title: Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging.
abstract: With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd(3+) toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd(3+) and a 10(11)-fold greater selectivity for Gd(3+) over Zn(2+) compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol(-1)⋅s(-1)/89.2 mmol(-1)⋅s(-1) per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.
authors.affiliation: Departments of Biology and Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
authors.forename: Shenghui
authors.identifier: http://orcid.org/0000-0001-8670-2131
authors.initials: S
authors.lastname: Xue
authors.affiliation: Departments of Ophthalmology and.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303; Inlighta Biosciences LLC, Marietta, GA 30068;
authors.forename: Jingjuan
authors.initials: J
authors.lastname: Qiao
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303; Inlighta Biosciences LLC, Marietta, GA 30068;
authors.forename: Fan
authors.initials: F
authors.lastname: Pu
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
authors.forename: Kendra
authors.initials: K
authors.lastname: Hubbard
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602;
authors.forename: Khan
authors.initials: K
authors.lastname: Hekmatyar
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30322; and.
authors.forename: Jason
authors.initials: J
authors.lastname: Langley
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303;
authors.forename: Mani
authors.initials: M
authors.lastname: Salarian
authors.affiliation: Radiology, Emory University, Atlanta, GA 30322;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Long
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, VA 22904.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bryant
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA 30322; and.
authors.forename: Xiaoping Philip
authors.initials: XP
authors.lastname: Hu
authors.affiliation: Departments of Ophthalmology and.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.affiliation: Departments of Biology and.
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Liu
authors.affiliation: Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303; jenny@gsu.edu.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D005682:Gadolinium; D057230:Limit of Detection; D008114:Liver Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism* / Q000556:secondary; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008546:Melanoma, Experimental / Q000175:diagnosis* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010320:Parvalbumins / Q000737:chemistry / Q000493:pharmacokinetics; D015202:Protein Engineering; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D003287:Contrast Media; D010320:Parvalbumins; D011994:Recombinant Proteins; D005682:Gadolinium
keywords: MRI; T2/T1 ratio imaging; contrast agents; metastasis; uveal melanoma