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

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.

From alkaline earth to coinage metal carboranyls

“…Hydrogen atoms have been omitted for clarity while THF carbon atoms and Dipp substituents are displayed as wireframes, also for visual ease; displacement ellipsoids at 30%. Selected bond lengths (Å) and angles (°): Ca1-N1 2.304(3), Ca1-N2 2.301(3), Ca1-O1 2.299 (3), Ca1-C30 2.478(4), O1-Ca1-N1 112.76 (10), O1-Ca1-N2 111.17 (10), O1-Ca1-C30 100.34 (11), N1-Ca1-C30 117.03 (11), N2-Ca1-N1 84.63( 9), N2-Ca1-C30 130.88 (11). 5) was ultimately verified by X-ray diffraction analysis of a single crystal isolated by crystallisation of the crude reaction product from hexane solution.…”

“…8 Similarly, o-carborane has attracted significant attention in future antitumour therapeutics, specifically boron neutron capture therapy (BNCT). [9][10][11] Much research, therefore, has focused upon the modification of carboranes as a means to enhance their biologically relevant properties, commonly via ligand or indeed metal functionalisation. 7,9,11 There has, for example, been specific recent interest directed toward the luminescent and/or antimicrobial properties of derivatives in which the carboranyl unit is C-functionalised by one of the coinage metals of group 11 (Cu, Ag, and Au).…”

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment

“…80 Promising next generation of nanoparticles could be using two different isotopic elements, as investigated by Mikami et al, where NPs contained both boron and gadolinium (GdBO 3 ) with low cytotoxicity and low accumulation because of retention effects and enhanced permeability (Figure 6). 81 In addition, o-carborane loaded right-handed coiled coil-Nanotube (RHCC-NT) 82 has also been investigated as shown in Figure 6.…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…Nanoparticles are able to enhance permeability and retention effects as well as targeting effects, and thus can deliver 10 B atoms into tumor tissues with high concentrations. 40 , 41 , 42 , 43 , 44 , 45 Using nanomaterials to deliver 10 B-containing compounds for BNCT can potentially improve drug accumulation in tumor tissues. 46 Hydrophobic carborane fragments and the polymerized nanoparticles can be formed on a single backbone chain.…”