Peidang Liu

Enhanced Fluorescence of Gold Nanoclusters Composed of HAuCl4 and Histidine by Glutathione: Glutathione Detection and Selective Cancer Cell Imaging

Glutathione (GSH) can significantly and selectively enhance the fluorescence intensity of Au nanoclusters (NCs) prepared by blending HAuCl4 and histidine in solution. The quantum yield of the Au NCs after adding GSH can reach above 10%. Besides, GSH capping shifts the excitation peak of Au NCs from ultraviolet (386 nm) to visible light (414 nm) and improves the stability of the Au NCs. The cytotoxicities of the Au NCs with and without GSH for normal lung cells (ATII) and cancerous lung cells (A549) are evaluated. The GSH-capped Au NCs have much less cytotoxicity to both normal and cancer cells, as compared to those without GSH. For Au NCs without GSH, less cytotoxicity is observed in cancer cells than in normal cells. In addtion, the Au NCs can selectively detect GSH over cysteine and homocysteine, the two biothiols which commonly exist in cells that can seriously affect GSH detection. Most importantly, Au NCs without GSH can selectively image the cancer cells, especially for the liver cancer cells whose GSH content is much higher than other cell types. This property makes the Au NCs a powerful probe to distinguish cancer cells from normal cells.

Silver nanoparticles: a novel radiation sensitizer for glioma?

Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.

Synthesis of Ultrastable Copper Sulfide Nanoclusters via Trapping the Reaction Intermediate: Potential Anticancer and Antibacterial Applications

Copper-based nanomaterials have broad applications in electronics, catalysts, solar energy conversion, antibiotics, tissue imaging, and photothermal cancer therapy. However, it is challenging to prepare ultrasmall and ultrastable CuS nanoclusters (NCs) at room temperature. In this article, a simple method to synthesize water-soluble, monodispersed CuS NCs is reported based on the strategy of trapping the reaction intermediate using thiol-terminated, alkyl-containing short-chain poly(ethylene glycol)s (HS-(CH2)11-(OCH2CH2)6-OH, abbreviated as MUH). The MUH-coated CuS NCs have superior stability in solutions with varied pH values and are stable in pure water for at least 10 months. The as-prepared CuS NCs were highly toxic to A549 cancer cells at a concentration of higher than 100 μM (9.6 μg/mL), making them be potentially applicable as anticancer drugs via intravenous administration by liposomal encapsulation or by direct intratumoral injection. Besides, for the first time, CuS NCs were used for antibacterial application, and 800 μM (76.8 μg/mL) CuS NCs could completely kill the E. coli cells through damaging the cell walls. Moreover, the NCs synthesized here have strong near-infrared (NIR) absorption and can be used as a candidate reagent for photothermal therapy and photoacoustic imaging. The method of trapping the reaction intermediate for simple and controlled synthesis of nanoclusters is generally applicable and can be widely used to synthesize many metal-based (such as Pt, Pd, Au, and Ag) nanoclusters and nanocrystals.

Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy

Radiation therapy performs an important function in cancer treatment. However, resistance of tumor cells to radiation therapy still remains a serious concern, so the study of radiosensitizers has emerged as a persistent hotspot in radiation oncology. Along with the rapid advancement of nanotechnology in recent years, the potential value of nanoparticles as novel radiosensitizers has been discovered. This review summarizes the latest experimental findings both in vitro and in vivo and attempts to highlight the underlying mechanisms of response in nanoparticle radiosensitization.

Is the autophagy a friend or foe in the silver nanoparticles associated radiotherapy for glioma

Malignant glioma is the most common intracranial tumor with a dismal prognosis. The radiosensitizing effect of silver nanoparticles (AgNPs) on glioma both in vitro and in vivo had been demonstrated in the previous studies of our group. However, the underlying mechanism is still unclear. Consistent with previous studies, a size and dose dependent antitumor effect and significant radiosensitivity enhancing effect of AgNPs were observed in our experiment system. We also found that cell protective autophagy could be induced by AgNPs and/or radiation, which was verified by the use of 3-MA. The mechanism through which had autophagy and the enhancement of radiosensitivity taken place was further investigated with inhibitors of ERK and JNK pathways. We demonstrated that ERK and JNK played pivotal roles in the radiosensitivity enhancement. Inhibiting ERK and JNK with U0126 and SP600125 respectively, we found that the autophagy level of the cells treated with AgNPs and radiation were attenuated. Moreover, SP600125 down-regulated the apoptosis rate of the co-treated cells significantly. Taken together, the present study would have important impact on biomedical applications of AgNPs and clinical treatment for glioma.

Exposure to silver nanoparticles does not affect cognitive outcome or hippocampal neurogenesis in adult mice.

Due to the unique antimicrobial and many other broad spectrum biotechnological advantages, silver nanoparticles (Ag-NPs) are widely used in biomedical and general applications. However, the current knowledge about the impact of Ag-NPs on the central nervous system is extremely limited. To assess whether Ag-NPs influence spatial cognition and adult hippocampal neurogenesis, male ICR mice received intraperitoneal administration of Ag-NPs (10, 25, and 50 mg/kg body weight) or vehicle every day for 7 days. At the end of this time period, Morris water maze test was performed for the spatial learning and memory. Subsequently, mice were injected with bromodeoxyuridine and sacrificed 1 day or 28 days after the last injection in order to evaluate cell proliferation, survival and differentiation in the hippocampus. Results showed that compared with the control group, both reference memory and working memory were not impaired in Ag-NPs exposed groups. In addition, no differences were observed in hippocampal progenitor proliferation, new born cell survival or differentiation. These data reveal that exposure to Ag-NPs does not affect spatial cognition or hippocampal neurogenesis in mice.

Shape-Dependent Radiosensitization Effect of Gold Nanostructures in Cancer Radiotherapy: Comparison of Gold Nanoparticles, Nanospikes, and Nanorods

The shape effect of gold (Au) nanomaterials on the efficiency of cancer radiotherapy has not been fully elucidated. To address this issue, Au nanomaterials with different shapes but similar average size (∼50 nm) including spherical gold nanoparticles (GNPs), gold nanospikes (GNSs), and gold nanorods (GNRs) were synthesized and functionalized with poly(ethylene glycol) (PEG) molecules. Although all of these Au nanostructures were coated with the same PEG molecules, their cellular uptake behavior differed significantly. The GNPs showed the highest cellular responses as compared to the GNSs and the GNRs (based on the same gold mass) after incubation with KB cancer cells for 24 h. The cellular uptake in cells increased in the order of GNPs > GNSs > GNRs. Our comparative studies indicated that all of these PEGylated Au nanostructures could induce enhanced cancer cell-killing rates more or less upon X-ray irradiation. The sensitization enhancement ratios (SERs) calculated by a multitarget single-hit model were 1.62, 1.37, and 1.21 corresponding to the treatments of GNPs, GNSs, and GNRs, respectively, demonstrating that the GNPs showed a higher anticancer efficiency than both GNSs and GNRs upon X-ray irradiation. Almost the same values were obtained by dividing the SERs of the three types of Au nanomaterials by their corresponding cellular uptake amounts, indicating that the higher SER of GNPs was due to their much higher cellular uptake efficiency. The above results indicated that the radiation enhancement effects were determined by the amount of the internalized gold atoms. Therefore, to achieve a strong radiosensitization effect in cancer radiotherapy, it is necessary to use Au-based nanomaterials with a high cellular internalization. Further studies on the radiosensitization mechanisms demonstrated that ROS generation and cell cycle redistribution induced by Au nanostructures played essential roles in enhancing radiosensitization. Taken together, our results indicated that the shape of Au-based nanomaterials had a significant influence on cancer radiotherapy. The present work may provide important guidance for the design and use of Au nanostructures in cancer radiotherapy.

Synthesis of ultrastable and multifunctional gold nanoclusters with enhanced fluorescence and potential anticancer drug delivery application.

The problem of stability hinders the practical applications of nanomaterials. In this research, an innovative and simple synthetic method was developed for preparing ultrastable and multifunctional gold nanoclusters (Au NCs). HS-C11-EG6-X is a class of molecules consisting of four components: a mercapto group (-SH), an alkyl chain (C11), a short chain of polyethylene glycols (EG6) and a functional group (X, X=OH, COOH, NH2, GRGD, etc). The present work demonstrated the importance of using HS-C11-EG6-X to prepare Au NCs with excellent properties and the role each component in this molecule played for synthesizing Au NCs. Au NCs with tunable surface functionalities were successfully synthesized and characterized. It was found that Au NC precursors had a fluorescent quantum yield of 0.4%; in contrast, after capping with HS-C11-EG6-X, the quantum yield significantly increased to 1.3-2.6%. The HS-C11-EG6-X capped Au NCs exhibited superior stability under various solution conditions (including extreme pH, high salt concentration, phosphate buffered saline and cell medium) for at least 6 months, even after conjugation with anticancer drug doxorubicin. Besides, we have also demonstrated that other commonly employed thiol-containing ligands failed to prepare stable fluorescent Au NCs. Moreover, the Au NCs showed negligible toxicity to A549 lung cancer cells up to 100 μM, and the application of the ultrastable Au NCs for anticancer drug delivery has also been demonstrated.

Plasma membrane activatable polymeric nanotheranostics with self-enhanced light-triggered photosensitizer cellular influx for photodynamic cancer therapy

&NA; To address the issue of low cellular uptake of photosensitizers by cancer cells in photodynamic therapy (PDT), we designed a smart plasma membrane‐activatable polymeric nanodrug by conjugating the photosensitizer protoporphyrin IX (PpIX) and polyethylene glycol (PEG) with glycol chitosan (GC). The as‐prepared GC‐PEG‐PpIX can self‐assemble into core‐shell nanoparticles (NPs) in aqueous solution and the fluorescence of PpIX moieties in the inner core is highly quenched due to strong &pgr;–&pgr; stacking. Interestingly, when encountering plasma membranes, the GC‐PEG‐PpIX NPs can disassemble and stably attach to plasma membranes due to the membrane affinity of PpIX moieties, which effectively suppresses the self‐quenching of PpIX, leading to significantly enhanced fluorescence and singlet oxygen (1O2) production upon laser irradiation. The massively produced 1O2 can compromise the integrity of the plasma membrane, enabling the influx of extracellular nanoagents into cells to promote cell death upon further laser irradiation. Through local injection, the membrane anchored GC‐PEG‐PpIX enables strong physical association with tumor cells and exhibits highly enhanced in vivo fluorescence at the tumor site. Besides, excellent tumor accumulation and prolonged tumor retention of GC‐PEG‐PpIX were realized after intravenous injection, which ensured its effective imaging‐guided PDT. Graphical abstract Figure. No caption available.

Action of Gold Nanospikes-Based Nanoradiosensitizers: Cellular Internalization, Radiotherapy, and Autophagy

A major challenge to achieve effective X-ray radiation therapy is to use a relatively low and safe radiation dose. Various radiosensitizers, which can significantly enhance the radiotherapeutic performance, have been developed. Gold-based nanomaterials, as a new type of nanoparticle-based radiosensitizers, have been extensively used in researches involving cancer radiotherapy. However, the cancer therapeutic effect using the gold nanoparticle-based radiotherapy is usually not significant because of the low cellular uptake efficiency and the autophagy-inducing ability of these gold nanomaterials. Herein, using gold nanospikes (GNSs) as an example, we prepared a series of thiol-poly(ethylene glycol)-modified GNSs terminated with methoxyl (GNSs), amine (NH2-GNSs), folic acid (FA) (FA-GNSs), and the cell-penetrating peptide TAT (TAT-GNSs), and evaluated their effects on X-ray radiotherapy. For the in vitro study, it was found that the ionizing radiation effects of these GNSs were well correlated with their cellular uptake amounts, with the same order of GNSs < NH2-GNSs < FA-GNSs < TAT-GNSs. The sensitization enhancement ratio (SER), which is commonly used to evaluate how effectively radiosensitizers decrease cell proliferation, reaches 2.30 for TAT-GNSs. The extremely high SER value for TAT-GNSs indicates the superior radiosensitization effect of this nanomaterial. The radiation enhancement mechanisms of these GNSs involved the increased reactive oxygen species (ROS), mitochondrial depolarization, and cell cycle redistribution. Western blotting assays confirmed that the surface-modified GNSs could induce the up-regulation of autophagy-related protein (LC3-II) and apoptosis-related protein (active caspase-3) in cancer cells. By monitoring the degradation of the autophagy substrate p62 protein, GNSs caused impairment of autolysosome degradation capacity and autophagosome accumulation. Our data demonstrated that autophagy played a protective role against caner radiotherapy, and the inhibition of protective autophagy with inhibitors would result in the increase of cell apoptosis. Besides the above in vitro experiments, the in vivo tumor growth study also indicated that X-ray + TAT-GNSs treatment had the best tumor growth inhibitory effect, which confirmed the highest radiation sensitizing effect of TAT-GNSs. This work furthered our understanding on the interaction mechanism between gold nanomaterials and cancer cells and should be able to promote the development of nanoradiosensitizers for clinical applications.