Smart-Dust-Nanorice for Enhancement of Endogenous Raman Signal, Contrast in Photoacoustic Imaging, and T2-Shortening in Magnetic Resonance Imaging.

Raman microspectroscopy provides chemo-selective image contrast, sub-micrometer resolution, and multiplexing capabilities. However, it suffers from weak signals resulting in image-acquisition times of up to several hours. Surface-enhanced Raman scattering (SERS) can dramatically enhance signals of molecules in close vicinity of metallic surfaces and overcome this limitation. Multimodal, SERS-active nanoparticles are usually labeled with Raman marker molecules, limiting SERS to the coating material. In order to realize multimodal imaging while acquiring the rich endogenous vibronic information of the specimen, a core-shell particle based on "Nanorice", where a spindle-shaped iron oxide core is encapsulated by a closed gold shell, is developed. An ultrathin layer of silica prevents agglomeration and unwanted chemical interaction with the specimen. This approach provides Raman signal enhancement due to plasmon resonance effects of the shell while the optical absorption in the near-infrared spectral region provides contrast in photoacoustic tomography. Finally, T2-relaxation of a magnetic resonance imaging (MRI) experiment is altered by taking advantage of the iron oxide core. The feasibility for Raman imaging is evaluated by nearfield simulations and experimental studies on the primate cell line COS1. MRI and photoacoustics are demonstrated in agarose phantoms illustrating the promising translational nature of this strategy for clinical applications in radiology.

Increased optical contrast in imaging of epidermal growth factor receptor using magnetically actuated hybrid gold/iron oxide nanoparticles.

We describe a new approach for optical imaging that combines the advantages of molecularly targeted plasmonic nanoparticles and magnetic actuation. This combination is achieved through hybrid nanoparticles with an iron oxide core surrounded by a gold layer. The nanoparticles are targeted in-vitro to epidermal growth factor receptor, a common cancer biomarker. The gold portion resonantly scatters visible light giving a strong optical signal and the superparamagnetic core provides a means to externally modulate the optical signal. The combination of bright plasmon resonance scattering and magnetic actuation produces a dramatic increase in contrast in optical imaging of cells labeled with hybrid gold/iron oxide nanoparticles.

Preventing protein adsorption and macrophage uptake of gold nanoparticles via a hydrophobic shield.

Polyethylene glycol (PEG) surface coatings are widely used to render stealth properties to nanoparticles in biological applications. There is abundant literature on the benefits of PEG coatings and their ability to reduce protein adsorption, to diminish nonspecific interactions with cells, and to improve pharmacokinetics, but very little discussion of the limitations of PEG coatings. Here, we show that physiological concentrations of cysteine and cystine can displace methoxy-PEG-thiol molecules from the gold nanoparticle (GNP) surface that leads to protein adsorption and cell uptake in macrophages within 24 h. Furthermore, we address this problem by incorporating an alkyl linker between the PEG and the thiol moieties that provides a hydrophobic shield layer between the gold surface and the hydrophilic outer PEG layer. The mPEG-alkyl-thiol coating greatly reduces protein adsorption on GNPs and their macrophage uptake. This has important implications for the design of GNP for biological systems.

Gold nanorod light scattering labels for biomedical imaging.

Gold nanorods can be used as extremely bright labels for differential light scattering measurements using two closely spaced wavelengths, thereby detecting human disease through several centimeters of tissue in vivo. They have excellent biocompatibility, are non-toxic, and are not susceptible to photobleaching. They have narrow, easily tunable plasmon spectral lines and thus can image multiple molecular targets simultaneously. Because of their small size, gold nanorods can be transported to various tissues inside the human body via the vasculature and microvasculature, and since they are smaller than vascular pore sizes, they can easily cross vascular space and enter individual cells.

Small multifunctional nanoclusters (nanoroses) for targeted cellular imaging and therapy.

The ability of 20-50 nm nanoparticles to target and modulate the biology of specific types of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Herein we report approximately 30 nm stable uniformly sized near-infrared (NIR) active, superparamagnetic nanoclusters formed by kinetically controlled self-assembly of gold-coated iron oxide nanoparticles. The controlled assembly of nanocomposite particles into clusters with small primary particle spacings produces collective responses of the electrons that shift the absorbance into the NIR region. The nanoclusters of approximately 70 iron oxide primary particles with thin gold coatings display intense NIR (700-850 nm) absorbance with a cross section of approximately 10(-14) m(2). Because of the thin gold shells with an average thickness of only 2 nm, the r(2) spin-spin magnetic relaxivity is 219 mM(-1) s(-1), an order of magnitude larger than observed for typical iron oxide particles with thicker gold shells. Despite only 12% by weight polymeric stabilizer, the particle size and NIR absorbance change very little in deionized water over 8 months. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast in dark field and hyperspectral microscopy, both in cell culture and an in vivo rabbit model of atherosclerosis. Small nanoclusters with optical, magnetic, and therapeutic functionality, designed by assembly of nanoparticle building blocks, offer broad opportunities for targeted cellular imaging, therapy, and combined imaging and therapy.