Advances in Gold Nanoparticles: Synthesis, Functionalization Strategies, and Theranostic Applications in Cancer.

Cancer is among the leading causes of mortality and morbidity in the world. Metallic nanoparticles, especially gold nanoparticles (AuNPs) have emerged to be attractive systems to circumvent the associated adverse effects. By the virtue of their unique properties of tunable size, shape, composition, optical properties, biocompatibility, minimal toxicity, multivalency, fluorescence-luminescence property and surface plasmon resonance; AuNPs have the potential to be used as drug delivery systems. It is vital to ensure that the drug reaches the target site of action for selective kill of cancer cells without harm to healthy cells. These AuNPs can be easily functionalized with a wide array of ligands like peptides, oligonucleotides, polymers, carbohydrates for active targeting to ensure site specific delivery and reduced systemic effects. AuNPs have been in-vestigated as carriers for gene delivery, drug delivery with or without photothermal therapy, in diagnosis based on radiation or spectroscopy. They have emerged as attractive theranostic approach in the overall management of cancer with superior benefit to risk features. In this review, we have discussed synthesis of different AuNPs (nanorods, spherical nanoparticles, and hollow AuNPs), their functionalization strategies and their applications in biomedical domain. Various research studies and clinical trials on application of AuNPs in diagnosis and therapeutics are highlighted.

Deoxyglucose-conjugated persistent luminescent nanoparticles for theragnostic application in fibrosarcoma tumor model.

Deoxyglucose conjugated nanoparticles with persistent luminescence have shown theragnostic potential. In this study, deoxyglucose-conjugated nano-particles with persistent luminescence properties were synthesized, and their theragnostic potential was evaluated in fibrosarcoma cancer cells and a tumor model. The uptake of nano-formulation was found to be higher in mouse fibrosarcoma (WEHI-164) cells cultured in a medium without glucose. Nanoparticles showed a higher killing ability for cancer cells compared to normal cells. A significant accumulation of nanoparticles to the tumor site in mice was evident by the increased tumor/normal leg ratio, resulting in a significant decrease in tumor volume and weight. Histopathological studies showed a significant decrease in the number of dividing mitotic cells but a greater number of apoptotic/necrotic cells in nanoparticle-treated tumor tissues, which was correlated with a lower magnitude of Ki-67 expression (a proliferation marker). Consequently, our results showed the potential of our nano-formulation for cancer theragnosis.

Development of Core@Shell γ-Fe2O3@MnxOy@SiO2 Nanoparticles for Hyperthermia, Targeting, and Imaging Applications.

Monodispersed core@shell γ-Fe2O3@MnxOy nanoparticles have been prepared through thermolysis of iron and manganese oleate. Further, these prepared nanoparticles are coated with biocompatible substances such as silica and polyethylene glycol. These particles are highly biocompatible for different cell lines such as normal and cancer cell lines. The nanoparticles are used as hyperthermia agents, and successful hyperthermia treatment in cancer cells is carried out. As compared to γ-Fe2O3@SiO2, γ-Fe2O3@MnxOy@SiO2 shows the enhanced killing of cancer cells through hyperthermia. In order to make them potential candidates for targeting to cancer cells, folic acid (FA) is tagged to the nanoparticles. Fluorescein isothiocyanate (FITC) is also tagged onto these nanoparticles for imaging. The developed γ-Fe2O3@MnxOy@SiO2 nanoparticle can act as a single entity for therapy through AC magnetic field, imaging through FITC and targeting through folic acid simultaneously. This is the first report on this material, which is highly biocompatible for hyperthermia, imaging, and targeting.

Synthesis of Hollow Gold Nanoparticles - Impact of Variables on Process Optimization.

Hollow gold nanoparticles (HAuNPs) are gold nanostructures with hollow interior. These particles have attracted a lot of interest due their excellent physicochemical and optical properties and their potential applications in diagnostics, sensing, imaging and assisting in tumor tracing and evaluating the effect of chemotherapy on tumor size, drug delivery and photothermal therapy. Sacrificial galvanic replacement using cobalt core is the most commonly used method for synthesis of HAuNPs. However, lack of reproducibility in synthesizing particles with desired surface plasmon resonance (SPR) is one of the major concerns for clinical application of these particles. In this work, we have identified and categorized various factors that could affect uniformity of cobalt core and subsequent formation of gold shell. Using slight modifications in the method, we have been able to synthesize HAuNPs with SPR in near infrared region at 808 nm with size of particles around 50-80 nm. HAuNPs can be further functionalized with suitable ligands like glutathione, polyethylene glycol, nucleic acids, sugars, fatty acids, proteins and peptides to promote enhanced permeability and retention in cancer cells and thus can serve as potential candidates in treatment of cancer.

Enrichment of Crystal Field Modification via Incorporation of Alkali K+ Ions in YVO4:Ho3+/Yb3+ Nanophosphor and Its Hybrid with Superparamagnetic Iron Oxide Nanoparticles for Optical, Advanced Anticounterfeiting, Uranyl Detection, and Hyperthermia Applications.

In this work, we report a polyol route for easy synthesis of upconversion (UC) phosphor nanoparticles, YVO4:Ho3+-Yb3+-K+, which enables large-scale production and enhancement of luminescence. Upon 980 nm laser excitation, the UC emission spectrum shows a sharp bright peak at ∼650 nm of Ho3+ ion; and the luminescence intensity increases twofold upon K+ codoping. Upon 300 nm excitation, the downconversion emission spectrum shows a broad peak in the 400-500 nm range (related to the charge transfer band of V-O) along with Ho3+ peaks. In addition, the polyethylene glycol-coated UC nanoparticles are highly water-dispersible and their hybrid with Fe3O4 nanoparticles shows magnetic-luminescence properties. A hyperthermia temperature is achieved from this hybrid. Both UC and hybrid nanoparticles show interesting security ink properties upon excitation by a 980 nm laser. The particles are invisible in normal light but visible upon 980 nm excitation and are useful in display devices, advanced anticounterfeiting purposes, and therapy of cancer via hyperthermia and bioimaging (since it shows red emission at ∼650 nm). Using UC nanoparticles, detection of uranyl down to 20 ppm has been achieved.

A Nitronaphthalimide Probe for Fluorescence Imaging of Hypoxia in Cancer Cells.

The bioreductive enzymes typically upregulated in hypoxic tumor cells can be targeted for developing diagnostic and drug delivery applications. In this study, a new fluorescent probe 4-(6-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)benzaldehyde (NIB) based on a nitronaphthalimide skeleton that could respond to nitroreductase (NTR) overexpressed in hypoxic tumors is designed and its application in imaging tumor hypoxia is demonstrated. The docking studies revealed favourable interactions of NIB with the binding pocket of NTR-Escherichia coli. NIB, which is synthesized through a simple and single step imidation of 4-nitro-1,8-naphthalic anhydride displayed excellent reducible capacity under hypoxic conditions as evidenced from cyclic voltammetry investigations. The fluorescence measurements confirmed the formation of identical products (NIB-red) during chemical as well as NTR-aided enzymatic reduction in the presence of NADH. The potential fluorescence imaging of hypoxia based on NTR-mediated reduction of NIB is confirmed using in-vitro cell culture experiments using human breast cancer (MCF-7) cells, which displayed a significant change in the fluorescence colour and intensity at low NIB concentration within a short incubation period in hypoxic conditions.

Metallic nanoparticles as drug delivery system for the treatment of cancer.

INTRODUCTION: The targeted delivery of anticancer agents to tumor is a major challenge because most of the drugs show off-target effect resulting in nonspecific cell death. Multifunctionalized metallic nanoparticles (NPs) are explored as new carrier system in the era of cancer therapeutics. Researchers investigated the potential of metallic NPs to target tumor cells by active and passive mechanisms, thereby reducing off-target effects of anticancer agents. Moreover, photocatalytic activity of upconversion nanoparticles (UCNPs) and the enhanced permeation and retention (EPR) effect have also gained wide potential in cancer treatment. Recent advancement in the field of nanotechnology highlights their potency for cancer therapy. AREAS COVERED: This review summarizes the types of gold and silver metallic NPs with targeting mechanisms and their potentiality in cancer therapy. EXPERT OPINION: Recent advances in the field of nanotechnology for cancer therapy offer high specificity and targeting efficiency. Targeting tumor cells through mechanistic pathways using metallic NPs for the disruption/alteration of molecular profile and survival rate of the tumor cells has led to an effective approach for cancer therapeutics. This alteration in the survival rate of the tumor cells might decrease the proliferation thereby resulting in more efficient management in the treatment of cancer.

Super Bright Red Upconversion in NaErF4:0.5%Tm@NaYF4:20%Yb Nanoparticles for Anti-counterfeit and Bioimaging Applications.

Nanocrystals having single-band red emission under near-infrared (NIR) excitation through the upconversion process offer great advantages in terms of enhanced cellular imaging in in vitro and in vivo experiments in the biological window (600-900 nm), as a security ink, in photothermal therapy (PTT), in photodynamic therapy (PDT), and so forth but are challenging for materials scientists. In this work, we report for the first time the preparation of a super bright red emitter at 655 nm from monodispersed NaErF4:0.5%Tm@NaYF4:20%Yb nanocrystals (core@active shell). This phosphor exhibits 35 times stronger photoluminescence as compared to NaErF4:0.5%Tm@NaYF4 (core@inactive shell). Here, an Er3+-enriched host matrix works simultaneously as an activator and a sensitizer under NIR excitation. Upconversion red emission at 655 nm arises due to the electronic transition of Er3+ via the involvement of a three-photon absorption (expected to be a two-photon absorption), which has been confirmed via a power-dependent luminescence study. Tm3+ ions incorporated into the core with the active shell act as trapping centers, which promote the red band emission via the back-energy transfer process. Moreover, the active shell containing Yb3+ ions efficiently transfers the energy to the Er3+-enriched core, which suppresses the nonradiative channel rate, and Tm3+ ions act as trapping centers, which reduce the luminescence quenching via reduction of energy migration to the surface of the host lattice. Also, we have shown the potential applications of these nanocrystals: cellular imaging through downconversion and upconversion processes and security ink.

Induction Heating Efficiency of Water-Dispersible Mn0.5Fe2.5O4@YVO4:Eu3+ Magnetic-Luminescent Nanocomposites in an Acceptable ac Magnetic Field: Hemocompatibility and Cytotoxicity Studies.

Not many reports are available on magnetic-luminescent nanocomposites for cancer hyperthermia applications. Further, such nanocomposites on Mn2+-doped iron oxide may be available rather rarely. Studies on the induction heating properties within the threshold magnetic field and frequency factors are still rare. In most cases, magnetic nanoparticles are studied for hyperthermia and lanthanide-doped luminescent nanoparticles for certain biomedical applications. Here, we report on water-dispersible superparamagnetic manganese-doped iron oxide (Mn0.5Fe2.5O4) nanoparticles and a polyethylene glycol6000-coated magnetic-luminescent nanocomposite. The nanocomposite is composed of magnetic Mn0.5Fe2.5O4 (average size 10-20 nm) nanoparticles and red-emitting YVO4:Eu3+ (average size 40-50 nm) nanoparticles. These magnetic nanoparticles and nanocomposites are studied for their induction heating abilities at different acceptable Hf values ( H, strength of alternating magnetic field and f, the operating frequency). The operational Hf values lie in the ranges of 2.15 × 106 to 4.58 × 106 kA m-1 s-1 that are well below the threshold limit of 5 × 106 kA m-1 s-1. A specific absorption rate as high as 132 and 63 W/g, respectively, for Mn0.5Fe2.5O4 and Mn0.5Fe2.5O4@YVO4:Eu3+, can be achieved. The rate of heating and the temperature achieved with time can be tuned with concentrations as well as magnetic constituents in the nanocomposites. Hemocompatibility analysis revealed high blood compatibility with <5% hemolysis. The cytotoxicity analysis in the MCF-7 cell line showed that the cell viability is 74-85% for 0.2-0.5 mg of the magnetic-luminescent nanocomposites. Beyond this concentration, the percentage of cell death is very high. The red-emitting magnetic-luminescent nanocomposites will be useful for in vitro optical imaging and tracking of magnetic nanoparticles. The magnetization analysis showed that the samples have high enough saturation magnetization and low residual magnetization, which is quite suitable for clinical applications. The water dispersibility, hemocompatibility, and cytotoxicity assay in conjunction with their efficient induction heating abilities have shown that these magnetic-luminescent nanocomposites will have potential applications in magnetic fluid hyperthermia and optical imaging.

Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation.

PURPOSE: We have evaluated the hyperthermia efficacy of oleic acid-functionalised Fe(3)O(4) magnetic nanoparticles (MN-OA) under in vivo conditions and elucidated the underlying mechanism of tumour growth inhibition. MATERIALS AND METHODS: The efficacy and mechanism of tumour growth inhibition by MN-OA-mediated magnetic hyperthermia therapy (MHT) was evaluated in a murine fibrosarcoma tumour model (WEHI-164) using techniques such as TUNEL assay, Western blotting (WB), immunofluorescence (IF) staining and histopathological examination. In addition, bio-distribution of MN-OA in tumour/other target organs and its effect on normal organ function were studied by Prussian blue staining and serum biochemical analysis, respectively. RESULTS: MN-OA-induced MHT resulted in significant inhibition of tumour growth as determined by measurement of tumour volume, as well as by in vivo imaging of tumour derived from luciferase-transfected WEHI-164 cells. Histopathology analysis showed presence of severe apoptosis and reduced tumour cells proliferation, which was further confirmed by TUNEL assay, reduced expression of Ki-67 and enhanced level of cleaved caspase-3, in tumours treated with MHT. Moreover, expression of heat stress marker, Hsp90 and its client protein, AKT/PKB was reduced by ∼50 and 80%, respectively, in tumours treated with MHT as studied by WB and IF staining. Serum analysis suggested insignificant toxicity of MN-OA (in terms of liver and kidney function), which was further correlated with minimal accumulation of MN-OA in target organs. CONCLUSIONS: These results suggest the involvement of apoptosis and Hsp90/AKT modulation in MN-OA-mediated MHT-induced tumour growth inhibition.

Enhanced specific absorption rate in silanol functionalized Fe3O4 core-shell nanoparticles: study of Fe leaching in Fe3O4 and hyperthermia in L929 and HeLa cells.

Core-shell Fe3O4-SiO2 magnetic nanoparticles (MNPs) have been synthesized using a simple synthesis procedure at different temperatures. These MNPs are used to investigate the effect of surface coating on specific absorption rate (SAR) under alternating magnetic field. The temperature achieved by silica coated Fe3O4 is higher than that by uncoated MNPs (Fe3O4). This can be attributed to extent of increase in Brownian motion for silica coated MNPs. The sample prepared at optimized temperature of 80°C shows the highest SAR value of 111W/g. It is found that SAR value decreases with increase in shell thickness. The chemical stability of these samples is analyzed by leaching experiments at pH 2-7. The silica coated samples are stable up to 7 days even at pH 2. Biocompatibility of the MNPs is evaluated in vitro by assessing their cytotoxicity on L929 and human cervical cancer cells (HeLa cells) using sulforhodamine-B assay. Their hyperthermic killing ability is also evaluated in HeLa cells using the same method. Cells treated with MNPs along with induction heating show decrease in viability as compared to that without induction heating. Further, cell death is found to be ∼55% more in cells treated with silica coated MNPs under induction heating as compared to untreated control. These results establish the efficacy of Fe3O4-SiO2 prepared at 80°C in killing of tumor cells by cellular hyperthermia.