Engineered αvβ6-targeting peptide‒BSH conjugates for boron neutron capture therapy of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dense stroma that impedes drug penetration and establishes an immune-“cold” microenvironment. Conventional external beam radiotherapy is often limited by off-target toxicity to surrounding normal tissues due to the complex anatomy of the pancreas. Boron neutron capture therapy (BNCT) is a binary targeted radiotherapy that utilizes a focused thermal neutron beam to trigger the in situ production of high-energy particles, enabling single-cell-scale tumor cell ablation. However, the efficacy of BNCT in PDAC critically depends on the ability of B-10 carriers to effectively penetrate the dense stromal barrier and achieve efficient internalization into tumor cells. Herein, we developed nine α v β 6 integrin-targeting peptide‒BSH conjugates to optimize the BNCT therapeutic index. By optimizing linker structure and the number of BSH moieties, amphiphilic agents with enhanced PDAC cellular uptake were obtained. The lead compound, namely DOTA-2BB, adopts a “trident-shaped” structure that facilitates stromal penetration and exhibits the optimal tumor uptake and retention. In a PDAC mouse model, administration of DOTA-2BB followed by thermal neutron irradiation resulted in suppression of tumor growth with favorable biosafety. These findings establish DOTA-2BB as a promising B-10 carrier for PDAC and provide a strategy for treating stroma-rich tumors.