Casp3/7-Instructed Intracellular Aggregation of Fe₃O₄ Nanoparticles Enhances T₂ MR Imaging of Tumor Apoptosis

Abstract

Large magnetic nanoparticles or aggregates are advantageous in their magnetic resonance properties over ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (NPs), but the former are cleared faster from the blood pool. Therefore, the "smart" strategy of intracellular aggregation of USPIO NPs is required for enhanced T2-weighted MR imaging. Herein, employing an enzyme-instructed condensation reaction, we rationally designed a small molecule Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys-CBT (1) to covalently modify USPIO NPs to prepare monodispersive Fe3O4@1 NPs. In vitro results showed that Fe3O4@1 NPs could be subjected to caspase 3 (Casp3)-instructed aggregation. T2 phantom MR imaging showed that the transverse molar relaxivity (r2) of Fe3O4@1 NPs with Casp3 or apoptotic HepG2 cells was significantly larger than those of control groups. In vivo tumor MR imaging results indicated that Fe3O4@1 NPs could be specifically applied for enhanced T2 MR imaging of tumor apoptosis. We propose that the enzyme-instructed intracellular aggregation of Fe3O4 NPs could be a novel strategy for the design of "smart" probes for efficient T2 MR imaging of in vivo biomarkers.

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…18a). 197 Caspase-3/7-mediated self-assembly of Fe 3 O 4 @1 NPs ( r 2 = 185 mM −1 s −1 ) induced an approximately 65% increase of r 2 value when compared to the control group ( r 2 = 112 mM −1 s −1 ) (Fig. 18b).…”

“…For example, such a self-assembly strategy allows for small NPs to circulate in the blood pool over a prolonged time duration, which can then be triggered in the tumor to self-assemble into a large structure for enhanced MRI. The trigger may include many physiological characteristics, such as molecular interactions, 195 enzymes, 196 receptors, 197 and redox status. 198 On the other hand, the disassembly strategy utilizes the different tumor microenvironments to release CAs preconfined in NPs, also achieving amplified MRI contrast.…”

Furin‐Controlled Fe3O4 Nanoparticle Aggregation and 19F Signal “Turn‐On” for Precise MR Imaging of Tumors

“…Clinical T 1 -type CAs such as Gd-DOTA and Gd-DTPA are used for soft tissue angiography but not suitable for tumor imaging. [17] Since there is abundant water in human bodies, high sensitivity of a carefully designed SPIO NP for tumor 1 H MRI could be achieved. [11,12] It has been proved that magnetization and size of SPIO NPs significantly contributed to the transverse relaxation rate (R 2 ) of proximal water protons, and higher magnetic fields generally lead to larger R 2 values.…”

Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma

“…Compared with gadolinium-based MRI contrast agents, including Magnevist ® (Gd-DTPA; Bayer Schering Pharma, Berlin, Germany) and Multihance ® (Gd-BOPTA; Bracco Diagnostics Inc., Princeton, NJ, USA), 14,15 superparamagnetic iron oxide NPs have been intensively investigated as promising MRI probes because of their biocompatibility and safety profiles as well as suitable magnetic properties. [16][17][18] However, limitations such as low sensitivity have hindered the further application of MRI as the sole methodology in the diagnosis…”