Density-tunable conjugation of cyclic RGD ligands with polyion complex vesicles for the neovascular imaging of orthotopic glioblastomas

• Published in: Science and technology of advanced materials 2015-06, Vol.16 (3), p.035004-35016
• Main Authors: Kawamura, Wataru, Miura, Yutaka, Kokuryo, Daisuke, Toh, Kazuko, Yamada, Naoki, Nomoto, Takahiro, Matsumoto, Yu, Sueyoshi, Daiki, Liu, Xueying, Aoki, Ichio, Kano, Mitsunobu R, Nishiyama, Nobuhiro, Saga, Tsuneo, Kishimura, Akihiro, Kataoka, Kazunori
• Format: Article
• Language: English
• Subjects: Blood circulation; Conjugation; Coordination compounds; cyclic RGD; Density; Diagnostic software; Diagnostic systems; drug delivery; Drug delivery systems; Endothelial cells; glioblastoma; Imaging; Iron oxides; Ligands; Macromolecules; Magnetic resonance imaging; Medical imaging; MRI (magnetic resonance imaging); Nanostructure; NMR; Nuclear magnetic resonance; Polyethylene glycol; polymersome; Reagents; Scanning microscopy; Tumors; Vesicles; Water circulation
• ISSN: 1468-6996; 1878-5514
• DOI: 10.1088/1468-6996/16/3/035004

Introduction of ligands into 100 nm scaled hollow capsules has great potential for diagnostic and therapeutic applications in drug delivery systems. Polyethylene glycol-conjugated (PEGylated) polyion complex vesicles (PICsomes) are promising hollow nano-capsules that can survive for long periods in the blood circulation and can be used to deliver water-soluble macromolecules to target tissues. In this study, cyclic RGD (cRGD) peptide, which is specifically recognized by α V β 3 and α v β 5 integrins that are expressed at high levels in the neovascular system, was conjugated onto the distal end of PEG strands on PICsomes for active neovascular targeting. Density-tunable cRGD-conjugation was achieved using PICsomes with definite fraction of end-functionalized PEG, to substitute 20, 40, and 100% of PEG distal end of the PICsomes to cRGD moieties. Compared with control-PICsomes without cRGD, cRGD-PICsomes exhibited increased uptake into human umbilical vein endothelial cells. Intravital confocal laser scanning microscopy revealed that the 40%-cRGD-PICsomes accumulated mainly in the tumor neovasculature and remained in the perivascular region even after 24 h. Furthermore, we prepared superparamagnetic iron oxide (SPIO)-loaded cRGD-PICsomes for magnetic resonance imaging (MRI) and successfully visualized the neovasculature in an orthotopic glioblastoma model, which suggests that SPIO-loaded cRGD-PICsomes might be useful as a MRI contrast reagent for imaging of the tumor microenvironment, including neovascular regions that overexpress α V β 3 integrins.