title: Re-assessing the enhanced permeability and retention effect in peripheral arterial disease using radiolabeled long circulating nanoparticles.
abstract: As peripheral arterial disease (PAD) results in muscle ischemia and neovascularization, it has been claimed that nanoparticles can passively accumulate in ischemic tissues through the enhanced permeability and retention (EPR) effect. At this time, a quantitative evaluation of the passive targeting capabilities of nanoparticles has not been reported in PAD. Using a murine model of hindlimb ischemia, we quantitatively assessed the passive targeting capabilities of (64)Cu-labeled PEGylated reduced graphene oxide - iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) through the EPR effect using positron emission tomography (PET) imaging. Serial laser Doppler imaging was performed to monitor changes in blood perfusion upon surgical induction of ischemia. Nanoparticle accumulation was assessed at 3, 10, and 17 days post-surgery and found to be highest at 3 days post-surgery, with the ischemic hindlimb displaying an accumulation of 14.7 ± 0.5% injected dose per gram (%ID/g). Accumulation of (64)Cu-RGO-IONP-PEG was lowest at 17 days post-surgery, with the ischemic hindlimb displaying only 5.1 ± 0.5%ID/g. Furthermore, nanoparticle accumulation was confirmed by photoacoustic imaging (PA). The combination of PET and serial Doppler imaging showed that nanoparticle accumulation in the ischemic hindlimb negatively correlated with blood perfusion. Thus, we quantitatively confirmed that (64)Cu-RGO-IONP-PEG passively accumulated in ischemic tissue via the EPR effect, which is reduced as the perfusion normalizes. As (64)Cu-RGO-IONP-PEG displayed substantial accumulation in the ischemic tissue, this nanoparticle platform may function as a future theranostic agent, providing both imaging and therapeutic applications.
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison, Madison, WI 53705, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: England
authors.affiliation: Department of Radiology, University of Wisconsin - Madison, WI 53705, USA; Department of Molecular Medicine and Biopharmaceutical Sciences, Department of Nuclear Medicine, Seoul National University, Seoul 110-744, South Korea.
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Im
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 Radiology, University of Wisconsin - Madison, WI 53705, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison, Madison, WI 53705, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Graves
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison, Madison, WI 53705, USA.
authors.forename: Reinier
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: Department of Surgery, University of California-Davis, Sacramento, CA 95817, USA.
authors.forename: Hakan
authors.initials: H
authors.lastname: Orbay
authors.affiliation: Department of Radiology, University of Wisconsin - Madison, WI 53705, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Radiology, University of Wisconsin - Madison, WI 53705, USA.
authors.forename: Steve Y
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison, Madison, WI 53705, USA.
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, South Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Medical Physics, University of Wisconsin - Madison, Madison, WI 53705, USA; Department of Radiology, University of Wisconsin - Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA. Electronic address: wcai@uwhealth.org.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D003301:Copper Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D006108:Graphite / Q000737:chemistry* / Q000493:pharmacokinetics; D006614:Hindlimb / Q000098:blood supply / Q000000981:diagnostic imaging*; D007511:Ischemia / Q000000981:diagnostic imaging*; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000032:analysis / Q000737:chemistry*; D058729:Peripheral Arterial Disease / Q000000981:diagnostic imaging*; D010539:Permeability; D061088:Photoacoustic Techniques; D049268:Positron-Emission Tomography / Q000379:methods
chemical_list: D003301:Copper Radioisotopes; D005290:Ferric Compounds; C000499:ferric oxide; D006108:Graphite
keywords: Enhanced permeability and retention (EPR) effect; Hindlimb ischemia; Iron oxide nanoparticle (IONP); Photoacoustic imaging; Positron emission tomography (PET); Reduced graphene oxide (RGO)