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.

Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy

“…Immunohistochemical and FACS analyses identified these cells as type A synoviocytes (macrophage-like), type B synoviocytes (fibroblast-like) and dendritic cells. The internalization of different HPMA copolymers by murine macrophages and fibroblasts has been reported previously [19,20]. The internalization and subcellular partitioning of P-Dex, however, have not been evaluated.…”

Macromolecules, Dendrimers, and Nanomaterials in Magnetic Resonance Imaging: The Interplay between Size, Function, and Pharmacokinetics

“…For example, DTPA and sulfadiazine were incorporated into polyaspartamide, and then labeled with Gd 3+ to produce a tumor specific polymer contrast agent, exhibiting preferential uptake in, and significant MR enhancement of hepatoma in a mouse model 165. Similarly, N -(2-hydroxypropyl)methacrylamide was co-polymerized with mannosamine and then labeled with Gd 3+ -DOTA to produce a contrast agent specific for mannose receptors over-expressed in activated macrophages 166. More recently, polydiamidopropanoyl dendrimer was labeled with multiple Gd 3+ chelates and then conjugated with a peptide nucleic acid as a MR hybridization probe capable of hybridizing with specific mRNA 167…”

Cell-mediated drug delivery

“…Another class of imaging agents, N -(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium (Gd) chelates, were used for enhanced magnetic resonance imaging (MRI) of macrophage-mediated malignancies 104. To increase the nanoparticles uptake in macrophages, copolymers were vectorized with mannosamine, which was shown to increase mannose receptor mediated uptake in human MP.…”