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.

Self-assembly of affinity-controlled nanoparticles via host-guest interactions for drug delivery.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.