title: Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe.
abstract: The measurement of extracellular pH (pHe ) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44 -G5, a G5-PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1 ) increased from 7.91 to 9.65 mM(-1) s(-1) (on a per Gd(3+) basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2 ) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44 -G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2 /R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44 -G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44 -G5 shows pH response in the range commonly found in the microenvironment of solid tumors.
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Mohammed P I
authors.initials: MP
authors.lastname: Bhuiyan
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Madhava P
authors.initials: MP
authors.lastname: Aryal
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Branislava
authors.initials: B
authors.lastname: Janic
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Kishor
authors.initials: K
authors.lastname: Karki
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Nadimpalli R S
authors.initials: NR
authors.lastname: Varma
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Ewing
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Meser M
authors.initials: MM
authors.lastname: Ali
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry; D045604:Extracellular Fluid / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D014867:Water
chemical_list: D003287:Contrast Media; D050091:Dendrimers; C471303:Gd-DOTA-4amP; D006573:Heterocyclic Compounds, 1-Ring; D009942:Organometallic Compounds; C104700:PAMAM Starburst; D014867:Water; D005682:Gadolinium
keywords: dendritic agent; magnetic resonance imaging; noninvasive pH measurement; responsive agent