期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 229, 期 -, 页码 696-712出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2022.12.111
关键词
Dasatinib; Chitosan; Redox-sensitive; Micelles; Inflammation; Macrophages
Dasatinib (DAS) was conjugated to two molecular weights of chitosan (CHIT) using disulfide bond-containing linker to synthesize CHIT-S-S-DAS amphiphilic conjugates. The resulting redox-responsive micelles showed potential for passive targeting and on-demand drug release for DAS delivery to macrophages. In vitro and in vivo studies demonstrated that the optimized redox-responsive micelles were highly efficient in reducing inflammation and had better therapeutic effects compared to non-redox responsive micelles and free DAS.
Dasatinib (DAS) exhibits anti-inflammatory effects by retrieving the balance between inflammatory and anti-inflammatory cytokines secreted by macrophages. The aim of this study was the development of redox-responsive micelles with the potential of passive targeting and on-demand drug release for DAS delivery to macrophages. For this purpose, two molecular weights of chitosan (CHIT) were conjugated to DAS at different molar ratios using 3,3 '-dithiodipropionic anhydride (DTDPA) as disulfide bond containing linker to synthesize a series of CHIT-S-S-DAS amphiphilic conjugates. Micelles obtained by the sonication method had particle sizes of 129.3-172.2 nm, zeta potentials of +17.5 to +20.9 mV, drug contents of 0.90-7.20 %, CMC values of 35.3-96.6 mu g/ml, and exhibited redox-responsive in vitro drug release. Optimized micelles were non-toxic and dramatically more efficient than non-redox responsive micelles in reducing TNF-alpha and IL-6 and increasing IL-10 secretion from LPS-stimulated RAW264.7 cells. Furthermore, the redox-responsive micelles were able to reduce the mice paw edema, reduce the plasma levels of pro-inflammatory cytokines and increase plasma level of IL-10, considerably more than free DAS and non-redox responsive micelles in carrageenan-induced mice paw edema model of inflammation.
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