title: Enhanced tumor accumulation and cellular uptake of liposomes modified with ether-bond linked cholesterol derivatives.
abstract: Novel liposomal formulations based on cholesterol modification had been designed previously by our lab, but we found them with a poor stability and short half-life, especially in blood circulation. The results might be attributed to the hydrolysis of ester linked cholesterol derivatives by esterase in plasma. Thus, in this study, we newly synthesized ether-linked cholesterol derivatives and compared them to other preparations. A comparison with the substrate cholesterol-PEG2000-maleimide showed that ether-linked cholesterol-PEG2000-maleimide could relatively maintain integrity in serum, with only a small mottle emerging on TLC (thin-layer chromatography) plates through the experiment. Then a cell-penetrating peptide TAT was attached to the distal end of CHO-PEG2000 to prepare liposomes and to further evaluate the two cholesterol derivatives. Optimized liposomes (65:35, lipid/cholesterol, molar ratio) composed of 3% CHO-PEG2000 and 3% CHO-PEG2000-TAT showed good stability in 50%FBS (fetal bovine serum). In vitro experiments showed that as incubation time prolonged, ether-linked-TAT LIP showed a 3.67-fold higher uptake amount than ester-linked-TAT LIP. In vivo, ether-linked-TAT LIP accumulated better in tumors and had a 40% higher cellular uptake amount. Altogether, we could conclude that our newly ether-linked cholesterol derivatives possessed better stability especially in blood circulation which led to increased tumor cellular uptake in vitro and in vivo. Our study may offer a better way in cholesterol modification to prepare functionalized liposomes.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, P. R. China.
authors.forename: R
authors.initials: R
authors.lastname: Ran
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.forename: Y J
authors.initials: YJ
authors.lastname: Yin
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.forename: Y Y
authors.initials: YY
authors.lastname: Liu
authors.forename: Z R
authors.initials: ZR
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry*; D004355:Drug Stability; D004563:Electrochemistry; D004987:Ethers / Q000737:chemistry; D015696:Gene Products, tat / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D004987:Ethers; D015696:Gene Products, tat; D008081:Liposomes; D011092:Polyethylene Glycols; D002784:Cholesterol