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

Abstract

Actinium-225 (225Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing neighboring healthy tissue. The objective of our study was the evaluation of a gold nanoparticle radiolabeled with 225Ac as an injectable radiopharmaceutical form of brachytherapy for local radiation treatment of cancer. Au@TADOTAGA was radiolabeled with 225Ac at pH 5.6 (30 min at 70 °C), and in vitro stability was evaluated. In vitro cytotoxicity was assessed in U-87 MG cancer cells, and in vivo biodistribution was performed by intravenous and intratumoral administration of [225Ac]225Ac-Au@TADOTAGA in U-87 MG tumor-bearing mice. A preliminary study to assess therapeutic efficacy of the intratumorally-injected radio-nanomedicine was performed over a period of 22 days, while the necrotic effect on tumors was evaluated by a histopathology study. We have shown that [225Ac]225Ac-Au@TADOTAGA resulted in the retardation of tumor growth after its intratumoral injection in U87MG tumor-bearing mice, even though very low activities were injected per mouse. This gold nanoparticle radiopharmaceutical could be applied as an unconventional brachytherapy in injectable form for local radiation treatment of cancer.

Nanoparticles in Targeted Alpha Therapy

“…After a simple wash with metabisulfite, the retention of 211 AtCl@US-tubes was 60.7%. The overall labelling yield of the 211 AtCl@US-tubes was comparable to the other elaborated astatination methods [48][49][50][51][52]. An important feature of functionalised SWNTs as drug carriers is their rapid clearance via renal glomerular filtration, despite their large molecular weights [112].…”

“…In another work proposed by Salvanou et al, 225 Ac radionuclide was conjugated to 2-3 nm gold nanoparticles via a DOTA-derivative chelator (TADOTAGA) for local radiation treatment of cancer ( Figure 5) [52]. Radiochemical yield assessed by ITLC was ~86%.…”

“…However, they require a complicated implantation technique under general anaesthesia. Furthermore, seed migration may also occur after implantation, and seed removal is required [52].…”

“…This strategy is less invasive than inserting solid seeds into the body. Additionally, their nanometer size permits local diffusion from the injection site, thus further homogenising the radiation dose deposition in the tumour [52]. Multiple small injections can achieve a more homogeneous distribution of the gold nanoseeds.…”

Radiolabeled Gold Nanoparticles for Imaging and Therapy of Cancer

“…Bouziotis et al have reported on the synthesis of AuNPs functionalized with a thioctic acid-modified DOTAGA and radiolabeled with 225 Ac. The resulting 225 Ac-labeled AuNPs were evaluated as an injectable radiopharmaceutical form of brachytherapy for local radiation cancer treatment, using cellular and animal models of glioblastoma multiforme [133]. In vitro radiocytotoxicity studies in glioblastoma multiforme U87MG cells showed a significant cell death upon exposure to the radiolabeled AuNPs.…”