title: Accelerated Blood Clearance Phenomenon Reduces the Passive Targeting of PEGylated Nanoparticles in Peripheral Arterial Disease.
abstract: Peripheral arterial disease (PAD) is a leading global health concern. Due to limited imaging and therapeutic options, PAD and other ischemia-related diseases may benefit from the use of long circulating nanoparticles as imaging probes and/or drug delivery vehicles. Polyethylene glycol (PEG)-conjugated nanoparticles have shown shortened circulation half-lives in vivo when injected multiple times into a single subject. This phenomenon has become known as the accelerated blood clearance (ABC) effect. The phenomenon is of concern for clinical translation of nanomaterials as it limits the passive accumulation of nanoparticles in many diseases, yet it has not been evaluated using inorganic or organic-inorganic hybrid nanoparticles. Herein, we found that the ABC phenomenon was induced by reinjection of PEGylated long circulating organic-inorganic hybrid nanoparticles, which significantly reduced the passive targeting of (64)Cu-labeled PEGylated reduced graphene oxide-iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) in a murine model of PAD. Positron emission tomography (PET) imaging was performed at 3, 10, and 17 days postsurgical induction of hindlimb ischemia. At day 3 postsurgery, the nanoparticles displayed a long circulation half-life with enhanced accumulation in the ischemic hindlimb. At days 10 and 17 postsurgery, reinjected mice displayed a short circulation half-life and lower accumulation of the nanoparticles in the ischemic hindlimb, in comparison to the naïve group. Also, reinjected mice showed significantly higher liver uptake than the naïve group, indicating that the nanoparticles experienced higher sequestration by the liver in the reinjected group. Furthermore, photoacoustic (PA) imaging and Prussian blue staining confirmed the enhanced accumulation of the nanoparticles in the liver tissue of reinjected mice. These findings validate the ABC phenomenon using long circulating organic-inorganic hybrid nanoparticles upon multiple administrations to the same animal, which may provide valuable insight into the future clinical applications of nanoparticles for imaging and treatment of PAD.
authors.affiliation: Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.|Department of Molecular Medicine and Biopharmaceutical Sciences, Department of Nuclear Medicine, Seoul National University , Seoul 110-744, Korea.
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Im
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: England
authors.affiliation: Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices Laboratory, Soochow University Suzhou , Jiangsu 215123, China.
authors.forename: Liangzhu
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Graves
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Reinier
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nickles
authors.affiliation: Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices Laboratory, Soochow University Suzhou , Jiangsu 215123, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Department of Nuclear Medicine, Seoul National University , Seoul 110-744, Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Steve Y
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.|Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.|University of Wisconsin Carbone Cancer Center , Madison, Wisconsin 53705, United States.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D003301:Copper Radioisotopes / Q000097:blood / Q000737:chemistry; D005260:Female; D005290:Ferric Compounds / Q000097:blood / Q000737:chemistry; D006108:Graphite / Q000097:blood / Q000737:chemistry; D006614:Hindlimb / Q000098:blood supply; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D010087:Oxides / Q000097:blood / Q000737:chemistry; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000000981:diagnostic imaging; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography
chemical_list: D003301:Copper Radioisotopes; D005290:Ferric Compounds; D010087:Oxides; C000499:ferric oxide; D011092:Polyethylene Glycols; D006108:Graphite
keywords: accelerated blood clearance (ABC); anti-PEG antibody; hindlimb ischemia; iron oxide nanoparticle (IONP); peripheral arterial disease; photoacoustic imaging; positron emission tomography (PET); reduced graphene oxide (RGO)