The 7.2-h half life radiohalogen 211At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the 209Bi(α,2n)211At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident α-particle energy for maximizing 211At production while minimizing production of 210At, which is problematic because of its 138.4-day half life α-particle emitting daughter, 210Po. The intrinsic cost for producing 211At is reasonably modest and comparable to that of commercially available 123I. The major impediment to 211At availability is attributed to the need for a medium energy α-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for 211At production.

Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a ¹³¹I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer. Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with ¹³¹I using [¹³¹I]SGMIB and evaluated in vitro. Biodistribution was evaluated in two HER2⁺ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [¹³¹I]SGMIB-2Rs15d was investigated in two HER2⁺ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [¹²⁷I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d–HER2 complex was determined by X-ray crystallography. Results: [¹³¹I]SGMIB-2Rs15d bound specifically to HER2⁺ cells (K_d = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo. [¹³¹I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [¹²⁷I]SGMIB-2Rs15d. Conclusions: These findings demonstrate the theranostic potential of [¹³¹I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [¹³¹I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2⁺ breast cancer patients. Clin Cancer Res; 23(21); 6616–28. ©2017 AACR.

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.