Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization

Abstract

Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar.

A Proof-of-Concept Study on the Therapeutic Potential of Au Nanoparticles Radiolabeled with the Alpha-Emitter Actinium-225

“…While uptake of NPs by the RES organs is always an issue when these are systemically administered, previous results with Au@TADOTAGA radiolabeled with Indium-111 showed low to moderate liver and spleen uptake, which is in accordance to our results [28]. This study revealed a similar distribution of the radiolabeled NPs, however the NPs were monitored up to 72 h post intravenous injection.…”

“…The present work provides in vivo data up to 120 h after intravenous injection and 288 h after intratumoral injection of these NPs radiolabeled with 225 Ac in U-87 MG tumor-bearing mice. A major difference between our study and the study by Laurent et al is the high tumor uptake of [ 225 Ac] 225 Ac-Au@TADOTAGA after intratumoral administration when compared to their intravenous administration, which is expected [28].…”

“…After their intravenous injection, [ 225 Ac] 225 Ac-Au@TADOTAGA NPs were mainly located in the kidneys, liver and spleen. Initial high kidney uptake demonstrates route of clearance, as noted in the literature for such gold NPs [28][29][30]. Tumor uptake peaked at 2 h p.i.…”

Evaluation of spectral photon counting computed tomography K-edge imaging for determination of gold nanoparticle biodistribution in vivo

“…Gold nanoparticles are being explored in many applications in the biomedical field such as contrast agents for medical imaging 11,14 , drug delivery, targeted killing of cells 21 and also therapeutic applications, such as theranostic agents 37 and radiosensitization 38 . This has led to numerous investigations of their toxicity and biodistribution.…”

Import and Export of Gold Nanoparticles: Exchange Rate in Cancer Cells and Fibroblasts

“…Among gold nanoparticles, the ultrasmall gadolinium chelate-coated gold nanoparticles (Au@DTDTPA-Gd) received much attention since their biodistribution and preferential accumulation in solid tumors can be monitored by magnetic resonance imaging (MRI) -more suited for clinical tumor imaging than X-ray imaging 11 . Au@DTDTPA-Gd nanoparticles paved the way to MRI-guided radiosensitization in order to improve significantly the selectivity and therefore the efficacy of the radiotherapy 12 . The ultrasmall size of these nanoparticles is an asset for the in vivo application since it allows renal clearance which is a pre-requisite in the case of non-biodegradable nanoparticles, but also for the enhancement of the dose effect.…”