Abstract
Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). The size, shape, morphology, and zeta potential of the 5 nm synthesized AuNPs were characterized by TEM (Transmission Electron Microscopy) and DLS (Dynamic Light Scattering) techniques. The gold nanoparticle surface was modified by PEG and subsequently used for antibody immobilization. Utilizing the high affinity of gold for heavy halogens, the bioconjugate was labelled with 211At obtained by α irradiation of the bismuth target. The labeling yield of 211At was greater than 99%. 211At bioconjugates were stable in human serum. Additionally, in vitro biological studies indicated that 211At-AuNP-PEG-trastuzumab exhibited higher affinity and cytotoxicity towards the HER2-overexpressing human ovarian SKOV-3 cell line than unmodified nanoparticles. Confocal and dark field microscopy studies revealed that 211At-AuNP-PEG-trastuzumab was effectively internalized and deposited near the nucleus. These findings show promising potential for the 211At-AuNP-PEG-trastuzumab radiobioconjugate as a perspective therapeutic agent in the treatment of unresectable solid cancers expressing HER2 receptors.
Highlights
Localized radionuclide therapy with radioisotopes has become a standard treatment option for many malignant tumors
We propose for the first time a novel α-nanobrachytherapy approach for selective treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles labeled with 211At and modified with polyethylene glycol (PEG) chains linked to trastuzumab, which bind the radiobioconjugate to HER2-positive tumor cells
To determine the affinity of 131I-AuNP-S-PEG-trastuzumab to HER2 receptors overexpressed on SKOV-3 cells and for comparison with the reference compound (131I-trastuzumab), saturation cell-binding assays were performed
Summary
Localized radionuclide therapy with radioisotopes has become a standard treatment option for many malignant tumors. Et al proposed a novel targeted nanomedicine brachytherapy approach for the treatment of locally advanced breast cancer They used intratumoral injection of gold nanoparticles (diameter: 30 nm) modified with a polyethylene glycol (PEG) polymer with an attached DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator that complexes with the β− radionuclide 177Lu. The conjugate links to panitumumab, which exhibits affinity to epidermal growth factor receptor (EGFR)-positive tumor cells, or to trastuzumab, which binds to human epidermal growth factor receptor 2 (HER2) receptors [29,30]. We propose for the first time a novel α-nanobrachytherapy approach for selective treatment of HER2-positive breast cancer This uses local intratumoral injection of 5-nm-diameter gold nanoparticles labeled with 211At and modified with PEG chains linked to trastuzumab, which bind the radiobioconjugate to HER2-positive tumor cells
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