Nanodiamond–Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field

Abstract

The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond–gadolinium(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium(III) [Gd(III)]–nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd(III) compared to that of clinical Gd(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG-labeled flank tumors by T1- and T2-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities.

Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions

“…In fact, this concentration-dependent shift in contrast was further analyzed by relaxation time in comparison to healthy tissue, and from this data a model was developed which was used to predict tumor morphology and cellular architecture at day 26 based on MR images alone. This model, which was verified in this study by comparison with histology, can be used in future studies to monitor growth dynamics and morphological changes during tumor progression [180]. Furthermore, ND-Gd labeling was noted to have no noticeable effect on cell growth or differentiation, and biodistribution studies after 26 days concluded that 95% of ND-Gd remained within the labeled cells throughout the entire duration of the study.…”

“…By conjugating paramagnetic ions to NDs, their relaxivity is improved due to the increased interaction of the ions with water of the solvent phase present on the ND surface. To demonstrate this concept, Gd(III) chelates were chemically conjugated with amino-functionalized NDs by carbodiimide crosslinking to form ND-Gd aggregates [180]. ND-Gd displayed a 10-fold increase in relaxivity with respect to unmodified Gd.…”

Nanodiamonds and Their Applications in Cells

“…e) A high‐field magnetic resonance imaging (MRI) of cells labeled with nanodiamond–gadolinium (III) aggregates (NDG). Reproduced with permission . Copyright 2016, American Chemical Society.…”

“…T 2 contrast can be achieved via metallic impurities in the diamond material . Recently, Meade and co‐workers conjugated gadolinium (III) (Gd(III)) to the surface of NDs for improving MR imaging . NDs enhance T 1 and T 2 contrast, while Gd(III) is typically effective for T 1 positive contrast .…”

A Markedly Improved Synthetic Approach for the Preparation of Multifunctional Au-DNA Nanoparticle Conjugates Modified with Optical and MR Imaging Probes

“…40–45 This synthetic strategy consisted of covalently attaching Gd(III) complexes to thiol-modified oligonucleotides (via click chemistry) and conjugating this derivative to 13.1 nm gold nanoparticles (AuNPs). 5,42 Because of the increased local concentration of Gd(III) per particle, there is a significant increase in the observed r 1 (relaxivity mM −1 s −1 , particularly at low magnetic field strengths).…”