Neha B. Shah

Biodistribution of TNF-α-coated gold nanoparticles in an in vivo model system

AIM In this study, we describe the biodistribution of CYT-6091, a colloidal gold (Au)-based nanomedicine that targets the delivery of TNF-alpha to solid tumors. MATERIALS & METHODS A single intravenous injection of CYT-6091 coated with 5 microg TNF-alpha was given to human prostate tumor-bearing or naive (without tumor) nude mice. Tissues were harvested and analyzed at specific time points for Au nanoparticles by atomic emission spectroscopy and TNF-alpha by ELISA. RESULTS The two constituents of CYT-6091, TNF-alpha and Au, exhibited different behavior in blood, with TNF-alpha showing a faster decay than the Au nanoparticles. Between 0 and 4 h after injection, TNF-alpha showed a preferential accumulation in the tumor. Au was observed to accumulate preferentially in the liver between 4 and 12 h, and showed some clearance over time (4 months). CONCLUSION These data suggest that CYT-6091 delivers TNF-alpha preferentially to the tumor and that upon TNF-alpha degradation, the liver takes up Au, which is cleared slowly over time.

BLOOD-NANOPARTICLE INTERACTIONS AND IN VIVO BIODISTRIBUTION: IMPACT OF SURFACE PEG AND LIGAND PROPERTIES

Theranostic nanoparticles (NPs) cannot reach their target tissue without first passing through blood; however, the influence of blood protein and blood cell interactions on NP biodistribution are not well understood. The current work shows that 30 nm PEGylated gold NPs (GNPs) interact not only with blood proteins as thought before but also with blood cells (especially platelets and monocytes) in vivo and that longer blood circulation correlates strongly with tumor uptake. Further, GNP surface properties such as negative charge or lyophilization had either a minimal (i.e., charge) or 15-fold increase (i.e., fresh vs lyophilized) in blood retention times and tumor uptake. Tumor accumulation was increased over 10-fold by use of a bioactive ligand (i.e., TNF) on the lyophilized GNP surface. Resident macrophages were primarily responsible for the bulk of GNP uptake in liver while spleen uptake was highly surface property dependent and appears to involve macrophages and cellular interaction between the red and white pulp. This study shows that the PEG layer and ligand on the surface of the NP are critical to blood interactions and eventual tumor and RES organ biodistribution in vivo.

Cellular uptake and nanoscale localization of gold nanoparticles in cancer using label-free confocal Raman microscopy

This work demonstrates the use of confocal Raman microscopy (CRM) to measure the dynamics of cellular uptake and localization of gold nanoparticles (GNP) with nanoscale resolution. This is important as nanoparticle cellular interactions are increasingly under investigation to support applications as diverse as drug delivery, gene transfection and a variety of heat and radiation based therapeutics. At the heart of these applications is a need to know the dynamics of nanoparticle cellular uptake and localization (i.e., cell membrane, cytoplasm or nucleus). This process can change dramatically based on size, charge, shape and ligand attached to the nanoparticle. While electron microscopy, atomic emission spectroscopy and histology can be used to assess cellular uptake, they are labor intensive and post-mortem and can miss critical dynamics of the process. For this reason investigators are increasingly turning to optically active nanoparticles that allow direct microscopic interrogation of uptake. Here we show that CRM adds to this evolving armamentarium as a fast, noninvasive, and label-free technique to dynamically study cellular uptake of GNPs with subcellular detail in cancer. Raman laser interaction with GNPs inside cells shows unique spectroscopic features corresponding to the intracellular localization of GNPs over 2 to 24 h at the membrane, cytoplasm or nucleus that are separately verified by histology (silver staining) and electron microscopy. These results show that CRM has the potential to facilitate high-throughput study of the dynamics and localization of a variety of GNPs in multiple cell types.

Blood protein and blood cell interactions with gold nanoparticles: the need for in vivo studies

Abstract Gold nanoparticles (GNPs) have gained in prominence within the field of nanomedicine with recent advancement of several embodiments to clinical trials. To ensure their success in the clinic it has become increasingly clear that a deeper understanding of the biological interactions of GNPs is imperative. Since the majority of GNPs are intended for systemic intravenous use, an immediate and critical biological interaction is between the blood and the GNP. Blood is composed of plasma proteins and cells. Both of these components can induce downstream effects upon interacting with GNPs that ultimately influence their medical impact. For instance, proteins from the blood can cover the GNP to create a biological identity through formation of a protein corona that is quite different from the originally synthesized GNP. Once in the bloodstream this protein coated GNP evokes both positive and negative physiological responses such as biodistribution into tissue for therapy (i.e., cancer) and toxicity or off target accumulation in the reticuloendothelial system (RES) that must be controlled for optimal use. In this review, we summarize predominantly in vitro studies of GNP interactions with blood plasma proteins and blood cells and make the case that more in vivo study is urgently needed to optimal design and control GNP use in medicine. In some cases where no specific GNP blood studies exist, we draw the readers’ attention to studies conducted with other types of nanoparticles as reference.

Thermal Analysis Measurement of Gold Nanoparticle Interactions With Cell and Biomaterial

The rapidly evolving field of nanomedicine focuses on the design and application of multi-functional nanoparticles for diagnosis and treatment of diseases especially cancer1. Many of these nanomaterials are designed to serve as drug delivery or image contrast agents, or even to generate heat for hyperthermia (i.e. treatment), of cancer. Heating examples include gold nanoparticles (GNPs) for photothermal therapy3, and superparamagnetic nanoparticles for magnetic fluid hyperthermia4.© 2012 ASME

Effect of Surface Charge on Gold Nanoparticle Biotransport: An In Vivo Blood and Biodistribution Study

Intravenously injected nanoparticles (NPs) hold great promise for clinical diagnostic and therapeutic applications. While several NPs for such clinical applications have emerged in various designs (metallic, polymeric, quantum dots etc.) [1], a critical issue in their in vivo use is the lack of fundamental studies examining the effects of physicochemical parameters (shape, size, surface properties etc.) on blood circulation, kinetics of accumulation and elimination as well as toxicity [2–4]. We hypothesize that blood, the first medium of interaction in the body, is a major determinant of biotransport and biodistribution. Recent and past in vitro studies have shown that NPs interact with serum proteins (including complement factors), cause platelet aggregation and red blood cell hemolysis, and are taken up by phagocytic cells. However, to our knowledge a detailed in vivo study of the interaction of metallic nanoparticles with blood components as a function of their surface properties does not yet exist.Copyright

Biodistribution of TNF-alpha coated gold nanoparticles in an in vivo cancer model

Over the past several years, there has been an increasing interest in the use of nanoparticles as a tool for treatment of cancer. We have shown tremendous augmentation and control (without toxicity) of both heat and cold-based thermal therapy for cancer treatment with a gold based nanodrug-CYT-6091 (Cytimmune Sciences, Inc.) [1–3]. To reach the full potential of these nanodrugs for both stand-alone solid cancer treatment and as adjuvant to thermal therapy, there is a need to understand the in vivo biodistribution and their short-term and long-term tissue interaction.Copyright