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Published on: March 25, 2020
Poly-β-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals
Yan Zhang1, Fanglin Gong1,2, Yue Wu1,2
1State Key Laboratory of Natural Medicines, Center of Advanced Pharmaceuticals and Biomaterials, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Abstract:
Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. β-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the in vivo application of CD for removing lysosomal CCs. Here, we exploit poly-β-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to self-assemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF-ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann-Pick type C diseases with excessive cholesterol accumulation in the lysosome.
