LAUSR

Boron neutron capture therapy (BNCT) induces intracellular nuclear reactions that release heavy charged particles to destroy cancer cells during thermal neutron radiation. In order to selectively eliminate cancer cells but avoid harmful effects to normal tissues, targeted delivery of boron-10 in cancer cells is required, whereas the conventional boron delivery agent phenylalanine (BPA) is unsatisfactory. Angiopep-2 is a cell-penetrating peptide that can trigger transcytosis and traverse the blood-brain barrier by recognizing low density lipoprotein-related protein 1. In this study, we developed angiopep-2 for boron delivery in BNCT. Angiopep-2 was labeled with boron-10 using solid-phase peptide synthesis with 4-carboxyphenylboronic acid and fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids, namely ANG-B. Molecular mass of the synthesized ANG-B were validated by mass spectrometry. In a cell proliferation assay, little toxicity of ANG-B was detected. Boron concentrations in 6 cell lines from different cancer types and an intracranial glioblastoma mouse model after treatment with ANG-B or BPA were analyzed by ICP-AES. The in vivo distribution of ANG-B showed that the ratio of boron content of tumor tissue to that of blood (T/B ratio) was 9.42±2.47 at 4h post treatment, while the ratio of boron content of tumor tissue to that of normal brain tissue (T/N ratio) was 5.61±1.0, demonstrated an optimal tumor targeting ability of ANG-B. We further measured the effects of ANG-B in BNCT by clonogenic cell survival assay in vitro or by PET/CT imaging on a glioblastoma mouse model in vivo. Radiation for BNCT was given with neutron flux at 3.0±0.4 × 1011 n/cm2. BNCT with 5 mM ANG-B resulted in 86.5%±5.3% clonogenic cell death, while the number was 72.9%±5.1% for BPA. The effect of ANG-B based BNCT in vivo was also better than BPA. The glioblastoma tumors in ANG-B treated group at 31 days after BNCT were shrank by 62.9% in average, while the BPA treated tumors shrank by only 23.0% (P<0.05). Therefore, we concluded that ANG-B is an efficient boron delivery agent, which may improve BNCT performance in clinical trials. Citation Format: Qi Liu, Jing Xiang, Lin Ma, Qiushi Ren. Assessment of boron delivery peptides with angiopep-2 for boron neutron capture therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5051.