Combined magnetic resonance and optical imaging of head and neck tumor xenografts using Gadolinium-labelled phosphorescent polymeric nanomicelles

Abstract

BackgroundThe overall objective of this study was to develop a nanoparticle formulation for dual modality imaging of head and neck cancer. Here, we report the synthesis and characterization of polymeric phospholipid-based nanomicelles encapsulating near-infrared (NIR) phosphorescent molecules of Pt(II)-tetraphenyltetranaphthoporphyrin [Pt(TPNP)] and surface functionalized with gadolinium [Pt(TPNP)-Gd] for combined magnetic resonance imaging (MRI) and NIR optical imaging applications.MethodsDynamic light scattering, electron microscopy, optical spectroscopy and MR relaxometric measurements were performed to characterize the optical and magnetic properties of nanoparticles in vitro. Subsequently, in vivo imaging experiments were carried out using nude mice bearing primary patient tumor-derived human head and neck squamous cell carcinoma xenografts.ResultsThe nanomicelles were ~100 nm in size and stable in aqueous suspension. T1-weighted MRI and relaxation rate (R1 = 1/T1) measurements carried out at 4.7 T revealed enhancement in the tumor immediately post injection with nanomicelles, particularly in the tumor periphery which persisted up to 24 hours post administration. Maximum intensity projections (MIPs) generated from 3D T1-weighted images also demonstrated visible enhancement in contrast within the tumor, liver and blood vessels. NIR optical imaging performed (in vivo and ex vivo) following completion of MRI at the 24 h time point confirmed tumor localization of the nanoparticles. The large spectral separation between the Pt(TPNP) absorption (~700 nm) and phosphorescence emission (~900 nm) provided a dramatic decrease in the level of background, resulting in high contrast optical (NIR phosphorescence) imaging.ConclusionsIn conclusion, Pt(TPNP)-Gd nanomicelles exhibit a high degree of tumor-avidity and favorable imaging properties that allow for combined MR and optical imaging of head and neck tumors. Further investigation into the potential of Pt(TPNP)-Gd nanomicelles for combined imaging and therapy of cancer is currently underway.

Advantages and Limitations of Current Techniques for Analyzing the Biodistribution of Nanoparticles

“…Gadolinium-based contrast agents can be incorporated into nanoparticles to enable real-time imaging of their in vivo biodistribution using MRI. A number of nanoparticle types have incorporated these contrast agents, including liposomes (Unger et al, 1989 ; Saito et al, 2005 ; Hossann et al, 2013 ; Smith et al, 2013 ; Skupin-Mrugalska et al, 2018 ), dendrimers (Margerum et al, 1997 ; Lee et al, 2005 ; Rongzuo et al, 2007 ), micelles (Parac-Vogt Tatjana et al, 2004 ; Kumar et al, 2010 ), polymeric-based nanoparticles (Liu et al, 2011 ), carbon-based nanotubes (Hartman et al, 2008 ; Richard et al, 2008 ), and mesoporous silica nanoparticles (Kobayashi et al, 2007 ; Kim et al, 2008 ; Taylor et al, 2008 ). For example, Saito et al ( 2005 ) manufactured gadoteridol-loaded liposomes for real-time MRI evaluation of convection-enhanced delivery in the primate brain.…”

Rational chemical design of the next generation of molecular imaging probes based on physics and biology: mixing modalities, colors and signals

“…Although little toxicity data are currently available, organic molecules may prove to be more biocompatible and therefore may be more relevant clinically. Organic molecules capable of linking to paramagnetic chelates include dendrimers, 63,81–83 nanomicelles 64,84–88 liposomes 89–93 viral capsids, 94–97 and even natural products such as functionalized low density lipoprotein particles. 69,98 Chelating the gadolinium with a strong macrocyclic chelate greatly reduces the chance of toxicity due to the release of free gadolinium ion.…”

“…50,51 With this in mind, several combinations of PET/optical agents have been developed. For example, an optical quantum dot (QD) with NIR fluorescence can be attached to a chelating agent to bind 64 Cu for PET imaging, and to a vascular endothelial growth factor (VEGF) protein analog for site-specific targeting of the VEGF receptor. The pharmacokinetic properties and efficacy of this dual labeled probe were evaluated for tumor-specific imaging in an early clinical trial.…”

Photoacoustic and Magnetic Resonance Imaging of Hybrid Manganese Dioxide-Coated Ultra-Small NaGdF4 Nanoparticles for Spatiotemporal Modulation of Hypoxia in Head and Neck Cancer

“…PAI provides non-invasive, real-time imaging of tumor oxygenation levels with the potential to yield spatial and temporal information on hypoxia modification. MRI, on the other hand, is a clinically relevant imaging technique that offers high spatial resolution with excellent soft tissue contrast and provides information on tumor morphology and vascular function [20,25]. Our dual modality approach not only enabled cross-validation of data but also provided complimentary information on tumor biology (MRI to visualize nanoparticle distribution within hypoxic regions) and response (PAI to examine modulation of hypoxia in vivo).…”

“…MRI is a clinically relevant imaging technique that offers high spatial resolution with excellent soft tissue contrast. Using gadolinium (Gd) enhanced MRI, we have previously reported on the angiogenic heterogeneity in HNSCC xenografts [20]. However, commercially available Gd agents exhibit low relaxivity and pose the risk of toxicities in some patients [21].…”