Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.

Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations

Nanotechnology has the potential to circumvent several drawbacks of conventional therapeutic formulations. In fact, significant strides have been made towards the application of engineered nanomaterials for the treatment of cancer with high specificity, sensitivity and efficacy. Tailor-made nanomaterials functionalized with specific ligands can target cancer cells in a predictable manner and deliver encapsulated payloads effectively. Moreover, nanomaterials can also be designed for increased drug loading, improved half-life in the body, controlled release, and selective distribution by modifying their composition, size, morphology, and surface chemistry. To date, polymeric nanomaterials, metallic nanoparticles, carbon-based materials, liposomes, and dendrimers have been developed as smart drug delivery systems for cancer treatment, demonstrating enhanced pharmacokinetic and pharmacodynamic profiles over conventional formulations due to their nanoscale size and unique physicochemical characteristics. The data present in the literature suggest that nanotechnology will provide next-generation platforms for cancer management and anticancer therapy. Therefore, in this critical review, we summarize a range of nanomaterials which are currently being employed for anticancer therapies and discuss the fundamental role of their physicochemical properties in cancer management. We further elaborate on the topical progress made to date toward nanomaterial engineering for cancer therapy, including current strategies for drug targeting and release for efficient cancer administration. We also discuss issues of nanotoxicity, which is an often-neglected feature of nanotechnology. Finally, we attempt to summarize the current challenges in nanotherapeutics and provide an outlook on the future of this important field.

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Current trends and challenges in cancer management and therapy using designer nanomaterials

Functionalized graphene nanocomposites for enhancing photothermal therapy in tumor treatment

Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy.

Nanocarbons with different dimensions (e.g., 0D fullerenes and carbon nanodots, 1D carbon nanotubes and graphene nanoribbons, 2D graphene and graphene oxides, and 3D nanodiamonds) have attracted enormous interest for applications ranging from electronics, optoelectronics, and photovoltaics to sensing, bioimaging, and therapeutics due to their unique physical and chemical properties. Among them, nanocarbon-based theranostics (i.e., therapeutics and diagnostics) is one of the most intensively studied applications, as these nanocarbon materials serve as excellent biosensors, versatile drug/gene carriers for specific targeting in vivo, effective photothermal nanoagents for cancer therapy, and promising fluorescent nanolabels for cell and tissue imaging. This review provides a systematic overview of the latest theranostic applications of nanocarbon materials with a comprehensive comparison of the characteristics of different nanocarbon materials and their influences on theranostic applications. We first introduce the different carbon allotropes that can be used for theranostic applications with their respective preparation and surface functionalization approaches as well as their physical and chemical properties. Theranostic applications are described separately for both in vitro and in vivo systems by highlighting the protocols and the studied biosystems, followed by the toxicity and biodegradability implications. Finally, this review outlines the design considerations for nanocarbon materials as the key unifying themes that will serve as a foundational first principle for researchers to study, investigate, and generate effective, biocompatible, and nontoxic nanocarbon materials-based models for cancer theranostics applications. Finally, we summarize the review with an outlook on the challenges and novel theranostic protocols using nanocarbon materials for hard-to-treat cancers and other diseases. This review intends to present a comprehensive guideline for researchers in nanotechnology and biomedicine on the selection strategy of nanocarbon materials according to their specific requirements.

Nanocarbons for Biology and Medicine: Sensing, Imaging, and Drug Delivery

One-step reduction and PEGylation of graphene oxide for photothermally controlled drug delivery.

In the present work, we report a facile and rapid green strategy to fabricate functionalized reduced nano-graphene oxide (nrGO) as a cooperative nanotemplate for both photothermal therapy and drug loading. Graphite oxide was firstly oxidated by nitronium ions (NO2
 +) solution at the aid of microwave heating to obtain nano-GO (nGO) with about 50 nm of diameter, and the nGO was then reduced in pure glucose at 135 °C for 30 min to obtain nrGO with about 40 nm of diameter. The nrGO exhibits excellent biocompatibility including stable dispersibility in cell culture medium and rapid cellular uptake as well as non-cytotoxicity up to 100 μg/mL. Absorption of the nrGO at 808 nm wavelength increased more than 10-folds compared with nGO. Moreover, the nrGO has the ability to load about 317 % (w/w) of doxorubicin (DOX), and the loaded DOX could be effectively released by acid condition and/or glutathione (GSH) and/or heating. Finally, a greater cancer cell death efficacy was observed in nrGO/DOX-treated cells with GSH and heating stimulation respectively or their combination. Collectively, the nrGO developed here is an outstanding cooperative nano-platform for high-efficiency photothermal therapy and controllable drug delivery.

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Glucose-Reduced Graphene Oxide with Excellent Biocompatibility and Photothermal Efficiency as well as Drug Loading

Graphene oxide (GO) has great potential in biomedical applications due to its excellent photothermal effect and drug loading. Herein, dual-functionalized reduced nano-GO (nrGO–PEG/PEI) has been developed as a synergistic system of drug delivery and an NIR-light-absorbing agent. Covalently PEGylated nanographene oxide (nGO–PEG) was simultaneously reduced and PEIylated by bathing with polyethylenimine (PEI 1.8 kDa) solution in water at 80 °C for 2 h to obtain nrGO–PEG/PEI. nrGO–PEG/PEI exhibited low cytotoxicity and excellent dispersibility in physiological environments. Furthermore, nrGO–PEG/PEI had ∼20-fold increment in NIR absorption at 808 nm and ∼2.7-fold increment in doxorubicin (DOX) loading over unreduced nGO–PEG. Loaded DOX could be efficiently released from nrGO–PEG/PEI/DOX in an acidic environment (pH 5.0) and by NIR irradiation. In addition, nrGO–PEG/PEI could be rapidly encapsulated into cells and targeted to the nucleus region. In vitro and in vivo studies demonstrated the remarkable anticancer effects of nrGO–PEG/PEI/DOX with NIR laser irradiation. These results suggest that nrGO–PEG/PEI may be a novel drug delivery platform for controlling chemo-photothermal synergistic cancer therapy.

One-step reduction and PEIylation of PEGylated nanographene oxide for highly efficient chemo-photothermal therapy.

In this study, a physiologically stable dual-polymer-functionalized reduced nanographene oxide (nrGO) conjugate (PEG–nrGO–PEI, RGPP) with high efficiency of gene delivery is successfully synthesized through mixing PEGylated nanographene oxide (PEG–nGO, GP) and polyethylenimine (PEI, 25 kDa) solution under 80 °C for 2 h. This hydrothermal reduction of GP during PEIylation promotes the nucleophilic reaction between the amino moieties of PEI and the epoxy groups (or carboxylic groups) in GP and then forms C–NH– groups (or NH–CO groups) to covalently connect PEI and GP, which makes the RGPP nanocomposite more stable in physiological environments and has superior gene transfection efficiency compared with the nonhydrothermally reduced PEG–nGO/PEI conjugate (GPP) obtained by mixing GP and PEI under 20 °C for 2 h. Moreover, 808 nm laser irradiation (2 W/cm2) for 25 min increases ∼1.5-fold of gene transfection efficiency for RGPP but does not increase the gene transfection efficiency of GPP. Finally, RGPP is also...

Tan Li

Papers

One-step reduction and PEGylation of graphene oxide for photothermally controlled drug delivery.

Glucose-Reduced Graphene Oxide with Excellent Biocompatibility and Photothermal Efficiency as well as Drug Loading

One-step reduction and PEIylation of PEGylated nanographene oxide for highly efficient chemo-photothermal therapy.

Hydrothermal Reduction of Polyethylenimine and Polyethylene Glycol Dual-Functionalized Nanographene Oxide for High-Efficiency Gene Delivery

Potent proapoptotic actions of dihydroartemisinin in gemcitabine-resistant A549 cells.