Tumor vasculature-targeted 10B delivery by an Annexin A1-binding peptide boosts effects of boron neutron capture therapy

Shingo Hatakeyama,Motohiro Nonaka,Tsuyoshi Uemura,Shintaro Ishiyama,Shingo Hachinohe,Chikara Ohyama,Tohru Yoneyama,Takehiro Ishizu,Mihoko Sutoh Yoneyama,Taku Yoshiya,Minoru Suzuki,Michiko N. Fukuda

doi:10.1186/s12885-020-07760-x

Abstract

Backgroundp-Boronophenylalanine (10BPA) is a powerful 10B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated 10BPA or borocaptate sodium (10BSH).Methods(1) IF7 conjugates of either 10B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-10B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice.ResultsIntravenous injection of IF7C conjugates of either 10B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10–20 mg/kg) doses of IF7-10B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes.ConclusionsWe conclude that IF7 serves as an efficient 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.

Highlights

Boron neutron capture therapy (BNCT) is based on a nuclear fission reaction between nonradioactive isotope 10B atoms and low-energy thermal neutrons, which generates high linear energy transfer α particles and a recoiled lithium nucleus (7Li) that selectively destroy the DNA helix in tumor cells [1, 2]
We conclude that IF7 serves as an efficient 10B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs
We report that administration of an ultralow dose (10– 20 mg/kg) of IF7C(10BPA)RR or IF7K(10BSH)RR to bladder tumor-bearing mice enhanced the ability of BNCT to induce rapid 10B accumulation in tumor tissues and significantly suppressed tumor growth with no apparent side effects

Summary

Introduction

Boron neutron capture therapy (BNCT) is based on a nuclear fission reaction between nonradioactive isotope 10B atoms and low-energy thermal neutrons, which generates high linear energy transfer α particles and a recoiled lithium nucleus (7Li) that selectively destroy the DNA helix in tumor cells [1, 2]. Α particles and 7Li generated from 10BSH sometimes do not reach tumor cell DNA, minimizing the therapeutic effect of 10BSH-mediated BNCT. Iguchi et al reported that 10BSH fused with a short arginine peptide (3R, 10BSH-3R) is internalized by cancer cells in vitro and in vivo [8]. These novel 10BPA and 10BSH pharmacophores have been used clinically as a second-generation boron compounds for BNCT, they must be administered at extremely high doses, and it takes several hours for the compound to reach a therapeutically effective 10B concentration in tumor cells

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