Rational Design, Multistep Synthesis and in Vitro Evaluation of Poly(glycerol) Functionalized Nanodiamond Conjugated with Boron-10 Cluster and Active Targeting Moiety for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT), advanced cancer treatment utilizing nuclear fission of ¹⁰ B atom in cancer cells, is attracting increasing attention. As ¹⁰ B delivery agent, sodium borocaptate (¹⁰ BSH, ¹⁰ B₁₂ H₁₁ SH ⋅ 2Na), has been used in clinical studies along with L-boronophenylalanine. Recently, this boron cluster has been conjugated with lipids, polymers or nanoparticles to increase selectivity to and retentivity in tumor. In this work, anticancer nanoformulations for BNCT are designed, consisting of poly(glycerol) functionalized detonation nanodiamonds (DND-PG) as a hydrophilic nanocarrier, the boron cluster moiety (¹⁰ B₁₂ H₁₁ ^2- ) as a dense boron-10 source, and phenylboronic acid or RGD peptide as an active targeting moiety. Some hydroxy groups in PG were oxidized to carboxy groups (DND-PG-COOH) to conjugate the active targeting moiety. Some hydroxy groups in DND-PG-COOH were then transformed to azide to conjugate ¹⁰ B₁₂ H₁₁ ^2- through click chemistry. The nanodrugs were evaluated in vitro using B16 murine melanoma cells in terms of cell viability, BNCT efficacy and cellular uptake. As a result, the ¹⁰ B₁₂ H₁₁ ^2- moiety is found to facilitate cellular uptake probably due to its negative charge. Upon thermal neutron irradiation, the nanodrugs with ¹⁰ B₁₂ H₁₁ ^2- moiety exhibited good anticancer efficacies with slight differences with and without targeting moiety.

Rational Design, Multistep Synthesis and in Vitro Evaluation of Poly(glycerol) Functionalized Nanodiamond Conjugated with Boron-10 Cluster and Active Targeting Moiety for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT), advanced cancer treatment utilizing nuclear fission of 10 B atom in cancer cells, is attracting increasing attention. As 10 B delivery agent, sodium borocaptate (10 BSH, 10 B12 H11 SH ⋅ 2Na), has been used in clinical studies along with L-boronophenylalanine. Recently, this boron cluster has been conjugated with lipids, polymers or nanoparticles to increase selectivity to and retentivity in tumor. In this work, anticancer nanoformulations for BNCT are designed, consisting of poly(glycerol) functionalized detonation nanodiamonds (DND-PG) as a hydrophilic nanocarrier, the boron cluster moiety (10 B12 H11 2- ) as a dense boron-10 source, and phenylboronic acid or RGD peptide as an active targeting moiety. Some hydroxy groups in PG were oxidized to carboxy groups (DND-PG-COOH) to conjugate the active targeting moiety. Some hydroxy groups in DND-PG-COOH were then transformed to azide to conjugate 10 B12 H11 2- through click chemistry. The nanodrugs were evaluated in vitro using B16 murine melanoma cells in terms of cell viability, BNCT efficacy and cellular uptake. As a result, the 10 B12 H11 2- moiety is found to facilitate cellular uptake probably due to its negative charge. Upon thermal neutron irradiation, the nanodrugs with 10 B12 H11 2- moiety exhibited good anticancer efficacies with slight differences with and without targeting moiety.

Tumor Eradication by Boron Neutron Capture Therapy with 10 B-enriched Hexagonal Boron Nitride Nanoparticles Grafted with Poly(Glycerol).

Boron neutron capture therapy (BNCT) has emerged as a treatment modality with high precision and efficacy of intractable tumors. At the core of effective tumor BNCT are 10 B carriers with facile preparation as well as advantageous pharmacokinetic and therapeutic profiles. Herein, the design and preparation of sub-10 nm 10 B-enriched hexagonal boron nitride nanoparticles grafted with poly(glycerol) (h-10 BN-PG), and their application to cancer treatment by BNCT are reported. By virtue of their small particle size and outstanding stealth property, h-10 BN-PG nanoparticles accumulate efficiently in murine CT26 colon tumors with a high intratumor 10 B concentration of 8.8%ID g-1 or 102.1 µg g-1 at 12 h post-injection. Moreover, h-10 BN-PG nanoparticles penetrate into the inside of the tumor parenchyma and then are taken up by the tumor cells. BNCT comprising a single bolus injection of h-10 BN-PG nanoparticles and subsequent one-time neutron irradiation results in significant shrinkage of subcutaneous CT26 tumors. h-10 BN-PG-mediated BNCT not only causes direct DNA damage to the tumor cells, but also triggers pronounced inflammatory immune response in the tumor tissues, which contributes to long-lasting tumor suppression after the neutron irradiation. Thus, the h-10 BN-PG nanoparticles are promising BNCT agents to eradicate tumor through highly efficient 10 B accumulation.

Polyglycerol Functionalized 10 B Enriched Boron Carbide Nanoparticle as an Effective Bimodal Anticancer Nanosensitizer for Boron Neutron Capture and Photothermal Therapies.

Boron neutron capture therapy (BNCT) is a non-invasive cancer treatment with little adverse effect utilizing nuclear fission of 10 B upon neutron irradiation. While neutron source has been developed from a nuclear reactor to a compact accelerator, only two kinds of drugs, boronophenylalanine and sodium borocaptate, have been clinically used for decades despite their low tumor specificity and/or retentivity. To overcome these challenges, various boron-containing nanomaterials, or "nanosensitizers", have been designed based on micelles, (bio)polymers and inorganic nanoparticles. Among them, inorganic nanoparticles such as boron carbide can include a much higher 10 B content, but successful in vivo applications are very limited. Additionally, recent reports on the photothermal effect of boron carbide are motivating for the addition of another modality of photothermal therapy. In this study, 10 B enriched boron carbide (10 B4 C) nanoparticle is functionalized with polyglycerol (PG), giving 10 B4 C-PG with enough dispersibility in a physiological environment. Pharmacokinetic experiments show that 10 B4 C-PG fulfills the following three requirements for BNCT; 1) low intrinsic toxicity, 2) 10 B in tumor/tumor tissue (wt/wt) ≥ 20 ppm, and 3) 10 B concentrations in tumor/blood ≥ 3. In vivo study reveals that neutron irradiation after intravenous administration of 10 B4 C-PG suppresses cancer growth significantly and eradicates cancer with the help of near-infrared light irradiation.

Effect of Protein Corona on Mitochondrial Targeting Ability and Cytotoxicity of Triphenylphosphonium Conjugated with Polyglycerol-Functionalized Nanodiamond.

Functionalization of nanoparticles (NPs) with targeting moieties has a high potential to advance precision nanomedicine. However, the targeting moieties on a NP surface are known to be masked by a protein corona in biofluids, lowering the targeting efficiency. Although it has been demonstrated at the cellular level, little is known about the influence of the protein corona on the subcellular targeting. Herein, we adopted triphenylphosphonium (TPP) as a mitochondrial targeting moiety and investigated the effects of protein coronas from fetal bovine serum and human plasma on its targeting ability and cytotoxicity. Specifically, we introduced TPP in low (l) and high (h) densities on the surface of nanodiamond (ND) functionalized with polyglycerol (PG). Despite the "corona-free" PG interface, we found that the TPP moiety attracted proteins to form a corona layer with clear linearity between the TPP density and the protein amount. By performing investigations on human cervix epithelium (HeLa) and human lung epithelial carcinoma (A549) cells, we further demonstrated that (1) the protein corona alleviated the cytotoxicity of both ND-PG-TPP-l and -h, (2) a smaller amount of proteins on the surface of ND-PG-TPP-l did not affect its mitochondrial targeting ability, and (3) a larger amount of proteins on the surface of ND-PG-TPP-h diminished its targeting specificity by restricting the NDs inside the endosome and lysosome compartments. Our findings will provide in-depth insights into the design of NPs with active targeting moiety for more precise and safer delivery at the subcellular level.

Fast and Scalable Hydrodynamic Synthesis of MnO2/Defect-Free Graphene Nanocomposites with High Rate Capability and Long Cycle Life.

The integration of metal oxides and carbon materials provides a great potential for enhancing the high energy and power densities of supercapacitors, but the rational design and scalable fabrication of such composite materials still remain a challenge. Herein, we report a fast, scalable, and one-pot hydrodynamic synthesis for preparing ion conductive and defect-free graphene from graphite and MnO2/graphene nanocomposites. The use of this hydrodynamic method using Taylor-Couette flow allows us to efficiently fast shear-exfoliate graphite into large quantities of high-quality graphene sheets. Deposition of MnO2 on graphene is subsequently performed in a fluidic reactor within 10 min. The prepared MnO2/graphene nanocomposite shows outstanding electrochemical performances, such as a high specific capacitance of 679 F/g at 25 mV/s, a high rate capability of 74.7% retention at an extremely high rate of 1000 mV/s, and an excellent cycling characteristic (∼94.7% retention over 20 000 cycles). An asymmetric supercapacitor device is fabricated by assembling an anode of graphene and a cathode of MnO2/graphene, which resulted in high energy (35.2 W h/kg) and power (7.4 kW/kg) densities (accounting for the mass of both electrodes and the electrolyte) with a high rate capability and long cycle life.