Mechanism of anti-angiogenic property of gold nanoparticles: role of nanoparticle size and surface charge

Abstract

Discovering therapeutic inorganic nanoparticles is evolving as an important area of research in the emerging field of nanomedicine. Recently, we reported the anti-angiogenic property of gold nanoparticles (GNPs): it inhibits the function of pro-angiogenic heparin-binding growth factors (HB-GFs) such as vascular endothelial growth factor 165 (VEGF165), basic fibroblast growth factor (bFGF), etc. However, the mechanism through which GNP imparts such an effect remains to be investigated. Using GNPs of different sizes and surface charges we demonstrate here that a naked GNP surface is required and core size plays an important role to inhibit the function of HB-GFs and subsequent intracellular signaling events. We also demonstrate that the inhibitory effect of GNPs is due to the change in HB-GFs conformation/configuration (denaturation) by the nanoparticles, whereas the conformations of non-HB-GFs remain unaffected. Significantly, this study will help structure-based design of therapeutic nanoparticles to inhibit the functions of disease causing proteins.

Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

“…Next we sought to determine the effect of these AuNPs on the proliferation of three different ovarian cancer cell lines-A2780, OVCAR5, and SKOV3-ip cells-and compare them with normal ovarian surface epithelial (OSE) (18) cells. Our findings demonstrated that both size and concentration of AuNPs play a pivotal role in inhibiting the proliferation of ovarian cancer cells (as determined by 3 [H]-Thymidine incorporation), in a timedependent manner ( Fig. 1 and Fig.…”

“…Furthermore, activation of this pathway is also known to induce EMT in cancer cells (19). Since AuNPs disrupt HB-GF-mediated signaling (3,20,21), we wanted to determine whether inhibition of AuNP-mediated proliferation could be due to an inhibition of MAPK activation in cancer cells. Our results revealed a substantial, concentration-dependent inhibition of p42/44 phosphorylation in ovarian cancer cells.…”

“…However, down-regulation of E-Cad expression by its transcriptional repressors such as Vimentin, Snail, Slug, Twist, etc., through several redundant and independent mechanisms, poses a challenge for anti-EMT therapy (11)(12)(13). Since AuNPs can inhibit the function of a multitude of HB-GFs responsible for EMT (3,15), it can potentially act as a multifunctional molecule to reverse epithelial plasticity, thereby inhibiting tumor growth and metastasis. In this study, we demonstrate that AuNPs exhibit unique antitumor and anti-EMT properties that inhibit tumor growth and metastasis in two orthotopic models of ovarian cancer.…”

“…The preferential binding of cysteine/lysine-rich proteins to AuNP may then alter their structure and biological functions, allowing AuNPs to be exploited as a therapeutic agent. We recently demonstrated that AuNPs upon binding HB-GFs (Heparin-binding growth factors) such as vascular endothelial GF 165 (VEGF165) and basic fibroblast GF (bFGF) inhibited their function due to the unfolding of the protein structure (3). Since HB-GFs are critically important for angiogenesis and epithelial-mesenchymal transition (EMT), a mechanism that confers metastatic potential to tumor cells, AuNPs may find wide applications as therapeutic agents in angiogenesisdependent disorders and in preventing tumor growth and metastasis in cancer (4).…”

“…Down-regulation of E-Cad expression by its transcriptional repressors through several compensatory and independent mechanisms poses a challenge for anti-EMT therapy (11)(12)(13). Since AuNPs can inhibit the function of a multitude of HB-GFs responsible for EMT (3,14,15), it can potentially act as a multifunctional molecule to reverse epithelial plasticity, thereby inhibiting tumor growth and metastasis. A number of inflammatory GFs containing the HB domain are pivotal in regulating EMT such as VEGF165, HB-EGF, bFGF, TGF-β, TNF-α, etc., which are overexpressed in ovarian cancer and other solid tumors (16).…”