Method for preparing camptothecin prodrug double drug-loaded supramolecular hydrogel for drug combination
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A supramolecular hydrogel, combined drug technology, applied in the field of biomedicine, can solve problems such as difficulty in achieving targeted drug release
Inactive Publication Date: 2018-02-23
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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However, this type of hydrogel lacks the phased release mechanism of the two drugs in time and space, and it is also d
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Embodiment 1
[0056] Embodiment 1: the preparation of camptothecin prodrug
[0057] (1) Synthesis of mPEG-COOH: In a 50 mL round bottom flask, weigh mPEG (10.0 g, 5 mmol, Mw=1900) and succinic anhydride (1.0 g, 10 mmol), add 25 mL of anhydrous dichloromethane , stirred to dissolve, then slowly added pyridine (0.8 mL, 10 mmol) dropwise, after the dropwise addition, refluxed for 3 days under the protection of nitrogen. The reaction solution was concentrated under reduced pressure and recrystallized to obtain mPEG-COOH (8.9 g, yield: 88%).
[0058] (2) Preparation of reductively responsive camptothecin prodrug monomer CPT-SS: After adding CPT (2 g, 5.74 mmol) into a 150 mL round bottom flask, add 75 mL of dichloromethane and stir until cloudy, then add DMAP (2.11g, 17.3 mmol), added triphosgene (0.567 g, 1.92 mmol) after ice bath for 5 min, stirred in ice bath for 2 h, then added dropwise to the above reaction solution containing bis(2-hydroxyethyl) disulfide ( 90%) in tetrahydrofuran (1.77 ...
Embodiment 2
[0061] Example 2, preparation of camptothecin prodrug supramolecular hydrogel loaded with 5-fluorouracil
[0062] Dissolve CPT-S-S-mPEG (20 mg, 8 µmol) in 1 ml of water to form a uniform aqueous solution; take water-soluble anticancer drug 5-FU (5 mg, 38 µmol) and add it to the aqueous solution of CPT-S-S-mPEG, Ultrasonic dissolution at room temperature; take α-CD (100 mg, 0.1 mmol), add it to the mixed aqueous solution of CPT-S-S-mPEG and 5-FU, ultrasonically disperse at room temperature for 5 min, and let it stand for 1 min to form a supramolecular hydrogel. The pH value of the hydrogel is 6~8.
Embodiment 3
[0063] Example 3, preparation of camptothecin prodrug supramolecular hydrogel loaded with cisplatin
[0064] Dissolve CPT-S-S-mPEG (20 mg, 8 µmol) in 1 ml of water to form a uniform aqueous solution; take water-soluble anticancer drug cisplatin (3 mg, 10 µmol) and add it to the aqueous solution of CPT-S-S-mPEG, Ultrasonic dissolution at room temperature, take α-CD (100 mg, 0.1 mmol), add it to the mixed aqueous solution of CPT-S-S-mPEG and cisplatin, ultrasonically disperse at room temperature for 5 min, and let it stand for 30 min to form a supramolecular hydrogel. The pH value of the hydrogel is 6-8.
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Abstract
The invention discloses a method for preparing camptothecin prodrug supramolecular hydrogel for drug combination. The method comprises adding alpha-CD and a water-soluble anticancer drug into an aqueous solution of a camptothecin prodrug to obtain a mixed solution, carrying out ultrasonic dispersion, and then carrying out standing so that the mixed solution undergoes self-assembly crosslinking through camptothecin prodrug hydrophobic polymerization and alpha-CD-PEG chain-based subject-object action to form supramolecular hydrogel. Through different loading methods of two drugs and reducing substances inside and outside tumor cells, two drugs with different hydrophobicity and anti-cancer mechanisms can be loaded, can be released at different time points in different zones in multiple stagesto be used in anti-tumor combined drug, and can realize coordinated treatment with drugs and inhibit tumors. The supramolecular hydrogel can be degraded, has good biocompatibility, is injectable, canbe implanted into a lesion site by injection, prevents the pain and tediousness of the surgical implantation and is favorable for damaged site irregular filling.
Description
technical field [0001] The invention relates to a method for combined administration of camptothecin prodrugs, in particular to the preparation of a camptothecin prodrug-loaded dual-drug supramolecular hydrogel, which belongs to the technical field of biomedicine. Background technique [0002] Cancer is a multifactorial disease, and the treatment effect of a single drug is not obvious. Therefore, multi-drug combination therapy with different mechanisms of action has gradually received attention. Combination drug therapy aims to improve the efficacy and reduce toxicity by controlling the dosage and administration sequence of different drugs and utilizing the synergistic effect between drugs. Combination drug strategy has become the first choice for clinical tumor treatment, and has achieved good therapeutic effect. However, problems such as poor water solubility, low tumor selectivity, and large toxic and side effects of individual anticancer drugs still exist in combinatio...
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