Engineered αvβ6-targeting peptide‒BSH conjugates for boron neutron capture therapy of pancreatic ductal adenocarcinoma
- 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- 2Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
- 3Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, Lanzhou 730000, China
Abstract
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 αvβ6 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.
Related
- Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma
- Antibody peptide conjugates as multifunctional therapeutics: Mechanisms, challenges, and prospects.
- In silico engineered multitarget-directed ligands for the polypharmaceutical treatment of PTEN loss of function endometrial adenocarcinoma
- Borderline resectable pancreatic ductal adenocarcinoma: a narrative review
- Combined halp and GRIm scores for risk stratification in metastatic pancreatic ductal adenocarcinoma
BibTeX
@article{li2026engineered,
title = {{Engineered αvβ6-targeting peptide‒BSH conjugates for boron neutron capture therapy of pancreatic ductal adenocarcinoma}},
author = {Linger Li and Xin Gao and Siqi Zhang and Xingkai Wang and Xueyao Chen and Yuan Miao and Tongtong Zhang and Mengjie Yang and Can Liu and Tianjiao Liang and Tiancheng Yi and Shuo Jiang and Hongyi Huang and Hailong Zhang and Jianfei Tong and Rui Wang and Kuan Hu},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = may,
doi = {10.1016/j.apsb.2026.05.012},
url = {https://europepmc.org/article/PMC/PMC13729520},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Engineered αvβ6-targeting peptide‒BSH conjugates for boron neutron capture therapy of pancreatic ductal adenocarcinoma
AU - Linger Li
AU - Xin Gao
AU - Siqi Zhang
AU - Xingkai Wang
AU - Xueyao Chen
AU - Yuan Miao
AU - Tongtong Zhang
AU - Mengjie Yang
AU - Can Liu
AU - Tianjiao Liang
AU - Tiancheng Yi
AU - Shuo Jiang
AU - Hongyi Huang
AU - Hailong Zhang
AU - Jianfei Tong
AU - Rui Wang
AU - Kuan Hu
PY - 2026
DA - 2026/05/19
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.05.012
UR - https://europepmc.org/article/PMC/PMC13729520
AB - 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 αvβ6 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.
SN - 2211-3835
SN - 2211-3843
ER -