Preparation method and application of reduction-sensitive drug delivery system with high drug loading rate
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A technology with high drug loading and delivery system, applied in the field of biomedicine and nanomedicine, can solve the problems of low bioavailability, low pharmacokinetics, obvious side effects, etc., and achieves simple preparation process, stable micelles, and encapsulation. Efficient effect
Inactive Publication Date: 2018-02-09
HENAN NORMAL UNIV
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However, because small molecule drugs such as camptothecin have poor water solubility, low pharmacokinetics and small accumulation in blood, low bioavailability and obvious side effects, polymer scientists are looking for biocompatible drugs. and biodegradable polymers improve many shortcomings of small molecule drugs
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Embodiment 1
[0024] Add 0.5g camptothecin (1.44mmol), 0.29g p-nitrophenyl chloroformate and 0.39g DMAP in a 100mL Shrek bottle, and dissolve in 25mL anhydrous CH 2 Cl 2 Under the protection of Ar gas, react at room temperature for 2h, wash with 25mL water 3 times, and use anhydrous MgSO for the organic phase 4 Dry and concentrate under reduced pressure to obtain the crude product of Intermediate 1.
Embodiment 2
[0026] The crude product obtained in Example 1 was dissolved in 25 mL of anhydrous CH 2 Cl 2 Add 92.5mg ethyl disulfide in 2.5mL THF and 7.5mL CH 2 Cl 2 The mixed solution was reacted at room temperature for 48h under the protection of Ar gas, filtered, concentrated, and purified by column chromatography (eluent: CH 3 OH / CH 2 Cl 2 ) Approximately 0.23 g of the target product camptothecin dimer was obtained, and the yield was 35.5%.
[0027] 1 H NMR(600MHz, CDCl 3 )δ8.39(s,1H), 8.18(d,1H), 7.93(d,1H), 7.82(t,1H), 7.66(t, 1H), 5.76(d,1H), 5.41-5.18(m ,1H),5.46-5.14(m,1H),4.00(d,1H),2.81(d,1H),2.23(d,1H), 2.09(d,1H),0.97(t,1H).ESI- MS for C 46 H 38 N 4 O 12 S 2 [M+H + ] And [M+Na + ]calcd: 902.1928, found: 903.2006 and 925.1786.
Embodiment 3
[0029]
[0030] Combine 0.464g mPEG and 0.204g CL2‰Sn(Oct) 2 Put it into the polymerization tube, dry it in a vacuum drying oven at 38°C, seal the tube when the vacuum is 1Pa, place the reaction in an oil bath at 140°C for polymerization, polymerize for 70h, dissolve the reactants in THF, and transfer to MW= After dialysis in a 14000 dialysis bag, the aqueous phase was lyophilized after dialysis with deionized water for 48 hours to obtain the amphiphilic block copolymer mPEG-b-PCL.
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Abstract
The invention discloses a preparation method and application of a reduction-sensitive drug delivery system with a high drug loading rate, belonging to the technical field of biomedicine and nanomedicine. According to a technical scheme in the invention, 2,2-dihydroxyethyl disulfide is bonded with camptothecin via a carbonate bond to construct a camptothecin dimer with reduction sensitivity; and then the camptothecin dimer is encapsulated into an amphiphilic block copolymer polyethylene glycol-polycaprolactone by using a dialysis method so as to prepare the reduction-sensitive drug delivery system with a high drug loading rate, wherein the camptothecin dimer has a structure formula as described in the specification. The invention also specifically discloses application of the reduction-sensitive drug delivery system with a high drug loading rate to preparation of sustained-release and controlled-release drugs with targeted anti-cancer effect. Compared with a camptothecin delivery system, the drug loading rate of the drug delivery system provided by the invention is increased from 1% to 12.6%, and the drug delivery system has reduction sensitivity, good biocompatibility and capacityof inhibiting proliferation of tumor cells.
Description
Technical field [0001] The invention belongs to the technical field of biomedicine and nanomedicine, and specifically relates to a preparation method and application of a reduction-sensitive drug delivery system with high drug loading. Background technique [0002] Camptothecin (CPT) is a plant anti-cancer drug, extracted from Camptotheca acuminata distributed in central and southwestern China. Camptothecin has a good effect on gastrointestinal and head and neck cancer, but it has side effects of hematuria in a few patients. The anti-cancer activity of 10-hydroxycamptothecin is higher than that of camptothecin, and it also has obvious curative effect on liver cancer and head and neck cancer, and has fewer side effects. Camptothecin and its derivatives have been widely used worldwide as anticancer drugs for many years. However, due to the poor water solubility, low pharmacokinetics and small accumulation in blood, low bioavailability and obvious side effects of small molecule dr...
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