Resham Bhattacharya

Biological properties of "naked" metal nanoparticles

Over the past few decades, inorganic nanoparticles, which exhibit significantly distinct physical, chemical and biological properties from their bulk counterparts, have elicited much interest. Discoveries in the past decade have demonstrated that the electromagnetic, optical and catalytic properties of noble-metal nanoparticles such as gold, silver and platinum, are strongly influenced by shape and size. This has motivated an upsurge in research on the synthesis routes that allow better control of shape and size for various nano-biotechnological applications. Biomedical applications of metal nanoparticles have been dominated by the use of nanobioconjugates that started in 1971 after the discovery of immunogold labeling by Faulk and Taylor. Currently metal-based nanoconjugates are used in various biomedical applications such as probes for electron microscopy to visualize cellular components, drug delivery (vehicle for delivering drugs, proteins, peptides, plasmids, DNAs, etc), detection, diagnosis and therapy (targeted and non-targeted). However biological properties of bare-metal (naked) nanoparticles have remained largely unexplored. Therefore, in this review we discuss the novel biological properties and applications of three most widely used metal nanoparticles, namely, the nanoparticles of gold, silver and platinum. We describe the novel properties and use of these nanoparticles in angiogenesis and cancer related disorders.

Intrinsic therapeutic applications of noble metal nanoparticles: Past, present and future

Biomedical nanotechnology is an evolving field having enormous potential to positively impact the health care system. Important biomedical applications of nanotechnology that may have potential clinical applications include targeted drug delivery, detection/diagnosis and imaging. Basic understanding of how nanomaterials, the building blocks of nanotechnology, interact with the cells and their biological consequences are beginning to evolve. Noble metal nanoparticles such as gold, silver and platinum are particularly interesting due to their size and shape dependent unique optoelectronic properties. These noble metal nanoparticles, particularly of gold, have elicited a lot of interest for important biomedical applications because of their ease of synthesis, characterization and surface functionalization. Furthermore, recent investigations are demonstrating another promising application of these nanomaterials as self-therapeutics. To realize the potential promise of these unique inorganic nanomaterials for future clinical translation, it is of utmost importance to understand a few critical parameters; (i) how these nanomaterials interact with the cells at the molecular level; (ii) how their biodistribution and pharmacokinetics influenced by their surface and routes of administration; (iii) mechanism of their detoxification and clearance and (iv) their therapeutic efficacy in appropriate disease model. Thus in this critical review, we will discuss the various clinical applications of gold, silver and platinum nanoparticles with relevance to above parameters. We will also mention various routes of synthesis of these noble metal nanoparticles. However, before we discuss present research, we will also look into the past. We need to understand the discoveries made before us in order to further our knowledge and technological development (318 references).

Effect of Nanoparticle Surface Charge at the Plasma Membrane and Beyond

Herein, we demonstrate that the surface charge of gold nanoparticles (AuNPs) plays a critical role in modulating membrane potential of different malignant and nonmalignant cell types and subsequent downstream intracellular events. The findings presented here describe a novel mechanism for cell-nanoparticle interactions and AuNP uptake: modulation of membrane potential and its effect on intracellular events. These studies will help understand the biology of cell-nanoparticle interactions and facilitate the engineering of nanoparticles for specific intracellular targets.

Antiangiogenic properties of gold nanoparticles.

Here, we report an intrinsic property of gold nanoparticles (nanogold): they can interact selectively with heparin-binding glycoproteins and inhibit their activity. Gold nanoparticles specifically bound vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-165 and basic fibroblast growth factor, two endothelial cell mitogens and mediators of angiogenesis resulting in inhibition of endothelial/fibroblast cell proliferation in vitro and VEGF-induced permeability as well as angiogenesis in vivo. In contrast, nanogold did not inhibit VEGF-121 or epidermal growth factor, two non–heparin-binding growth factors, mediated cell proliferation. Gold nanoparticles significantly inhibited VEGF receptor-2 phosphorylation, intracellular calcium release, and migration and RhoA activation in vitro. These results report for the first time a novel property of gold nanoparticles to bind heparin-binding proteins and thereby inhibit their subsequent signaling events.

Fabrication of gold nanoparticles for targeted therapy in pancreatic cancer

The targeted delivery of a drug should result in enhanced therapeutic efficacy with low to minimal side effects. This is a widely accepted concept, but limited in application due to lack of available technologies and process of validation. Biomedical nanotechnology can play an important role in this respect. Biomedical nanotechnology is a burgeoning field with myriads of opportunities and possibilities for advancing medical science and disease treatment. Cancer nanotechnology (1-100 nm size range) is expected to change the very foundations of cancer treatment, diagnosis and detection. Nanomaterials, especially gold nanoparticles (AuNPs) have unique physico-chemical properties, such as ultra small size, large surface area to mass ratio, and high surface reactivity, presence of surface plasmon resonance (SPR) bands, biocompatibility and ease of surface functionalization. In this review, we will discuss how the unique physico-chemical properties of gold nanoparticles may be utilized for targeted drug delivery in pancreatic cancer leading to increased efficacy of traditional chemotherapeutics.

Targeted Delivery of Gemcitabine to Pancreatic Adenocarcinoma Using Cetuximab as a Targeting Agent

One of the key challenges in anticancer therapy is the toxicity and poor bioavailability of the anticancer drugs. Nanotechnology can play a pivotal role by delivering drugs in a targeted fashion to the malignant cells that will reduce the systemic toxicity of the anticancer drug. In this report, we show a stepwise development of a nanoparticle-based targeted delivery system for in vitro and in vivo therapeutic application in pancreatic cancer. In the first part of the study, we have shown the fabrication and characterization of the delivery system containing gold nanoparticle as a delivery vehicle, cetuximab as a targeting agent, and gemcitabine as an anticancer drug for in vitro application. Nanoconjugate was first characterized physico-chemically. In vitro targeting efficacy, tested against three pancreatic cancer cell lines (PANC-1, AsPC-1, and MIA Paca2) with variable epidermal growth factor receptor (EGFR) expression, showed that gold uptake correlated with EGFR expression. In the second part, we showed the in vivo therapeutic efficacy of the targeted delivery system. Administration of this targeted delivery system resulted in significant inhibition of pancreatic tumor cell proliferation in vitro and orthotopic pancreatic tumor growth in vivo. Tumor progression was monitored noninvasively by measuring bioluminescence of the implanted tumor cells. Pharmacokinetic experiments along with the quantitation of gold both in vitro and in vivo further confirmed that the inhibition of tumor growth was due to targeted delivery. This strategy could be used as a generalized approach for the treatment of a variety of cancers characterized by overexpression of EGFR.

Gold nanoparticles: opportunities and challenges in nanomedicine

Importance of the field: Site-specific drug delivery is an important area of research that is anticipated to increase the efficacy of the drug and reduce potential side effects. Owing to this, substantial work has been done developing non-invasive and targeted tumor treatment with nanoscale metallic particles. Areas covered in this review: This review focuses on the work done in the last few years developing gold nanoparticles as cancer therapeutics and diagnostic agents. However, there are challenges in using gold nanoparticles as drug delivery systems, such as biodistribution, pharmacokinetics and possible toxicity. Approaches to limit these issues are proposed. What the reader will gain: Different approaches from several different disciplines are discussed. Potential clinical applications of these engineered nanoparticles are also presented. Take home message: As a result of their unique size-dependent physicochemical and optical properties, adaptability, subcellular size and biocompatibility, these nanosized carriers offer a suitable means of transporting small molecules as well as biomacromolecules to diseased cells/tissues.

Intracellular gold nanoparticles enhance non-invasive radiofrequency thermal destruction of human gastrointestinal cancer cells

BackgroundNovel approaches to treat human cancer that are effective with minimal toxicity profiles are needed. We evaluated gold nanoparticles (GNPs) in human hepatocellular and pancreatic cancer cells to determine: 1) absence of intrinsic cytotoxicity of the GNPs and 2) external radiofrequency (RF) field-induced heating of intracellular GNPs to produce thermal destruction of malignant cells. GNPs (5 nm diameter) were added to 2 human cancer cell lines (Panc-1, Hep3B). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and propidium iodide-fluorescence associated cell sorting (PI-FACS) assessed cell proliferation and GNP-related cytotoxicity. Other GNP-treated cells were exposed to a 13.56 MHz RF field for 1, 2, or 5 minutes, and then incubated for 24 hours. PI-FACS measured RF-induced cytotoxicity.ResultsGNPs had no impact on cellular proliferation by MTT assay. PI-FACS confirmed that GNPs alone produced no cytotoxicity. A GNP dose-dependent RF-induced cytotoxicity was observed. For Hep3B cells treated with a 67 μM/L dose of GNPs, cytotoxicity at 1, 2 and 5 minutes of RF was 99.0%, 98.5%, and 99.8%. For Panc-1 cells treated at the 67 μM/L dose, cytotoxicity at 1, 2, and 5 minutes of RF was 98.5%, 98.7%, and 96.5%. Lower doses of GNPs were associated with significantly lower rates of RF-induced thermal cytotoxicity for each cell line (P < 0.01). Cells not treated with GNPs but treated with RF for identical time-points had less cytotoxicity (Hep3B: 17.6%, 21%, and 75%; Panc-1: 15.3%, 26.4%, and 39.8%, all P < 0.01).ConclusionWe demonstrate that GNPs 1) have no intrinsic cytotoxicity or anti-proliferative effects in two human cancer cell lines in vitro and 2) GNPs release heat in a focused external RF field. This RF-induced heat release is lethal to cancer cells bearing intracellular GNPs in vitro.

Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles

Background Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution. Method/Principal Findings Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum. Conclusion Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both IP and IV administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting.

Inorganic Nanoparticles in Cancer Therapy

ABSTRACTNanotechnology is an evolving field with enormous potential for biomedical applications. The growing interest to use inorganic nanoparticles in medicine is due to the unique size- and shape-dependent optoelectronic properties. Herein, we will focus on gold, silver and platinum nanoparticles, discussing recent developments for therapeutic applications with regard to cancer in terms of nanoparticles being used as a delivery vehicle as well as therapeutic agents. We will also discuss some of the key challenges to be addressed in future studies.