Biosynthesis for the preparation of antimicrobial silver nanoparticles (Ag NPs) is a green method without the use of cytotoxic reducing and surfactant agents. Herein, shape-controlled and well-dispersed Ag NPs were biosynthesized using yeast extract as reducing and capping agents. The synthesized Ag NPs exhibited a uniform spherical shape and fine size, with an average size of 13.8 nm. The biomolecules of reductive amino acids, alpha-linolenic acid, and carbohydrates in yeast extract have a significant role in the formation of Ag NPs, which was proved by the Fourier transform infrared spectroscopy analysis. In addition, amino acids on the surface of Ag NPs carry net negative charges which maximize the electrostatic repulsion interactions in alkaline solution, providing favorable stability for more than a year without precipitation. The Ag NPs in combination treatment with ampicillin reversed the resistance in ampicillinresistant E. coli cells. These monodispersed Ag NPs could be a promising alternative for the disinfection of multidrugresistant bacterial strains, and they showed negligible cytotoxicity and good biocompatibility toward Cos-7 cells.

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The desired control of particle size, doping element composition, and surface structure of carbon dots (CDs) are vital for understanding the fluorescence mechanism and exploring their potential applications. Herein, nitrogen-doped CDs (N-doped CDs) have been synthesized with tartaric acid and various alkylol amines (monoethanolamine, biethanolamine and triethanolamine) under microwave irradiation. A systematic investigation was performed to characterize the N-doped CDs. It is found that with increasing nitrogen proportion, the fluorescent quantum yield and lifetime of N-doped CDs increases, whereas cell toxicity decreases. In other words, N-doped CDs synthesized by tartaric acid and monoethanolamine have the highest nitrogen content, the highest fluorescent quantum yield, the longest lifetime and the lowest cell toxicity. A corresponding mechanism has been proposed. Moreover, as-synthesized N-doped CDs have been applied for selectively detecting the Fe(3+) ion and writing letters as a fluorescent ink.

Recently, carbon dots (CDs) have been playing an increasingly important role in industrial production and biomedical field because of their excellent properties. As such, finding an efficient method to quickly synthesize a large scale of relatively high purity CDs is of great interest. Herein, a facile and novel microwave method has been applied to prepare nitrogen doped CDs (N-doped CDs) within 8 min using L-glutamic acid as the sole reaction precursor in the solid phase condition. The as-prepared N-doped CDs with an average size of 1.64 nm are well dispersed in aqueous solution. The photoluminescence of N-doped CDs is pH-sensitive and excitation-dependent. The N-doped CDs show a strong blue fluorescence with relatively high fluorescent quantum yield of 41.2%, which remains stable even under high ionic strength. Since the surface is rich in oxygen-containing functional groups, N-doped CDs can be applied to selectively detect Fe(3+) with the limit of detection of 10(-5) M. In addition, they are also used for cellular bioimaging because of their high fluorescent intensity and nearly zero cytotoxicity. The solid-phase microwave method seems to be an effective strategy to rapidly obtain high quality N-doped CDs and expands their applications in ion detection and cellular bioimaging.

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Dual -targeted therapy in HER2-positive breast cancer cells with the combination of carbon dots/HER3 siRNA and trastuzumab resulted in enhanced antitumor activity, which overcomes the resistance to trastuzumab monotherapy. Herein, we have developed branched polyethylenimine -functionalized carbon dot (BP-CD) nanocarriers, which exhibited efficient green fluorescent protein gene delivery and expression. The positively charged BP-CDs allowed for effective nucleic acid binding and displayed a high ly efficient small interfering RNA (siRNA)-mediated delivery targeting of cancer cells. The transfection of BP-CDs and HER3 siRNA complexes down-regulated HER3 protein expression and induced significant cell growth inhibition in BT-474 cells. BP-CDs/HER3 siRNA complexes induced cell death of BT-474 cells through G0/G1 cell cycle arrest and apoptosis. The combined treatment of BP-CDs/HER3 siRNA complexes and trastuzumab caused greater cell growth suppression in BT-474 cells when compared to either agent alone. The findings suggest that this dual -targeted therapy with the combination of BP-CDs/HER3 siRNA and trastuzumab represents a promising approach in breast cancer.

HER2 overexpression is frequently associated with tumor metastasis and poor prognosis of breast cancer. More evidence indicates that HER3 is involved in HER2-resistant therapies. Combination treatments with two or more different monoclonal antibodies are a promising strategy to overcome resistance to HER2 therapies. We presented a novel fully human HER2-targeted monoclonal antibody, GB235, screened from a phage-display library against the HER2 antigen. GB235 in combination with Trastuzumab overcomes resistance in HER2-positive tumors and results in more sustained inhibition of tumor growth over time. The competition binding assay showed that the epitopes of GB235 do not overlap with those of Pertuzumab and Trastuzumab on HER2. Further HER2 mutagenesis results revealed that the binding epitopes of GB235 were located in the domain III of HER2. The mechanism of action of GB235 in blocking HER2-driven tumors is different from the mechanisms of Trastuzumab or Pertuzumab. GB235 does not affect the heterodimerization of HER2 and HER3, whereas the GB235 combined treatment with Trastuzumab significantly inhibited heregulin-induced HER3 phosphorylation and downstream signaling. Moreover, GB235 in combination with Trastuzumab reversed the resistance to heregulin-induced proliferation in HER2-overexpressing cancer cell lines. GB235 combined with Trastuzumab treatment in xenograft models resulted in improved antitumor activity. Complete tumor suppression was observed in the HER2-positive NCI-N87 xenograft model treated with the combination treatment with GB235 and Trastuzumab. In a Trastuzumab-resistant patient-derived tumor xenograft model GA0060, GB235 plus Trastuzumab reversed the resistance to Trastuzumab monotherapy. Because GB235 showed a different working mechanism with Pertuzumab and Trastuzumab, these agents can be considered complementary therapy against HER2 overexpression tumors.www.nature.com/scientificreports www.nature.com/scientificreports/ to HER2 ECD proteins of three different species. GB235 specifically bound to human and rat HER2 ECD, but did not cross-react with the mouse HER2 ECD in the ELISA (Fig. 6C). Moreover, it was observed that 362D, 374Q, 395D, 456 H are phylogenetically conserved in human and rat HER2 ECD d III , but not in mouse HER2 ECD d III . The residues are conserved in the human and rat HER2 but not in the mouse HER2, thus explaining the lack of cross-reaction with mouse HER2. The binding of the full-length human HER2 ECD d I-IV to GB235 was abolished in site-directed mutants of human HER2 (D362N, Q374H and H456N) (Fig. 6D). The residues 362D, 374Q and 456 H in the human HER2 ECD d III were found to be critical for the binding of GB235.

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