No abstract

No abstract

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.

No abstract

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 andVEGF-induced permeability as well as angiogenesis in vivo. In contrast, nanogold did not inhibitVEGF-121or 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.Angiogenesis, the formation of new blood vessels is essential for the growth and progression of tumors (1, 2). This process is also important for the promotion and maintenance of other diseases like neoplasia and rheumatoid arthritis (3). As there are several reports that indicate that gold salts can retard the progression of rheumatoid arthritis (4), we reasoned that gold nanoparticles might also inhibit angiogenesis. Because vascular endothelial growth factor/vascular permeability factor (VEGF/ VPF; refs. 5, 6) and basic fibroblast growth factor (bFGF; ref. 7) are two critical cytokines for the induction of angiogenesis, we investigated whether nontoxic novel gold nanoparticles (8) being used at present in several biomedical applications could inhibit the functions of these two important proangiogenic growth factors.Here, we report for the first time that nanogold binds to heparin-binding growth factors like VEGF165 and bFGF and inhibit their activity, whereas it does not inhibit the activity of non -heparin-binding growth factors like VEGF121 and endothelial growth factor (EGF). We have found excellent correlation between our in vitro results and in vivo mouse ear and mouse ovarian tumor model systems, where VEGF/VPFinduced permeability was inhibited by nanogold.

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. Due 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 several 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 is also presented.Take home message-Because of their unique size-dependent physico-chemical and optical properties, adaptability, sub-cellular size, and bio-compatibility, these nanosized carriers offer an apt means of transporting small molecules as well as biomacromoleculs to diseased cells/ tissues.

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.

BackgroundEpithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer.Methods/Principal FindingsUsing patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics.ConclusionThe present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.