Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

Abstract

Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract

Astatine-211-Labeled Gold Nanoparticles for Targeted Alpha-particle Therapy via Intravenous Injection

“…In contrast, in vitro cellular uptake and DNA DSB induction of both mPEG-modi ed AuNPs were low. We also report that in vitro uptake of 211 At-labeled AuNPs does not correlate with their in vivo anticancer effects in our previous intratumoral administration study [13]. The 120 nm 211 At-AuNPs@mPEG showed evident cytotoxicity in an in vitro cellular assay, while 211 At-labeled AuNPs of smaller sizes did not show cytotoxicity.…”

“…We recently reported that 211 At-AuNPs@mPEG exhibited cytotoxicity when they were absorbed by the tumor cells and the intratumoral administration of 211 At-AuNPs@mPEG strongly suppressed the cancer growth in a particle size-dependent manner. Smaller particles showed a more rapid distribution in tumor regions, and 5 nm 211 At-AuNPs@mPEG showed the highest suppression of cancer growth among various sizes of AuNPs tested [13]. A similar nanoseed brachytherapy using 211 At-labeled gold nanostars has also reported signi cant inhibition of the growth of human gliomas in a murine model [25].…”

“…Various surface-modi ed 211 At-labeled AuNPs were also readily obtained at RCY. In addition, the At-Au bond was reported to be stable both in theory and experimentally [13,18,34]. Another major problem was that 211 At or 211 At-labeled compounds readily stick to the reaction vessel and reduce the yields of labeled products.…”

Covalent core-radiolabeling of polymeric micelles with 125I/211At for theranostic radiotherapy

“…This approach has been utilized in several reports and has already shown effective results when labeling antibodies with 211 At 42 , 43 . An additional possible use for NPs labeled with 211 At could be brachytherapy as shown in a recent report, where tumor growth was inhibited for 38 days 44 . When administering the 211 At-PMs directly at the tumor site, accumulation in the liver can be avoided and, therefore, the degradation of the micelles and consequent deastatination may be limited.…”

Optical magnetic multimodality imaging of plectin-1-targeted imaging agent for the precise detection of orthotopic pancreatic ductal adenocarcinoma in mice

“… 31 In the immunotherapy of PDAC, nanomedicines can be developed to facilitate antitumour immune responses through a series of immuno-potentiating functions after being directly injected into tumours. 32 , 33 Immunotherapy drug through intratumoural injection in PDAC exerted prominent antitumour effects and resulted in tumour decrease in several clinical trials (NCT02045589; NCT03198546). 34 , 35 Moreover, intra-tumoural delivery of agents has also been reported in the application of other tumour types.…”