanced hydrophobicity) and embedding the derivative in an amphiphilic polymer (FA-PEG-PCL) modified by folic acid. NM/DOC can target tumor cells by folic acid, and further in the process of X-ray local radiotherapy, the generated Cherenkov radiation breaks nitrobenzyl, so that the hydrophilicity of DOX is increased, the drug release is triggered, the chemoradiotherapy is organically integrated, the specificity of the effect of the chemoradiotherapy is enhanced by the active targeting and the response drug release of NM/DOC, and the toxic and side effects on organisms are greatly reduced.
The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (10)
1. The bispecific nano-micelle is characterized in that the bispecific nano-micelle takes folic acid modified amphiphilic block polymer FA-PEG-PCL as a nano-carrier, carries DOC capable of responding to Cherenkov radiation in a self-assembly manner, and obtains nano-micelle NM/DOC.
2. The bispecific nanomicelle based on folate targeting and Cerenkov radiation response according to claim 1, characterized in that it has regular morphology, average particle size of about 181nm and uniform particle distribution.
3. A preparation method of bispecific nano-micelle based on folic acid targeting and Cerenkov radiation response is characterized by comprising the following steps:
1) dissolving DOC in dimethyl sulfoxide;
2) dissolving an amphiphilic block polymer FA-PEG-PCL solution in tetrahydrofuran;
3) uniformly stirring and mixing the two solutions, dropwise adding the two solutions into continuously stirred ultrapure water, and fully stirring until tetrahydrofuran in a mixed solution system is volatilized to obtain a mixed solution;
4) filtering the mixed solution by using an ultrafiltration membrane, and performing ultrafiltration washing to prepare the bispecific nano micelle NM/DOC.
4. The preparation method of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 3, wherein in step 1), the ratio of DOC to dimethyl sulfoxide is 1 mg: (200-500) mu L.
5. The preparation method of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 3, wherein in step 2), the feed-to-liquid ratio of the amphiphilic block polymer FA-PEG-PCL to tetrahydrofuran is 10 mg: (1-2) mL.
6. The preparation method of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 3, wherein in the step 3), the dosage ratio of the added ultrapure water to the DOC is (10-15) mL: 1 mg.
7. The preparation method of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 3, wherein in step 3), a magnetic stirrer is adopted for sufficient stirring, and the rotation speed is 2000-8000 rpm/min.
8. The preparation method of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 3, wherein in the step 4), the ultrafiltration membrane adopts an ultrafiltration membrane with a filter head of 0.45 μm; the ultrafiltration washing is carried out for three times by adopting an ultrafiltration membrane with the molecular weight cutoff of 10000.
9. The use of the bispecific nanomicelle based on folate targeting and Cerenkov radiation response of claim 1 or 2 as a drug loading agent for anti-tumor drugs.
10. The use of the bispecific nanomicelle based on folate targeting and chencov radiation response of claim 1 or 2 as a potentiator for an anti-tumor drug.
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