Boron Nanocomposites for Boron Neutron Capture Therapy and in Biomedicine: Evolvement and Challenges

Abstract

Cancer remains a major concern for human health worldwide. To fight the curse of cancer, boron neutron capture therapy is an incredibly advantageous modality in the treatment of cancer as compared to other radiotherapies. Due to tortuous vasculature in and around tumor regions, boron (¹⁰B) compounds preferentially house into tumor cells, creating a large dose gradient between the highly mingled cancer cells and normal cells. Epithermal or thermal neutron bombardment leads to tumor-cell-selective killing due to the generation of heavy particles yielded from in situ fission reaction. However, the major challenges for boron nanocomposites' development have been from the synthesis part as well as the requirement for selective cancer targeting and the delivery of therapeutic concentrations of boron (¹⁰B) with nominal healthy tissue accumulation and retention. To circumvent the above challenges, this review discusses boride nanocomposite design, safety, and biocompatibility for biomedical applications for general public use. This review sparks interest in using boron nanocomposites as boron neutron capture therapy agents and repurposing them in comorbidity treatments, with future scientific challenges and opportunities, with a hope to accelerate the stimulus of developing possible boron composite nanomedicine research and applications worldwide.

Fig. 1.

The principle of boron neutron capture therapy (BNCT).

Fig. 2.

Overview of the review.

Fig. 3.

(A) The chemical structure and molecular design of sialic acid-linked phenylboronic acid polymeric nanoparticles (Nano^PBA). (B) Distinct cellular uptake of the boronophenylalanine (BPA)–fructose complex compared to Nano^PBA. (C) Passive tumor targeting via the enhanced permeability and retention (EPR) effect. (D) Facilitated endocytosis of Nano^PBA followed by nuclear fission in response to thermal neutron irradiation. Reproduced with permission from Ref. [34]. (E) Self-assembled sodium borocaptate polyanion (polyethylene glycol-β-poly((closo-dodecaboranyl)thiomethylstyrene)) nanoparticles coupled with cationic microbubbles (B-MBs) with focused-ultrasound (FUS)-enhanced boron drug delivery targeting brain tumor. Reproduced with permission from Ref. [35]. (F) PTL@BNNPs-based BNCT with on-demand degradation [38]. (G) DOX@BNNSs-based drug delivery for cancer radiochemotherapy. Reproduced with permission from Ref. [127]. PEG, poly(ethylene glycol); PLA, poly(lactic acid); LAT1, l-type amino acid transporter; BPA, boronophenylalanine; DSP–PEG2000, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; DOTAP, 1,2-dioleoyl-3-trimethylammonium propane; DPPC, dipalmitoylphosphatidylcholine; PEG-b-PMBSH, polyethylene glycol-b-poly((closo-dodecaboranyl)thiomethylstyrene; BH, borohydride (comes in sodium borohydride salt); PTL, phase-transitioned lysozyme; BNNPs, boron nitride nanoparticles; DOX, doxorubicin; BNNSs, ¹⁰B-rich nanosheets; PEG-b-PMBSH, polyethylene glycol-β-poly((closo-dodecaboranyl)thiomethylstyrene); DSPE, 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine.

Fig. 4.

(A) Synthetic route of ¹⁰B-enriched hexagonal boron nitride nanoparticles grafted with polyglycerol (h-¹⁰BN-PG NPs). (B) Transmission electron microscopy (TEM) images of ¹⁰B-enriched hexagonal boron nitride (h-¹⁰BN) and h-¹⁰BN-PG NPs. Reproduced with permission from Ref. [43]. (C) Synthesis of ¹⁰B-enriched (96% ¹⁰B) nanoparticles (¹⁰BSGRF NPs) [62]. (D) Gadolinium–boron-conjugated albumin (Gd-MID-BSA). (E) Representative T₁-weighted images of the tumor at 0 h and 3, 6, 12, and 24 h postdose and corresponding T₁ time course of the tumor. Reproduced with permission from Ref. [75]. PVP, polyvinylpyrrolidone; PG, polyglycerol; APTES, (3-aminopropyl)triethoxysilane; DTPA, diethylenetriamine pentaacetate; FITC, fluorescein isothiocyanate; MRI, magnetic resonance imaging; PDB, Protein Data Bank; BSA, bovine serum albumin; Gd-DO3-Mal, maleimide-functionalized gadolinium complex; GdNCT, gadolinium neutron capture therapy; MID, maleimide-functionalized closo-dodecaborate albumin.

Fig. 5.

(A) Hexagonal boron nitride (h-BN)-triggered cellular autophagy involves its uptake by alveolar lung cells making lipid granules, leading to autophagy due to overproduction of cellular lipid granules. Reproduced with permission from Ref. [84]. (B) Pulmonary toxicity of h-BN and boron nitride nanotubes (BNNTs). Scale bars: 20 μm. (C) Evaluation of inflammatory markers levels in lungs by multiplex enzyme-linked immunosorbent assay (ELISA) as log₂ fold change. (I) Acute inflammation; (II) late pro-inflammatory response; (III) anti-inflammatory response; (IV) adaptive immune activation. Reproduced with permission from Ref. [86]. *P < 0.05; **P < 0.01; ***P < 0.001. LC3, microtubule-associated protein 1A/1B-light chain 3; LAMP1, lysosomal associated membrane protein 1; 2D, 2-dimensional; IL, interleukin; TNF-α, tumor necrosis factor alpha; MCP-1, monocyte chemoattractant protein-1; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; LPS, lipopolysaccharide.

Fig. 6.

(A) Reverse transcription quantitative real-time polymerase (RT-qPCR) analysis of pro-inflammatory genes IL-1β, IL-6, and TNF-α in macrophages incubated with mesoporous bioactive glass (MBG) and boron-containing MBG for 4 h at 1 mg ml⁻¹. (B) RTqPCR analysis of pro-osteogenic genes COL1A1, ALPL, SPARC, RANKL, OPG, and RANKL/OPG in osteoblast-like SaOS2 cells incubated with MBG and boron-containing MBG at the concentration of 1 mg mL−1 for 72 h and 7 days. Reproduced with permission from Ref. [102]. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001. (C to E) Effects on collagen deposition and extracellular matrix (ECM) calcification. Bone-marrow-derived mesenchymal stromal cells (BMSCs) were cultured for 7 and 21 d in the presence of B, Mo, and their combinations at a total concentration of 2.0 mM. Reproduced with permission from Ref. [112]. Antibacterial activity of B₂O₃–ZnO NPs on (F) Escherichia coli and (H) Staphylococcus aureus agar plates treated by different materials at 1 mM. Bacterial survival of (G) E. coli and (I) S. aureus. Reproduced with permission from Ref. [92]. ***P < 0.001. 10B-MBG, 5.8 mol% B₂O₃–mesoporous bioactive glass nanoparticles; 15B-MBG, 6.5 mol% B₂O₃–mesoporous bioactive glass nanoparticles; Col1A, collagen, type I, alpha 1; ALPL, alkaline phosphatase, biomineralization associated; SPARC, secreted protein acidic and cysteine rich; RANKL, receptor activator of NF-κB (RANK) ligand; OPG, osteoprotegerin; d7, day 7; d21, day 21; d3, day 3; con, control; MG, malachite green.