Nanotoxicology and Nanomedicine: The Yin and Yang of Nano-Bio Interactions for the New Decade.

Nanotoxicology and nanomedicine are two sub-disciplines of nanotechnology focusing on the phenomena, mechanisms, and engineering at the nano-bio interface. For the better part of the past three decades, these two disciplines have been largely developing independently of each other. Yet recent breakthroughs in microbiome research and the current COVID-19 pandemic demonstrate that holistic approaches are crucial for solving grand challenges in global health. Here we show the Yin and Yang relationship between the two fields by highlighting their shared goals of making safer nanomaterials, improved cellular and organism models, as well as advanced methodologies. We focus on the transferable knowledge between the two fields as nanotoxicological research is moving from pristine to functional nanomaterials, while inorganic nanomaterials - the main subjects of nanotoxicology - have become an emerging source for the development of nanomedicines. We call for a close partnership between the two fields in the new decade, to harness the full potential of nanotechnology for benefiting human health and environmental safety.

Dissecting the molecular mechanism of apoptosis during photothermal therapy using gold nanoprisms.

The photothermal response of plasmonic nanomaterials can be exploited for a number of biomedical applications in diagnostics (biosensing and optoacoustic imaging) and therapy (drug delivery and photothermal therapy). The most common cellular response to photothermal cancer treatment (ablation of solid tumors) using plasmonic nanomaterials is necrosis, a process that releases intracellular constituents into the extracellular milieu producing detrimental inflammatory responses. Here we report the use of laser-induced photothermal therapy employing gold nanoprisms (NPRs) to specifically induce apoptosis in mouse embryonic fibroblast cells transformed with the SV40 virus. Laser-irradiated "hot" NPRs activate the intrinsic/mitochondrial pathway of apoptosis (programmed cell death), which is mediated by the nuclear-encoded proteins Bak and Bax through the activation of the BH3-only protein Bid. We confirm that an apoptosis mechanism is responsible by showing how the NPR-mediated cell death is dependent on the presence of caspase-9 and caspase-3 proteins. The ability to selectively induce apoptotic cell death and to understand the subsequent mechanisms provides the foundations to predict and optimize NP-based photothermal therapy to treat cancer patients suffering from chemo- and radioresistance.

Gold nanoprisms for photothermal cell ablation in vivo.

AIM: To develop new methodologies for selective cell ablation in a temporally and spatially precise fashion in model organisms. MATERIALS & METHODS: living polyps (Hydra vulgaris) treated with gold nanoprisms were near-infrared (NIR) irradiated and the photothermal effects evaluated at whole-animal, cellular and molecular levels. RESULTS: Nanoprisms showed good efficiency of internalization in living specimens, with no sign of toxicity; under NIR irradiation they induced cell death and the overexpression of the hsp70 gene. CONCLUSION: gold nanoprisms could be employed as efficient heat mediators in model organisms, and NIR-triggered cell ablation may represent a new advanced tool to study cell function. Solving bioethical and economical issues, invertebrates may provide alternative models bridging the gap between cell research and preclinical studies of photothermal therapy.

CuTe nanocrystals: shape and size control, plasmonic properties, and use as SERS probes and photothermal agents.

We report a procedure to prepare highly monodisperse copper telluride nanocubes, nanoplates, and nanorods. The procedure is based on the reaction of a copper salt with trioctylphosphine telluride in the presence of lithium bis(trimethylsilyl)amide and oleylamine. CuTe nanocrystals display a strong near-infrared optical absorption associated with localized surface plasmon resonances. We exploit this plasmon resonance for the design of surface-enhanced Raman scattering sensors for unconventional optical probes. Furthermore, we also report here our preliminary analysis of the use of CuTe nanocrystals as cytotoxic and photothermal agents.

Gene silencing mediated by magnetic lipospheres tagged with small interfering RNA.

Lipospheres made from soy bean oil and a combination of the cationic lipid Metafectene and the helper lipid dioleoylphosphatidyl-ethanolamine were functionalized with magnetic nanoparticles (NPs) and small interfering RNA (siRNA). The resulting magnetic lipospheres loaded with siRNA are proven here as efficient nonviral vectors for gene silencing. Embedding magnetic NPs in the shell of lipospheres allows for magnetic force-assisted transfection (magnetofection) as well as magnetic targeting in both static and fluidic conditions mimicking the bloodstream.

The effect of PEG-coated gold nanoparticles on the anti-proliferative potential of Specific Nutrient Synergy.

The role of PEG-coated gold nanoparticles (Au NPs) on the anti-proliferative effect of Specific Nutrient Synergy (SNS) on HTLV-1 infected (C91-PL and HuT-102) and non-infected (CEM and Jurkat) malignant T-lymphocytes cells, was investigated. When PEG-coated Au NPs (of different molecular weights) were added alone, there was no effect on either viability or proliferation of the leukemic cell lines studied. Treatment of cells with SNS and PEG (5 or 10 kDa) coated Au NP reduced significantly the proliferation in all cell lines tested; this reached more than 50% reduction as compared to the control for cells treated for 96 h. Data showed that the best anti-proliferative effect was obtained using SNS and Au NP coated with PEG of molecular weights of 5 and 10 kDa with almost no effect of PEG of lower molecular weights (0.75 and 2 kDa) or higher ones (20 kDa). This was true as well for HTLV-1 infected as for non-infected malignant T-lymphocytes. Electron microscopy results showed uptake of the gold particles to Jurkat cells. All described effects are specific to leukemia cell lines, and no effects were observed with freshly activated human mononuclear lymphocytes as control.

Magnetic targeting and cellular uptake of polymer microcapsules simultaneously functionalized with magnetic and luminescent nanocrystals.

By using a flow channel system for modeling the bloodstream in the circulatory system and by locally creating a magnetic field gradient caused by a permanent magnet, we demonstrate specific trapping of polymer capsules simultaneously functionalized with two types of nanoparticles--magnetic and luminescent nanocrystals. In the regions where the capsules were trapped by the magnetic field, drastically increased uptake of capsules by cells has been observed. The uptake of capsules by cells could be conveniently monitored with a fluorescence microscope by the luminescence of CdTe nanocrystals that had been embedded into the shells of the capsules. Our experiments envisage the feasibility of magnetic targeting of polymer capsules loaded by pharmaceutical agents to pathogenic parts of a tissue.

Sorting fluorescent nanocrystals with DNA.

Semiconductor nanocrystals with narrow and tunable fluorescence are covalently linked to oligonucleotides. These biocompounds retain the properties of both nanocrystals and DNA. Therefore, different sequences of DNA can be coded with nanocrystals and still preserve their ability to hybridize to their complements. We report the case where four different sequences of DNA are linked to four nanocrystal samples having different colors of emission in the range of 530-640 nm. When the DNA-nanocrystal conjugates are mixed together, it is possible to sort each type of nanoparticle by using hybridization on a defined micrometer-size surface containing the complementary oligonucleotide. Detection of sorting requires only a single excitation source and an epifluorescence microscope. The possibility of directing fluorescent nanocrystals toward specific biological targets and detecting them, combined with their superior photostability compared to organic dyes, opens the way to improved biolabeling experiments, such as gene mapping on a nanometer scale or multicolor microarray analysis.