title: Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses.
abstract: Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1, R2* relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1, T2 and T2*-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2* enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol.
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA.
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Shi
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pisani
authors.forename: Yauk K
authors.initials: YK
authors.lastname: Lee
authors.forename: Solomon
authors.initials: S
authors.lastname: Messing
authors.forename: Celina
authors.initials: C
authors.lastname: Ansari
authors.forename: Srabani
authors.initials: S
authors.lastname: Bhaumik
authors.forename: Lisa
authors.initials: L
authors.lastname: Lowery
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lee
authors.forename: Dan E
authors.initials: DE
authors.lastname: Meyer
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D003911:Dextrans / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D051381:Rats; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10