Aza-BODIPY: A New Vector for Enhanced Theranostic Boron Neutron Capture Therapy Applications.

Ghadir Kalot,Jean-Luc Coll,Benoît Busser,Jacques Pliquett,Lucie Sancey,Christine Goze,Vincent Motto-Ros,Karl David Wegner,Ute Resch-Genger,Franck Denat,Amélie Godard,Ulli Köster,Mans Broekgaarden,Ewen Bodio

doi:10.3390/cells9091953

Abstract

Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on the nuclear capture of slow neutrons by stable 10B atoms followed by charged particle emission that inducing extensive damage on a very localized level (<10 μm). To be efficient, a sufficient amount of 10B should accumulate in the tumor area while being almost cleared from the normal surroundings. A water-soluble aza-boron-dipyrromethene dyes (BODIPY) fluorophore was reported to strongly accumulate in the tumor area with high and BNCT compatible Tumor/Healthy Tissue ratios. The clinically used 10B-BSH (sodium borocaptate) was coupled to the water-soluble aza-BODIPY platform for enhanced 10B-BSH tumor vectorization. We demonstrated a strong uptake of the compound in tumor cells and determined its biodistribution in mice-bearing tumors. A model of chorioallantoic membrane-bearing glioblastoma xenograft was developed to evidence the BNCT potential of such compound, by subjecting it to slow neutrons. We demonstrated the tumor accumulation of the compound in real-time using optical imaging and ex vivo using elemental imaging based on laser-induced breakdown spectroscopy. The tumor growth was significantly reduced as compared to BNCT with 10B-BSH. Altogether, the fluorescent aza-BODIPY/10B-BSH compound is able to vectorize and image the 10B-BSH in the tumor area, increasing its theranostic potential for efficient approach of BNCT.

Highlights

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the vectorization of 10 B-rich compounds in tumor tissues before neutron exposure to selectively destroy cancer cells.Under low-energy neutron irradiation, the stable 10 B atoms may capture neutrons producing energetic alpha and 7 Li particles
Media, by substituting the fluorine atoms on the boron by alkyne ammonium groups [34,35,48]. We used this strategy on a particular Donor-AcceptorDonor’ aza-boron-dipyrromethene dyes (BODIPY) structure, which emits in the SWIR region, yielding a water-soluble derivative
To design an efficient theranostic boron vector, we used a fluorescent reporter platform based on the versatile BODIPY family (Figure 1a) displaying (i) a strong tumor accumulation and (ii)

Summary

Introduction

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the vectorization of 10 B-rich compounds in tumor tissues before neutron exposure to selectively destroy cancer cells.Under low-energy neutron irradiation, the stable 10 B atoms may capture neutrons producing energetic alpha and 7 Li particles. The generated high-linear energy transfer (LET) particles have a cell killing effect within a 10 μm-range [1,2]. Such type of cancer treatment may spare the surrounding healthy tissues but may be efficient to treat recurrent, or radioresistant to conventional X-ray photon therapy tumors [3,4,5,6]. BNCT has obtained promising clinical results for several pathologies as head and neck tumors including recurrent pathologies [3,5,7], malignant brain tumors [8,9], and malignant melanoma [10,11]. To be successful, 20 to 50 μg of 10 B per gram of tumor is necessary, with a tumor-to-normal tissue and tumor-to-blood ratio > 3:1 [15]

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Results

Conclusion