title: PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities.
abstract: Magnetic resonance imaging (MRI) has emerged as a leading diagnostic technique in clinical and preclinical settings. However, the application of MRI to assess specific disease markers for diagnosis and monitoring drug effect has been severely hampered by the lack of desired contrast agents with high relaxivities, and optimized in vivo retention time. We have reported the development of protein-based MRI contrast agents (ProCA1) by rational design of Gd(3+) binding sites into a stable protein resulting in significantly increased longitudinal (r(1)) and transverse (r(2)) relaxivities compared to Gd-DTPA. Here, we report a further improvement of protein contrast agents ProCA1 for in vivo imaging by protein modification with various sizes of polyethylene glycol (PEG) chain. PEGylation results in significant increases of both r(1) and r(2) relaxivities (up to 200%), and these high relaxivities persist even at field strengths up to 9.4 T. In addition, our experimental results demonstrate that modified contrast agents have significant improvement of in vivo MR imaging and biocompatibilities including dose efficiency, protein solubility, blood retention time and decreased immunogenicity. Such improvement can be important to the animal imaging and pre-clinical research at high or ultra-high field where there is an urgent need for molecular imaging probes and optimized contrast agent.
authors.affiliation: Department of Chemistry and Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Shunyi
authors.initials: S
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Jin
authors.initials: J
authors.lastname: Zou
authors.forename: Jingjuan
authors.initials: J
authors.lastname: Qiao
authors.forename: Shenghui
authors.initials: S
authors.lastname: Xue
authors.forename: Lixia
authors.initials: L
authors.lastname: Wei
authors.forename: Robert
authors.initials: R
authors.lastname: Long
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.forename: Adriana
authors.initials: A
authors.lastname: Castiblanco
authors.forename: Natalie
authors.initials: N
authors.lastname: White
authors.forename: Jen
authors.initials: J
authors.lastname: Ngo
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Liu
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D001665:Binding Sites; D057005:Bioengineering; D002352:Carrier Proteins / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D056831:Coordination Complexes / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D005682:Gadolinium / Q000737:chemistry; D019786:Gadolinium DTPA / Q000737:chemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D008422:Materials Testing; D051379:Mice; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D002352:Carrier Proteins; D003287:Contrast Media; D056831:Coordination Complexes; C492514:PROCA1 protein, human; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D005682:Gadolinium; D019786:Gadolinium DTPA