title: Stimuli-Responsive Biodegradable Hyperbranched Polymer-Gadolinium Conjugates as Efficient and Biocompatible Nanoscale Magnetic Resonance Imaging Contrast Agents.
abstract: The efficacy and biocompatibility of nanoscale magnetic resonance imaging (MRI) contrast agents depend on optimal molecular structures and compositions. Gadolinium [Gd(III)] based dendritic macromolecules with well-defined and tunable nanoscale sizes are excellent candidates as multivalent MRI contrast agents. Here, we propose a novel alternate preparation of biodegradable hyperbranched polymer-gadolinium conjugates via a simple strategy and report potentially efficient and biocompatible nanoscale MRI contrast agents for cancer diagnosis. The enzyme-responsive hyperbranched poly(oligo-(ethylene glycol) methacrylate)-gadolinium conjugate (HB-POEGMA-Gd) was prepared via one-step reversible addition-fragmentation chain transfer (RAFT) polymerization and Gd(III) chelating, and the cRGDyK functionalized polymer (HB-POEGMA-cRGD-Gd) was obtained via click chemistry. By using an enzyme similar to lysosomal cathepsin B, hyperbranched conjugates of high molecular weights (MW) (180 and 210 kDa) and nanoscale sizes (38 and 42 nm) were degraded into low MW (25 and 30 kDa) and smaller products (4.8 and 5.2 nm) below the renal threshold. Conjugate-based nanoscale systems had three-fold more T1 relaxivity compared to clinical agent diethylenediaminepentaacetic acid (DTPA)-Gd. Animal studies with the nanoscale system offered greater tumor accumulation and enhanced signal intensity (SI) in mouse U87 tumors of which the greatest activity was conferred by the cRGDyK moiety functionalized hyperbranched conjugate. In vitro cytotoxicity, hemocompatibility and in vivo toxicity studies confirmed no adverse events. This design strategy for multifunctional Gd(III)-labeled biodegradable dendritic macromolecules may have significant potential as future efficient, biocompatible polymeric nanoscale MRI diagnostic contrast agents for cancer.
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Pujun
authors.initials: P
authors.lastname: Guan
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Luo
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital and ‡Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D003287:Contrast Media; D005682:Gadolinium; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D051379:Mice; D049329:Nanostructures; D011108:Polymers
chemical_list: D001672:Biocompatible Materials; D003287:Contrast Media; D046911:Macromolecular Substances; D011108:Polymers; D005682:Gadolinium
keywords: biocompatibility; biodegradable; cancer diagnosis; hyperbranched polymer; nanoscale MRI contrast agent