title: Macrophage targeted N-(2-hydroxypropyl)methacrylamide conjugates for magnetic resonance imaging.
abstract: This study describes the synthesis, characterization and in vitro evaluation of targetable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium (Gd) chelates for enhanced magnetic resonance imaging (MRI) of macrophages. Copolymers of HPMA, methacryloylglycylglycyl-mannosamine (MA-GG-ManN), aminopropylmethacrylamide-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (APMA-DOTA), and 5-(3-(methacryloylaminopropyl)thioureidyl) fluorescein (MA-AP-FITC) were synthesized and characterized. Gd was chelated to the polymeric precursors. The conjugates were characterized for gadolinium content by inductively coupled plasma optical emission spectrometry (ICP-OES) and T1 relaxivity (r1) at room temperature and 1.5 T. The effect of ManN content on mannose receptor mediated uptake of THP-1 human macrophages was evaluated as a function of time and temperature. The polymer conjugates showed relaxivities in the range of 21.8-24.9 s(-1) mM(-1) Gd. Relaxivities of the conjugates per mM Gd were up to 7 times higher than that of a commercially available MR contrast agent Gd-DOTA. Significantly (p < 0.042) higher uptake was observed for targeted conjugates compared to nontargeted conjugates. The uptake of polymeric conjugates was time and concentration dependent and appears to be mannose receptor mediated. The increased relaxivity coupled with the ability to target these carriers to cells containing ManN receptors shows promise for the application of these agents in clinical MR imaging of macrophage mediated malignancies.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, Maryland 21201, USA. bzara001@umaryland.edu
authors.forename: Bahar
authors.initials: B
authors.lastname: Zarabi
authors.forename: Anjan
authors.initials: A
authors.lastname: Nan
authors.forename: Jiachen
authors.initials: J
authors.lastname: Zhuo
authors.forename: Rao
authors.initials: R
authors.lastname: Gullapalli
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D002460:Cell Line; D003287:Contrast Media / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D015394:Molecular Structure; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013696:Temperature; D013995:Time
chemical_list: D000178:Acrylamides; D003287:Contrast Media; D008689:Methacrylates; D011108:Polymers; D005682:Gadolinium; C045985:methacrylamide; C032802:hydroxypropyl methacrylate