LAT1-Targeted Alpha Therapy Using ²¹¹At-AAMT for Bone and Soft Tissue Sarcomas

Malignant bone and soft tissue tumors are often resistant to conventional treatment, and treatment options for unresectable and metastatic cases are limited. L-type amino acid transporter 1 (LAT1) is overexpressed in several malignancies, including sarcomas, making it an attractive target for targeted alpha therapy. In this study, we investigated the therapeutic efficacy of LAT1-targeted alpha therapy using a novel modified 3-astatin-211 Astato-α-methyl-L-tyrosine (²¹¹At-AAMT) for bone and soft tissue sarcomas. LAT1 expression and the specificity of LAT1-mediated uptake of ²¹¹At-AAMT were evaluated in bone and soft tissue sarcoma cell lines. Antiproliferative effects were assessed using cell viability and colony formation assays. DNA damage was assessed using immunostaining with phosphorylated histone γH2AX. In vivo efficacy of ²¹¹At-AAMT, determined using xenograft mouse models, was compared with that of doxorubicin. LAT1 was highly expressed in all cell lines, especially MP-CCS-SY and MG-63 cells. ²¹¹At-AAMT uptake was LAT1-dependent and significant in all cell lines. It inhibited cell proliferation in a dose-dependent manner, comparable to that of doxorubicin. In xenograft models, a single administration of ²¹¹At-AAMT significantly inhibited tumor growth without systemic toxicity, whereas doxorubicin caused weight loss. Histopathological analysis showed reduced cell density, inhibited proliferation, and extensive DNA damage in tumors treated with ²¹¹At-AAMT, whereas LAT1 expression was maintained in residual tumor tissues. LAT1-targeted alpha therapy with ²¹¹At-AAMT demonstrated antitumor efficacy comparable to that of first-line chemotherapy for osteosarcoma and soft tissue sarcoma. Sustained LAT1 expression suggests the potential for repeated or combination treatments, highlighting its promise as a novel therapy for advanced, treatment-resistant sarcomas.