Combined Magnetic Resonance Imaging and Photodynamic Therapy Using Polyfunctionalised Nanoparticles Bearing Robust Gadolinium Surface Units

Abstract

A robust dithiocarbamate tether allows novel gadolinium units based on DOTAGA (q=1) to be attached to the surface of gold nanoparticles (2.6–4.1 nm diameter) along with functional units offering biocompatibility, targeting and photodynamic therapy. A dramatic increase in relaxivity (r1) per Gd unit from 5.01 mm−1 s−1 in unbound form to 31.68 mm−1 s−1 (10 MHz, 37 °C) is observed when immobilised on the surface due to restricted rotation and enhanced rigidity of the Gd complex on the nanoparticle surface. The single‐step synthetic route provides a straightforward and versatile way of preparing multifunctional gold nanoparticles, including examples with conjugated zinc–tetraphenylporphyrin photosensitizers. The lack of toxicity of these materials (MTT assays) is transformed on irradiation of HeLa cells for 30 minutes (PDT), leading to 75 % cell death. In addition to passive targeting, the inclusion of units capable of actively targeting overexpressed folate receptors illustrates the potential of these assemblies as targeted theranostic agents.

Gold nanomaterials functionalised with gadolinium chelates and their application in multimodal imaging and therapy

“…Photosensitizers used in photo dynamic therapy (PDT) have also been attached to gold nanomaterials to allow delivery of localised cancer treatment through the generation of singlet oxygen. [95][96][97][98] A particularly noteworthy example featured a photosensitizer attached to a gadolinium-functionalised gold nanoshell for combined MRI, CT, PTT and PDT. 97 This approach highlighted the potential for gold nanomaterials to incorporate a combination of therapies into the same assembly, thereby augmenting the therapeutic potency.…”

Metallostar Assemblies Based on Dithiocarbamates for Use as MRI Contrast Agents

“…Higher relaxivity values (in mM −1 s −1 ) correlate with better contrast enhancement. 2 The contrast agents currently used in a clinical setting are almost all based on paramagnetic (4f 7 ) trivalent gadolinium ions.…”

“…This nephrogenic systemic fibrosis (NSF) can lead to severe renal impairment in patients and has led to restrictions in the use of contrast agents with acyclic chelates. 2 Figure 1. Two commonly used, clinically-approved gadolinium contrast agents, which both have a hydration number (q) of one.…”

“…Interactions between the paramagnet and coordinated and surrounding water molecules leads to an improvement in the relaxation rates of the surrounding water protons, enhancing image contrast and signal-to-noise performance. 2 Due to the inherent low sensitivity of MRI, very high concentrations (typically 0.1 mmol per kg patient weight) of contrast agent are required and so efforts have been made to increase the relaxivity performance of each Gd 3+ ion. This could also reduce the amount of contrast agent that needs to be administered.…”

“…In addition, the degree to which the relaxation of water protons changes is due to the multimeric effect which stems from the increased, localized contrast agent concentration. 2 Pioneering work by Tóth, 3 Helm, 4 Parac-Vogt 5 and Desreux 6 has focused on the synthesis of molecular multimetallic gadolinium compounds, either with an organic or metalbased core. These assemblies have demonstrated impressive relaxivity in many cases.…”