Study On Drug Delivery System Targeting Senescence-associated β-galactosidase

Senescence is a state of cell cycle arrest.The abnormal accumulation of senescent cells is associated with cancer and age-related diseases such as idiopathic pulmonary fibrosis(IPF).Elimination of senescent cells has recently emerged as a promising therapeutic approach.However,potential toxicity of senolytics may limit their application in clinical treatment.Based on the increased activity of β-gal in senescent cells,drug delivery system targetingβ-gal was designed to eliminate senescent cells selectively and improve the safety of drugs.Firstly,we synthesized a new water-soluble benzothiazole dye HT-4a,with the advantages of high fluorescence intensity,large Stokes shift and good stability.Probe FR-2a was synthesized by connecting HT-4a with β-gal trigger through a p-hydroxybenzyl quaternary ammonium linker.In the presence of β-gal,HT-4a was released through self-immolative process,resulting in effective fluorescence recovery.FR-2a shows high affinity to β-gal,exhibiting good sensitivity,selectivity and stability for imaging in senescent cells,which provides a powerful tool for selective imaging of senescent cells.Then,TR-8(prodrug of dasatinib)was prepared and complexed with SBE-β-CD.However,TR-8 showed limited selectivity in senescent cells.To improve selectivity,a novel branched linker 3-14 with the advantage of large-scale preparation was prepared.FA-5b-1(prodrug of dasatinib)and FA-7a-1(prodrug of OTX-015)were synthesized by 3-14.To improve the water solubility of FA-7a-1,FA-10 a was obtained by introducing PEG fragment to the branched chain of FA-7a-1.Enzymatic experiments showed that the release process was not affected by branched chain.Further researches are still in progress.