title: Annexin V-Conjugated Mixed Micelles as a Potential Drug Delivery System for Targeted Thrombolysis.
abstract: To alleviate the hemorrhagic side effect of thrombolysis therapy, a thrombus targeted drug delivery system based on the specific affinity of Annexin V to phosphatidylserine exposed on the membrane surface of activated platelet was developed. The amphiphilic and biodegradable biomaterial, polycaprolactone-block-poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-hydroxyethyl methacrylate) (PCL-b-PDMAEMA-b-PHEMA (PCDH)) triblock polymer, was synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) to use as the nanocarriers of thrombolytic drug. In order to conjugate Annexin V to the polymer, PCDH was modified by succinic anhydride via ring-opening reaction to introduce the carboxyl group (PCDH-COOH). After preparation of PCDH/PCDH-COOH (9/1, m/m) mixed micelles, Annexin V was coupled with the micelles using carbodiimide chemistry. The blood clot lysis assay in vitro confirmed that lumbrokinase-loaded targeted micelles (LKTM) had stronger thrombolysis potency than free lumbrokinase (LK) and LK-loaded nontargeted micelles (LKM, P < 0.05). In vivo thrombolytic assay, multispectral, optoacoustic tomography (MSOT) was used to assess the target ability of LKTM. The results of MSOT images indicated the fluorescence intensity of the LKTM group located in the blood clot position were significantly stronger than the LKM group. A 5 mm of carotid artery containing blood clot was cut out 24 h later after administration to assess the degree of thrombolysis. The results of thrombolytic assay in vivo were consistent with the assay in vitro, which the differences between LK, LKM, and LKTM groups were both statistically significant. All the results of thrombolysis assays above proved that the capacity of thrombolysis in the LKTM group was optimal. It suggested that Annexin V-conjugated micelles will be a potential drug delivery system for targeted thrombolysis.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Yang
authors.identifier: 0000-0002-8500-6270
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Ren
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Polymer Science and Engineering, Sichuan University , Chengdu, 610065, China.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , Chengdu, 610041, China.
authors.forename: Zongning
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000737:chemistry*; D001672:Biocompatible Materials / Q000737:chemistry; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D009757:Nylons / Q000737:chemistry; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D058105:Polymerization; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D017304:Annexin A5; D001672:Biocompatible Materials; D008689:Methacrylates; D008823:Micelles; D009757:Nylons; D011091:Polyesters; C407037:poly(2-(dimethylamino)ethyl methacrylate); C016240:polycaprolactone; C005044:hydroxyethyl methacrylate