Boron rich nanotube drug carrier system is suited for boron neutron capture therapy

Fabian Heide,David Davidson,Camila Aprosoff,Francis Lin,Roy Roshko,Aniel Moya-Torres,Candice Harder-Viddal,Jiandong Wu,Jörg Stetefeld,Matthew Mcdougall

doi:10.1038/s41598-021-95044-0

Abstract

Boron neutron capture therapy (BNCT) is a two-step therapeutic process that utilizes Boron-10 in combination with low energy neutrons to effectively eliminate targeted cells. This therapy is primarily used for difficult to treat head and neck carcinomas; recent advances have expanded this method to cover a broader range of carcinomas. However, it still remains an unconventional therapy where one of the barriers for widespread adoption is the adequate delivery of Boron-10 to target cells. In an effort to address this issue, we examined a unique nanoparticle drug delivery system based on a highly stable and modular proteinaceous nanotube. Initially, we confirmed and structurally analyzed ortho-carborane binding into the cavities of the nanotube. The high ratio of Boron to proteinaceous mass and excellent thermal stability suggest the nanotube system as a suitable candidate for drug delivery into cancer cells. The full physicochemical characterization of the nanotube then allowed for further mechanistic molecular dynamic studies of the ortho-carborane uptake and calculations of corresponding energy profiles. Visualization of the binding event highlighted the protein dynamics and the importance of the interhelical channel formation to allow movement of the boron cluster into the nanotube. Additionally, cell assays showed that the nanotube can penetrate outer membranes of cancer cells followed by localization around the cells’ nuclei. This work uses an integrative approach combining experimental data from structural, molecular dynamics simulations and biological experiments to thoroughly present an alternative drug delivery device for BNCT which offers additional benefits over current delivery methods.

Highlights

Are capable of targeting cancer cells for Boron neutron capture therapy (BNCT)
To further confirm the uptake of o-carborane into Right-Handed Coiled Coil-Nanotube (RHCC-NT), we performed a Boron Nuclear Magnetic Resonance experiment comparing liganded versus unliganded nanotube samples
Our results show chemical shifts corresponding to the boron nuclei moving from a hydrophilic to a hydrophobic environment in the presence of the nanotube (Fig. 1B)

Summary

Introduction

Are capable of targeting cancer cells for BNCT. These include lipid based nanocarriers[6], inorganic nanoparticles[7,8,9], drug conjugates[10] and more recently, peptide based carrier s ystems[11,12]. In order to present a novel nanoparticle for the use of drug delivery, the physicochemical properties have to be closely examined. Binding mechanisms and targeting are demonstrated which endorse further studies. We present an unconventional drug delivery device entitled Right-Handed Coiled Coil-Nanotube (RHCC-NT) which is ideally suited to uptake boron clusters into its large internal cavities. In addition to binding small molecules, this nanotube can be internalized by eukaryotic cells, which offers possibilities for targeted drug delivery in BNCT. Our data demonstrate that RHCC-NT can uptake o-carboranes, C2B10H12, and deliver them into tumor cells for the use in BNCT

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Results

Conclusion