CN116617158B - Temozolomide pre-hydrogel and application thereof - Google Patents
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Abstract
本发明提供了一种替莫唑胺前药水凝胶及其应用，所述替莫唑胺前药水凝胶是甲基丙烯酸2‑羟乙酯或丙烯酸2‑羟乙酯与抗癌药物替莫唑胺（Temozolomide，TMZ）通过共价酰胺键进行生物偶联而形成的，并通过光敏法与甲基丙烯酰胺类或丙烯酰胺类化合物交联而构建成为一种新型替莫唑胺前药水凝胶。所述前药水凝胶注射到胶质瘤术后切除腔中，在光照条件下凝胶化，在术后胶质瘤微环境下可生物降解，原位持续释放药物，提高了替莫唑胺在胶质瘤处的药物浓度，有效地抑制了残余胶质瘤的生长，降低了胶质瘤术后复发的风险。具备临床应用性和现实的治疗意义。
The present invention provides a temozolomide prodrug hydrogel and its application. The temozolomide prodrug hydrogel is formed by biocoupling 2-hydroxyethyl methacrylate or 2-hydroxyethyl acrylate with the anticancer drug temozolomide (TMZ) through a covalent amide bond, and is cross-linked with methacrylamide or acrylamide compounds by a photosensitization method to form a novel temozolomide prodrug hydrogel. The prodrug hydrogel is injected into the postoperative resection cavity of a glioma, gelled under light conditions, biodegradable under the postoperative glioma microenvironment, and continuously releases drugs in situ, thereby increasing the drug concentration of temozolomide at the glioma, effectively inhibiting the growth of residual gliomas, and reducing the risk of postoperative recurrence of gliomas. It has clinical applicability and practical therapeutic significance.
Description
Technical Field
The invention relates to temozolomide pre-hydrogel and application thereof, belonging to the field of tumor drug preparation.
Background
Among the most common intracranial primary malignancies, glioblastoma (Glioblastoma multiform, GBM) is undoubtedly the most prominent, and current studies indicate that it accounts for 45-50% of all intracranial tumors, with high invasiveness and mortality. According to the grading of WHO central nervous system tumors, GBM is a grade IV astrocytoma, originating from astrocytes or supportive brain tissue, a solid tumor consisting of rapidly proliferating non-glial cells, characterized by high wettability, intratumoral and intertumor heterogeneity, resistance to chemotherapy and poor prognosis, even after multiple surgeries and treatments. Clinically, signs and symptoms of GBM are often caused by infiltration or compression of the normal brain by tumors, oedema, hemorrhage, or elevated intracranial pressure, including headaches, seizures, focal neurological deficit, and mental state changes. GBM was found by research to be largely divided into two types, IDH-wild type, approximately 90% of which usually occur in an acute manner without early low grade pathology or symptoms, and IDH-mutant, 10% of which originate from the progressive evolution and transformation of low grade astrocytomas, usually affecting young patients. The average survival time of the glioma patients is about 14.6 months, and the average survival rate of 5 years is lower than 35 percent. Post-operative treatment is often necessary to prevent recurrence of gliomas. However, because the invasiveness of glioma and the edge of tumor are not clear, the tumor tissue can not be completely removed by adopting local surgical excision, so that the combination of radiotherapy and chemotherapy after the maximum surgical excision of tumor is the first choice for treating the malignant tumor. For GBM patients, clinical treatment is typically performed using standard treatment protocols, including surgical treatment, adjuvant radiation therapy, and chemotherapy drugs.
In recent years, with the continuous progress of a series of diagnostic techniques, surgical and non-surgical therapeutic techniques, the clinical therapeutic level for glioblastoma has been gradually increased. However, although some good progress has been made so far, the overall survival of glioblastoma patients is still short, with nearly 90% of patients relapsing in two years at the resected edges or other areas of the brain, and in most cases leading to patient death. Currently, in many clinical practice treatments, the clinical endpoint of GBM patients is only to control disease progression and extend the life span of the patient to the greatest extent, and to improve the quality of life at the end of disease progression, as against the reality that malignant gliomas remain incurable. For glioblastoma multiforme as well as anaplastic astrocytomas, temozolomide (Temozolomide, TMZ) is a relatively widely used and effective chemotherapeutic among the chemotherapeutic drugs currently in clinical use. The effect of tumor treatment in temozolomide is mainly achieved and completed by 5- (3-methyltriazin-1-yl) imidazole-4-carboxamide (5- (3-methyltriazene-1-yl) imidazole-4-formamide, MTIC), a product in metabolic processes with tumor cytotoxicity, which can methylate glioma DNA, resulting in destruction of DNA and death of cells. When temozolomide is taken by a patient into the body, it can undergo a hydrolysis process under in vivo conditions, MTIC as a product of preliminary hydrolysis, followed by further hydrolysis reaction to form 5-aminoimidazole-4-carboxamide (5-aminoimidazole-4-formamide, AIC) and methylhydrazine. In cell proliferation, AIC is a raw material for synthesizing biological genetic material such as purine and nucleic acid, and the latter is an alkylating active substance capable of damaging biological genetic information such as DNA. In molecular mechanism, the loss of activity of O6-methylguanine-deoxyribonucleic acid alkyl transferase results in insufficient amount of raw material deoxyribonucleic acid, double strand break and cell cycle arrest of the DNA in G2/M phase, and finally apoptosis. It has also been found that O6-methylguanine, after being damaged, can preferentially pair with thymine, resulting in an unreasonable mismatch. When such a base mismatch occurs, it stimulates the repair system that produces the pyrimidine to continue to mismatch, while the purine that undergoes methylation does not undergo significant quantitative changes. After repeated ineffective or abnormal repair is continuously carried out, replication load can be generated, and when the pressure exceeds the bearing capacity of cells in organisms, double strand break of deoxyribonucleic acid can be finally caused, so that cell tissues are damaged and even dead. Temozolomide can be rapidly absorbed in vivo, and the average time to reach peak concentration is 1-2 h when under fasted conditions. The bioavailability of temozolomide is 100%, the ratio of cerebrospinal fluid to plasma is 0.3:1, and the average elimination half-life of glioma patients is 1.8h. TMZ is one of the currently effective chemotherapeutics for the treatment of gliomas, as it is able to cross the blood brain barrier in humans. However, TMZ has only been found to have about 45% of its therapeutic effects on glioblastomas during clinical treatment, and a significant portion of gliomas develop resistance to TMZ during treatment. Drug resistance and subsequent recurrence of malignant tumors during chemotherapy have become urgent problems in glioma treatment.
Disclosure of Invention
In order to reduce the risk of postoperative recurrence of glioma, the invention provides temozolomide pre-hydrogel which can be injected in situ at the postoperative tumor cavity part, and can effectively inhibit the growth of residual tumor after glioma operation through the self degradation and release of hydrogel. The in-situ injection administration mode can avoid side effects generated by systemic administration and toxic and side effects of temozolomide on systemic organs, improves the local concentration of the medicine in a brain glioma cavity, and timely and effectively improves the effect of treating the brain glioma, thereby realizing effective treatment after the brain glioma operation.
The invention is realized by the following technical scheme: a temozolomide pre-hydrogel comprising: temozolomide prodrugs and methacrylamides, acrylamide compound hydrogels;
the temozolomide prodrug, the methacrylamide and the acrylamide compound hydrogel are crosslinked by a photosensitive method to form;
The temozolomide prodrug is methacrylate-temozolomide or acrylate-temozolomide formed by biological coupling of methacrylic acid-2-hydroxyethyl or acrylic acid-2-hydroxyethyl and anticancer drug temozolomide through covalent amide bond.
As a preferable scheme of temozolomide pre-hydrogel, the invention comprises the following steps: the preparation method of the methacrylate-temozolomide comprises the following steps:
step 1), preparation of Carboxylic acid-TMZ
Firstly, 2.29g of 11.8mmol of TMZ is dissolved in 23.6mL of 98% concentrated sulfuric acid in a round-bottomed flask equipped with a magnetic stirrer and an addition funnel to obtain a yellow solution, the yellow solution is cooled to 0 ℃ under nitrogen, 23.6mL of aqueous sodium nitrite solution is gradually dropwise added into the yellow solution in 45min until brown gas is observed in the adding process, ice bath is stopped, and the reaction solution is naturally warmed to room temperature under the condition of avoiding light; after stirring for 17h, the mixture was cooled to 0 ℃ again, and the temperature was rapidly reduced using ice; maintaining at 0deg.C, stirring the mixture until a fine white solid precipitate is obtained; separating by vacuum filtration with 3-6 times of cold water washing, and finally drying under vacuum to obtain the compound with 75% yield, namely carboxylic acid-TMZ;
step 2), preparation of methacrylate-temozolomide
In a round bottom flask equipped with a magnetic stirrer 592.5mg of carboxylic acid-TMZ was dissolved in 20ml of dichloromethane to form a suspension; to the suspension was added 2.91mmol of poly (hydroxyethyl methacrylate) and 0.29mmol of catalyst 4-dimethylaminopyridine, followed by 3.51mmol of 1-ethylcarbonyldiimmonium hydrochloride to form a homogeneous red mixture; after stirring under nitrogen at room temperature for 14h, the red mixture is filtered, the filtrate is diluted with 30ml of dichloromethane and washed with 0.1M hydrochloric acid solution according to 5X 50 ml; the filtrate was then dried over sodium sulfate and concentrated by rotary evaporation to form a white solid; drying in the dark under high vacuum, finally obtaining the compound with 71% yield, namely methacrylate-temozolomide (abbreviated as methacrylate-TMZ);
step 3), preparation of temozolomide pre-hydrogel
Preparing temozolomide pre-hydrogel by adopting a photosensitive method;
Firstly, fully dissolving the synthesized methacrylate-TMZ in pure water; dissolving the methacrylamide compound in water, fully oscillating and uniformly mixing the mixture, and uniformly heating the mixture in a constant-temperature water bath at 60 ℃ for 2 to 5 minutes until the mixture is changed into transparent clear liquid; weighing the photoinitiator (w/w) in a proportion of 1-3%, and adding the photoinitiator into the photophobic transparent liquid; and (3) placing the mixture under an ultraviolet lamp to irradiate for 10-15 s to obtain temozolomide pre-hydrogel.
As a preferable scheme of temozolomide pre-hydrogel, the invention comprises the following steps: the carboxylic acid-TMZ has the following structural formula;
As a preferable scheme of temozolomide pre-hydrogel, the invention comprises the following steps: the structural formula of the methacrylate-temozolomide is as follows;
As a preferable scheme of temozolomide pre-hydrogel, the invention comprises the following steps: the compound of the methacrylamide or the acrylamide is polyethylene glycol dimethacrylate, methacrylamide chitosan, methacrylamide hyaluronic acid, methacrylamide gelatin, ethylene glycol diacrylate, acrylamide chitosan, acrylamide hyaluronic acid or acrylamide gelatin.
As a preferable scheme of temozolomide pre-hydrogel, the invention comprises the following steps: the TMZ is temozolomide.
The hydrogel concentration in the above was 100mg/ml, and the methacrylate-TMZ was 4mg/ml.
The temozolomide pre-hydrogel is applied to the medicine injected into the excision cavity after glioma operation
Drawings
FIG. 1 shows a schematic diagram of the methacrylate-TMZ structure and the nuclear magnetic resonance test results;
FIG. 2 (A) hydrogel in bottle, (B) hydrogel in disk, (C) morphology before and after gel formation;
FIG. 3 rheological measurements of Gel/proTMZ hydrogels;
FIG. 4 is a scanning electron microscope image of Gel/proTMZ hydrogel;
FIG. 5 swelling curves of two sets of hydrogels in different solutions;
FIG. 6 in vitro degradation curves for various sets of hydrogels;
the in vitro simulated drug release profile of the hydrogel of fig. 7;
FIG. 8 cytotoxicity detection of hydrogel in vitro degradation solution;
FIG. 9 (A) shows the in vivo fluorescence results of each set of hydrogels after surgery, and FIG. 9 (B) shows the in vivo fluorescence intensity versus time.
The invention has the beneficial technical effects that: the hydrogel is injected into a glioma postoperative resection cavity, is gelled under the illumination condition, can be biodegraded under the postoperative glioma microenvironment, releases medicines in situ continuously, improves the medicine concentration of temozolomide at glioma, effectively inhibits the growth of residual glioma, reduces the risk of glioma postoperative recurrence, and has clinical applicability and practical therapeutic significance.
Detailed Description
The technical scheme of the invention is further described by specific examples.
TMZ (2.29 g,11.8 mmol) was first dissolved in concentrated sulfuric acid (23.6 ml) in a round bottom flask equipped with a magnetic stirrer and addition funnel to give a yellow solution which was cooled to 0 ℃ under nitrogen. Sodium nitrite (2.51 g,36.4 mmol) was gradually added dropwise over 45min in aqueous solution (23.6 ml) until brown gas formation was observed during the addition. The mixture was allowed to warm to room temperature while keeping out light. After stirring for 17h, the mixture was cooled to 0℃again and the temperature was rapidly reduced using ice (61 g). The mixture was kept at 0 ℃ and stirring was continued until a fine white solid precipitate was obtained. Isolation by vacuum filtration, with multiple cold water washes, and final drying under vacuum, gave the compound, i.e., carboxylic acid-TMZ, in 75% yield.
In a round bottom flask equipped with a magnetic stirrer, the product carboxylic acid-TMZ from the first step (592.5 mg,3.05 ml) was added to DCM (20 ml) to form a suspension. HEMA (353. Mu.l, 2.91 mmol) and catalytic DMAP (36.0 mg,0.29 mmol) were added to the suspension, followed by EDC (674 mg,3.51 mmol) to form a homogeneous red mixture. After stirring for 14h under nitrogen at room temperature, the mixture was filtered, and the filtrate was diluted with DCM (30 ml) and washed with 0.1M hydrochloric acid solution (5X 50 ml). After this time, it was dried over sodium sulfate and concentrated by rotary evaporation to form a white solid. Drying under high vacuum in the absence of light finally gives the compound, methacrylate-TMZ (see FIG. 1 for details) in 71% yield.
The methacrylate-TMZ thus synthesized was sufficiently dissolved in pure water. Next, the gelatin methacrylamide hydrogel was dissolved in water, the mixture was thoroughly mixed with shaking, and placed in a thermostatic water bath and heated uniformly for 2 to 5min (60 ℃) until a clear supernatant was obtained. Weighing the photoinitiator according to the proportion of 1% -3%, and adding the photoinitiator into the light-shielding transparent liquid. The Gel/proTMZ hydrogel (see figure 2 for details) which is chemically crosslinked can be obtained by irradiation under an ultraviolet lamp for 10-15 s, the concentration of the hydrogel is 100mg/ml, and the methacrylate-TMZ is 4mg/ml. Other sets of hydrogels, gel+DiR and Gel/ProTMZ +DiR were prepared in the same manner as described above, with DiR concentrations of 100g/ml.
TMZ in the above is temozolomide for short.
The rheological properties of the gels of the invention were tested. The Discovery HR-2 type rotational rheometer requires selection of the "test for oscillation" mode. The frequency sweep was in the range of 0.02 to 100rad/s, the strain was 5% under controlled conditions, the temperature was 37 ℃, and the storage modulus (G '), loss modulus (G') and angular frequency (ω) of the samples were measured (see FIG. 3 for details).
After the hydrogel sample preparation was completed, it was observed with a Scanning Electron Microscope (SEM) for analysis of its microstructure. The specific operations of the sample include: and placing a small amount of the prepared hydrogel sample into a sample platform hole, and carrying out sample transmission and treatment. The device is accompanied by liquid nitrogen, and the temperature inside can be quickly reduced to-210 ℃ and maintained for a period of time. The sample transfer rod within the device is then operated to automatically transfer it into the preparation chamber. The temperature of the interior was then adjusted to 90℃and maintained for 180 seconds, and after completion, the sample was subjected to platinum metal spraying treatment on the surface thereof for about 50 seconds. Finally, the sample is taken out, placed into an electron microscope operating room for observation and photographing, and the data are recorded and analyzed (see fig. 4 for details).
The swelling properties of the hydrogels of the present invention were measured as follows. The preparation of the hydrogel samples of the different groups was completed in the early stage, and air-drying treatment and weighing were performed to obtain the dry weight (Wd) result of the hydrogels. Subsequently, the sample is soaked into PBS buffer solution and H2O solution with pH of 7.4, and the sample is taken out for weighing measurement according to the fixed time set by experiments, so as to obtain a wet weight result (Ww). All measurements were performed on 3 duplicate samples to reduce errors. The expansion ratio (%) of the hydrogel was calculated as the expansion ratio (%) = [ Ww-Wd ]/[ Wd ] ×100%. The resulting swelling curve is shown in detail in FIG. 5.
The degree of in vitro degradation of the hydrogels of the present invention was measured using the following method. The hydrogels were incubated 2w in 5ml Eppendorf tubes with 2ml PBS, or 2ml PBS with 100ng/ml MMP2 solution at 37℃with an equivalent change of fresh solution every 3d interval to maintain the enzyme activity. At fixed sampling time points, samples were taken from solution, washed twice with sterile deionized water, lyophilized, and finally weighed and repeated 3 times to reduce errors. The degradation calculation formula of the hydrogel is degradation rate (%) = [ W 0-Wt]/[W0 ] ×100%. (wherein W 0 is the original weight and W t is the present weight) (see FIG. 6 for details)
The extent of responsive drug release of the hydrogels of the present invention under conditions simulating the microenvironment in vivo was measured using the following method. 200mg of each hydrogel was taken sequentially, the first set was placed in a 15ml EP centrifuge tube containing 10ml of PBS solution, the second set was added MMP2 in addition to the conditions described above, and the cerebrospinal fluid set was added in the experiment.
30 Cases of cerebrospinal fluid of the brain glioblast patients treated by the operation are counted and collected for treatment by neurosurgery in our hospital. Centrifuging at 2000rpm for 5min, collecting supernatant, and storing in a refrigerator at-20deg.C. In this section of the experiment 5ml of CSF was added to a centrifuge tube containing 200. Mu.l of hydrogel, 2ml was added every 3d to maintain an effective active concentration. The study content of this section has obtained informed consent from the patient and family members and signed the informed consent.
During the course of the experiment, an equivalent amount of MMP2 was added once at the 4 th, 8 th, 12d in the experiment. All EP centrifuge tubes in the experiment were placed in an incubator at 37℃and subjected to constant speed shaking at a speed of 70 rpm. According to the experimental plan, equal amounts of samples are respectively taken at 6h, 12h, 1d, 2d, 3d, 4d, 5d, 7d, 9d, 10d, 11d, 12d, 13d and 14d, 100 μl of supernatant is taken each time, 100 μl of PBS solution is continuously added, and the mixture is returned to a constant temperature oven at 37deg.C for continuous uniform shaking. Samples collected at each time point in the experiment were stored in a refrigerator at 4 ℃ for later use. And after all experimental samples are collected, carrying out HPLC liquid extraction measurement uniformly. And according to the detected concentration values at different time points, obtaining the drug release quantity, and drawing a drug release curve after counting data (see figure 7 for details).
Cytotoxicity of the hydrogels of the present invention was measured using the following method. The in vitro degradation liquid of the hydrogel is co-cultured with research cells, the effect of the in vitro degradation liquid on the cell activity is observed, and the MTT method is adopted for detection and analysis, and the steps are as follows:
(1) Selecting 96-well plates, adding about 5×10 3 GL261 or C6 cells into each hollow hole, and placing in an incubator for culturing for 1d;
(2) Sequentially adding the hydrogel in-vitro degradation solutions of 1,2, 3, 4, 5, 6 and 7d into the DMEM culture solution so as to detect cytotoxicity;
(3) After co-culturing for 1d, sucking redundant culture solution by a pipetting gun for further detection;
(4) Taking 2 mu L of prepared MTT solution, adding the MTT solution into each hole, horizontally placing the MTT solution in the plane of an incubator, and culturing for 3-4 hours;
(5) When the detection time was reached, the culture solution in each well was aspirated using a pipette, followed by adding 150. Mu.l of DMSO to each well, while gently shaking the whole well plate for 1200-1800 s, so that the solutions were well mixed. The measurement was performed in a spectrophotometer, and the condition for detecting the OD value was set to a wavelength of 570 nm. The cell viability calculation formula is as follows: [ OD (sample) -OD (a blank) ]/[ OD (control) -OD (b blank) ]. Times.100%. The above conclusion was repeated three times, the data was recorded, and the conclusion was reached after statistics (see fig. 8 for details).
The degree of degradation of the hydrogels of the present invention in vivo was measured as follows. Designing and constructing a C57BL/6 male black mouse GL261 glioblast model and an operation model, wherein the experiment is divided into two groups, namely, a control group is injected into a tumor cavity by adopting 10 mu lGel +DiR hydrogel (n=3); whereas the experimental group was injected into the tumor cavity with 10 μl Gel/proTMZ +dir hydrogel (n=3). The IVIS dynamic imaging system is adopted to measure the fluorescence signals of C57BL/6 male black mice of the 0 th, 5 th, 10 th, 15 th and 20 th days respectively, the experimental results are recorded, and after statistical data, in-vivo hydrogel degradation curves are drawn (see figure 9 for details).
Claims (5)
1. A temozolomide pre-hydrogel, which is characterized in that: comprising the following steps: temozolomide prodrugs and methacrylamide hydrogels;
The temozolomide prodrug and the methacrylamide compound form hydrogel through photo-crosslinking;
The temozolomide prodrug is methacrylate-temozolomide or acrylate-temozolomide formed by coupling methacrylic acid-2-hydroxyethyl or acrylic acid-2-hydroxyethyl with anticancer drug temozolomide TMZ through covalent amide bond;
The methacrylamide compound is methacrylamidoglycolate.
2. A temozolomide pre-hydrogel according to claim 1, wherein:
the preparation method of the methacrylate-temozolomide comprises the following steps:
step 1), preparation of Carboxylic acid-TMZ
Firstly, 2.29g of 11.8mmol of TMZ is dissolved in 23.6mL of 98% concentrated sulfuric acid in a round-bottom flask equipped with a magnetic stirrer and an addition funnel to obtain a yellow solution, the yellow solution is cooled to 0 ℃ under nitrogen, 23.6mL of aqueous sodium nitrite solution is gradually dropwise added to the yellow solution in 45min until brown gas is observed in the adding process, an ice bath is stopped, and the reaction solution is naturally warmed to room temperature under a dark condition; after stirring for 17h, the mixture was cooled to 0 ℃ again, and the temperature was rapidly reduced using ice; maintaining at 0deg.C, stirring the mixture until a fine white solid precipitate is obtained; separating by vacuum filtration with 3-6 times of cold water washing, and finally drying under vacuum to obtain the compound with 75% yield, namely carboxylic acid-TMZ;
step 2), preparation of methacrylate-temozolomide
In a round bottom flask equipped with a magnetic stirrer 592.5mg of carboxylic acid-TMZ was dissolved in 20ml of dichloromethane to form a suspension; to the suspension was added 2.91mmol of 2-hydroxyethyl methacrylate and 0.29mmol of the catalyst 4-dimethylaminopyridine, followed by 3.51mmol of 1-ethylcarbonyldiimmonium hydrochloride to form a homogeneous red mixture; after stirring under nitrogen at room temperature for 14h, the red mixture is filtered, the filtrate is diluted with 30ml of dichloromethane and washed with 0.1M hydrochloric acid solution according to 5X 50 ml; the filtrate was then dried over sodium sulfate and concentrated by rotary evaporation to form a white solid; drying in a dark place under high vacuum to finally obtain a compound with 71% yield, namely methacrylate-temozolomide;
the temozolomide pre-hydrogel is prepared by a photo-crosslinking method:
Firstly, fully dissolving the synthesized methacrylate-temozolomide in pure water; dissolving the methacrylamide compound in water, fully oscillating and uniformly mixing the mixture, and uniformly heating the mixture in a constant-temperature water bath at 60 ℃ for 2 to 5 minutes until the mixture is changed into transparent clear liquid; weighing the photoinitiator in a proportion of 1-3% w/w, and adding the photoinitiator into the transparent clear liquid in a dark place; and (3) placing the mixture under an ultraviolet lamp to irradiate for 10-15 s to obtain temozolomide pre-hydrogel.
3. A temozolomide pre-hydrogel according to claim 2, wherein: the carboxylic acid-TMZ has the following structural formula:
。
4. A temozolomide pre-hydrogel according to claim 2, wherein: the structural formula of the methacrylate temozolomide is as follows:
。
5. Use of a temozolomide pre-hydrogel according to any one of claims 1-4 for the preparation of a medicament for injection into a post-glioma resection cavity.
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| CN202310700906.3A CN116617158B (en) | 2023-06-14 | 2023-06-14 | Temozolomide pre-hydrogel and application thereof |
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| CN202310700906.3A CN116617158B (en) | 2023-06-14 | 2023-06-14 | Temozolomide pre-hydrogel and application thereof |
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| CN116617158B true CN116617158B (en) | 2024-08-06 |
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| CN107982217A (en) * | 2017-11-27 | 2018-05-04 | 徐州医科大学 | A kind of tool targeting and radio therapy sensitization dual-use function lipid-polymer, its preparation method and its application for containing hydrophobic drug |
| CN111150850A (en) * | 2020-01-07 | 2020-05-15 | 哈尔滨医科大学 | Nano inhibitor for enhancing sensitivity of glioma temozolomide and preparation method thereof |
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| DE102006007309B4 (en) * | 2005-02-17 | 2012-11-29 | Chemagis Ltd. | Improved process for the preparation of temozolomide |
| EP2509421B1 (en) * | 2009-12-10 | 2020-02-05 | Cedars-Sinai Medical Center | Drug delivery of temozolomide for systemic based treatment of cancer |
| JP6983815B2 (en) * | 2016-05-02 | 2021-12-17 | ダブル ボンド ファーマシューティカル アクチボラグ | A stable antitumor pharmaceutical composition containing temozolomide and a method for preparing the composition. |
| US10562901B2 (en) * | 2016-09-22 | 2020-02-18 | The University Of Massachusetts | Temozolomide compounds, polymers prepared therefrom, and method of treating a disease |
| CN111228218B (en) * | 2020-02-21 | 2021-11-02 | 江苏师范大学 | Temozolomide nanoprodrug micelle and preparation method and application thereof |
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| CN107982217A (en) * | 2017-11-27 | 2018-05-04 | 徐州医科大学 | A kind of tool targeting and radio therapy sensitization dual-use function lipid-polymer, its preparation method and its application for containing hydrophobic drug |
| CN111150850A (en) * | 2020-01-07 | 2020-05-15 | 哈尔滨医科大学 | Nano inhibitor for enhancing sensitivity of glioma temozolomide and preparation method thereof |
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