On-Demand Biodegradable Boron Nitride Nanoparticles for Treating Triple Negative Breast Cancer with Boron Neutron Capture Therapy

Abstract

Compared with photon-induced binary cancer therapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), boron neutron capture therapy (BNCT) emerges as an alternative noninvasive treatment strategy that could overcome the shallow penetration of light. One key factor in performing successful BNCT is to accumulate a sufficient amount of B-10 (>20 ppm) within tumor cells, which has been a long-standing challenge for small-molecule-based boron drugs. Boron nitride nanoparticles (BNNPs) are promising boron carriers due to their high boron content and good biocompatibility, as certain types of BNNPs can undergo rapid degradation under physiological conditions. To design an on-demand degradable boron carrier, BNNPs were coated by a phase-transitioned lysozyme (PTL) that protects BNNPs from hydrolysis during blood circulation and can be readily removed by vitamin C after neutron capture therapy. According to PET imaging, the coated BNNPs exhibited high tumor boron accumulation while maintaining a good tumor to nontumor ratio. Tail-vein injections of vitamin C were followed by neutron irradiation, and BNNPs were found to be rapidly cleared from major organs according to ex vivo ICP-OES analysis. Compared with the control group, animals treated with BNCT showed suppression of tumor growth, while almost negligible side effect was observed. This strategy not only utilized the high boron content of BNNPs but also successfully performed an on-demand degradation of BNNPs to avoid the potential toxicity caused by the long-term accumulation of nanoparticles.

Boron Chemistry for Medical Applications

“…Boron clusters have the following properties that are helpful in drug design: (a) the unique non-covalent interaction ability, including ionic interactions, σ-hole bonding and dihydrogen bond formation, is different from that of pure organic molecules due to its interaction with biological targets [21,44,45]; (b) ellipsoidal or spherical geometry and 3D arrangement which are helpful in the construction for 3D molecule; (c) the hydrophilicity, amphiphilicity, or lipophilicity allows the alteration of bioavaliabilty and pharmazcokinetics which is subject to the type of boron cluster utilized; (d) bioorthogonality, lessened vulnerability to metabolism and stability in a biological environment; (e) chemical stability and concurrent vulnerability to functionalization; (f) resistance to ionizing radiation, this property is essential for the radiopharmaceutical drug designing; and (g) high content of boron in the cluster is an important aspect to explore its application for BNCT [5,6,46].…”

“…Recently, many small molecule-based boron carriers have been explored in the preclinical trials, some of which are discussed here. However, due to their insufficient accumulation of boron in tumor cells, clinical studies have been limited [34,46].…”

“…These polymers undergo hydrolysis in a physiological environment due to their polyester structure. Compared to the natural degradation mentioned above, the exogenous response is more precise and controllable [84][85][86], compared to the on-demand decomposition process [46]. A third generation of boron-containing compounds were recently investigated.…”

“…Recently, it has been reported that boron nitride nanoparticles (BNNPs) exhibited good results in treating triple negative breast cancer in mice [46]. Since BNNPs show good biocompatibility and have high boron content capacity, they are considered as promising boron carriers.…”

“…(a) Schematic representation of the synthesis of the PTL@BNNPs, (b) Illustration of PTL@BNNPs Based BNCT and its degradation (Reprinted from Ref [46]…”