Development and in Vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor

Abstract

Recent emphasis has focused on the development of rationally-designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT™ micellar system, stabilized through Fe(III) crosslinking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted and/or uncrosslinked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R.

Polycatechol Nanoparticle MRI Contrast Agents

“…With regards to morphological stability, we propose that although many previously established micelle-based therapeutic systems have suffered from an inherent instability in vivo (generally undergoing collapse or break-up in the presence of serum lipids and proteins), [32] the micellar particles described here benefit from cross-linking networks of individual polymer chains in the micellar interface via the formation of interchain, multiple Fe III -catecholate coordination bonds. [12, 33] These crosslinks lead to the particles being stable for more than 20 days in fetal bovine serum (FBS, 100%) even at a high concentration (>20 mg/mL).…”

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…In 2011 and 2013, Barkey et al . attached hMC1R selective α-MSH analogs to stabilized triblock polymer micelles through Cu-catalyzed click chemistry [267, 268]. Though the ligand decreased binding affinity of the polymer micelles after attachment, it increased specificity for the hMC1R over the hMC4R and hMC5R [268].…”

“…Though the ligand decreased binding affinity of the polymer micelles after attachment, it increased specificity for the hMC1R over the hMC4R and hMC5R [268]. Further cross-linking the targeted polymer micelles generated constructs that were used as delivery systems for contrast-enhancing gadolinium complexes of texaphyrin (Gd-Tx) [267]. These agents were efficacious at penetrating and delivering the contrast agent into xenografted tumors in mice with minimal accumulation in healthy tissues, including the kidney and liver [267].…”

Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids

“…Stabilization of micelles by crosslinking can prevent disassembly, which directly translates into an improved cellular uptake, 23 as well as prolonged circulation time in vivo. 24 The aim of this study, in addition to the determination of the mode of micellar transport inside the MCTS, is to compare the penetration and drug delivery properties between selfassembled, uncrosslinked micelles (UCM) and shell-crosslinked micelles (CKM) inside the MCTS. The significance of the comparison of these two types of micelles is that they can be seen as representatives of a solid and stable system on one side and potentially degradable nanoparticles that may easily disintegrate on the other.…”