Cellular uptake, intracellular behavior, and acute/sub-acute cytotoxicity of a PEG-modified quantum dot with promising in-vivo biomedical applications.

Quantum Dots (QDs) modified with branched Polyethylene Glycol-amine (6- or 8-arm PEG-amine) coupled with methoxy PEG (mPEG) hold great promise for in vivo biomedical applications due to a long half-life in blood and negligible toxicity. However, the potential risks regarding their concomitant prolonged co-incubation with cardiovascular and blood cells remains inconclusive. In the present study, the feasible, effective and convenient proliferating-restricted cell line models representing the circulatory system were established to investigate the cellular internalization followed by intracellular outcomes and resulting acute/sub-acute cytotoxicity of the 6-arm PEG-amine/mPEG QDs. We found a dose-, time- and cell type-dependent cellular uptake of the 6-arm PEG-amine/mPEG QDs, which was ten-fold lower compared to the traditional linear PEG-modified counterpart. The QDs entered cells via multiple endocytic pathways and were mostly preserved in Golgi apparatus for at least one week instead of degradation in lysosomes, resulting in a minimal acute cytotoxicity, which is much lower than other types of PEG-modified QDs previously reported. However, a sub-acute cytotoxicity of QDs were observed several days post exposure using the concentrations eliciting no-significant acute cytotoxic effects, which was associated with elevated ROS generation caused by QDs remained inside cells. Finally, a non-cytotoxic concentration of the QDs was identified at the sub-acute cytotoxic level. Our study provided important information for clinical translation of branched PEG-amine/mPEG QDs by elucidating the QDs-cell interactions and toxicity mechanism using the proliferation-restricted cell models representing circulatory system. What's more, we emphasized the indispensability of sub-acute cytotoxic effects in the whole biosafety evaluation process of nanomaterials like QDs.

Effective suppression of triple negative breast cancer by paclitaxel nanoparticles conjugated with transmembrane TNF-α monoclonal antibody.

Transmembrane TNF-α (tmTNF), a transmembrane form of TNF-α, was reported overexpressed in approximately 84% of triple-negative breast cancer (TNBC) patients and has emerged as a valid candidate biomarker for targeting TNBC. Paclitaxel is a first-line chemotherapeutic agent for the treatment of triple-negative breast cancer, but suffers from low water solubility, resulting in its low bioavailability. To achieve site-specific delivery of the anticancer chemotherapeutic drug (paclitaxel) on TNBC, we developed tmTNF-α monoclonal antibody (mAb)-conjugated paclitaxel (PTX) nanoparticles (NPs) (tmTNF-α mAb-PTX NPs) as potential nanocarriers. This targeted delivery-therapy nanocarriers was conducted by using an emulsification-evaporation method. tmTNF-α mAb-PTX NPs displayed favorable physicochemical properties. Compared with the control groups, tumor growth in human MDA-MB-231 xenograft mice was suppressed significantly by tmTNF-α mAb-PTX NPs. TmTNF-α mAb-PTX NPs exerts anti-tumor effects via promoting apoptosis and regulating mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) cascade, as well as AMP-activated protein kinase (AMPK) and nuclear factor Kappa-B (NF-κB) pathways. Moreover, tmTNF-α mAb-PTX NPs can inhibit the process of epithelial-mesenchymal transition (EMT) in TNBC to suppress tumor progression and metastasis. Together, the novel tmTNF-α mAb-PTX NPs based targeted drug delivery system is a potentially highly effective approach for treating TNBC.

Kinetics and mechanism of Pseudoanabaena cell inactivation, 2-MIB release and degradation under exposure of ozone, chlorine and permanganate.

The organic pollutants produced by cyanobacteria cells, such as off-flavor compounds (e.g. 2-methylisoborneol, 2-MIB) and hazardous toxins (e.g. microcystins), are commonly detected in water sources. Although studies have shown that oxidation using potassium permanganate (KMnO4), chlorine and ozone helps to remove cyanobacteria cells, the potential effects of these oxidants on cell viability and the release of off-flavor substances have scarcely been explored. This study investigated the impacts of three widely used oxidants on Pseudanabaena sp. (a common species of 2-MIB producing cyanobacteria) inactivation, and on the release and degradation of intracellular 2-MIB. Experiments using KMnO4 showed that both the cell viability and 2-MIB release fit to a two-stage second-order kinetic model with a threshold of KMnO4 exposure (ct). No significant variations in the cell viability and 2-MIB release occurred until the exposure reached ct because KMnO4 was primarily consumed by the dissolved and cell-bound organic matters before it damaged the cell. However, chlorine permeates the cell membrane more easily, causing rapid algae inactivation and the subsequent cell lysis and 2-MIB release. Unlike permanganate and chlorine, which are unable to degrade the released 2-MIB because of their insufficient oxidation potentials, ozone is capable to inactivate the cell and degrade 2-MIB as well. When the initial O3 concentration is above a certain level (1.0 mg ·L-1 in this study), the released 2-MIB can be substantially oxidized. Therefore, the choice of a suitable oxidant and a proper dose is highly important in the control of off-flavor compounds during the treatment of algae-containing raw water.