Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages

Abstract

Spherical and rod-shaped gold nanoparticles with surface poly(ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6–8-week-old female nu/nu mice bearing orthotopic ovarian tumors, and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.

Introduction

Advances in nanotechnology have led to the design and synthesis of organic and inorganic nanoconstructs with defined geometries, surface properties, conductivity and susceptibility to environmental stimuli such as heat and light. These constructs can take the form of nanotubes [1], nanorods [2], nanowires [3], nanocages [4], nanoshells [5], nanodisks [6] and a number of other geometries [7]. Reports are emerging that size, shape and surface properties play an important role in determining the cellular uptake and toxicity of nanoparticles in mammalian cells [8], [9], [10]. An area where nanoparticles are intensively used is in the treatment and/or diagnosis of cancers. Epithelial ovarian cancer (EOC) ranks as the sixth most common cancer in women worldwide and causes more deaths than any other type of female reproductive tract cancer [11]. Current standard therapy, cytoreductive surgery followed by chemotherapy based on the combination of a platinum derivative with a taxane, results in a complete response in 70% of EOC cases. However, most patients will eventually relapse within 18 months presenting with chemoresistant disease [12]. Acquisition of platinum-resistance is a major obstacle in the long-term survival of ovarian cancer patients and invites exploration of novel therapeutic alternatives that may overcome this barrier.

One class of inorganic particles that shows promise in targeted cancer therapy including ovarian cancer is gold nanoconstructs. Gold nanoparticles have been used to deliver antitumor agents such as tumor necrosis factor (TNF) or paclitaxel through the enhanced permeability and retention (EPR) effect [13]. The potential of gold nanoparticles to act as non-viral-based gene delivery systems has also been explored [14], [15]. Physical and chemical properties of gold nanoparticles, in addition to their unique optical properties, make them particularly attractive for disease detection and therapy [16]. Gold nanoparticles with certain aspect ratios (e.g. rods) or compositions (spherical nanoshells) exposed to laser photoradiation can produce local heat that facilitates the destruction of diseased tissues such as solid tumors [17]. Previous studies have shown that size and surface chemistry of gold nanoparticles determine their biodistribution in non-tumor-bearing rats [18], [19]. In this study, the surface of gold nanoparticles has been modified with poly (ethylene glycol) (PEG) to prolong their circulation time and facilitate functionalization among other attributes [20]. Such variations in geometry and surface properties can influence cellular uptake [21] and biodistribution. This differential uptake across biological barriers as a function of geometry and surface properties can be exploited for specific biomedical applications such as targeted therapy and/or diagnosis.

In this work, we have compared the biodistribution of commercially available PEGylated gold nanoparticles of similar size but with varying shapes and surface charge in mice bearing orthotopic ovarian tumors as an in vivo EOC model. The EOC tumors were derived from human A2780 ovarian cancer cells, which were orthotopically inoculated into the ovarian bursa of female nude mice. Orthotopic implantation allows tumor cells to interact with ovarian stromal tissue and take advantage of the rich vascularization of the ovarian environment. Ovarian tumor formation and development are highly dependent upon angiogenesis, and the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) is increased in tumor development [22]. The ovarian microenvironment also allows for interaction with ovarian growth factors, signaling pathways and ECM molecules that affect tumor initiation, growth and progression. This approach recapitulates the clinical features of ovarian cancer and is thought to be a relevant EOC model. In addition to the in vivo biodistribution studies, the uptake of these nanoparticles by macrophages was evaluated.