Recent developments have greatly improved the sensitivity of optical sensors based on metal nanoparticle arrays and single nanoparticles. We introduce the localized surface plasmon resonance (LSPR) sensor and describe how its exquisite sensitivity to size, shape and environment can be harnessed to detect molecular binding events and changes in molecular conformation. We then describe recent progress in three areas representing the most significant challenges: pushing sensitivity towards the single-molecule detection limit, combining LSPR with complementary molecular identification techniques such as surface-enhanced Raman spectroscopy, and practical development of sensors and instrumentation for routine use and high-throughput detection. This review highlights several exceptionally promising research directions and discusses how diverse applications of plasmonic nanoparticles can be integrated in the near future.

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We report the first inert gas sensing and characterization studies based on high resolution-localized surface plasmon resonance (HR-LSPR) spectroscopy. HR-LSPR was used to detect the extremely small change (< 3 × 10−4) in bulk refractive index (RI) between He (g) and Ar (g) or He (g) and N2 (g). We also demonstrate sub-monolayer sensitivity to adsorbed water from exposure of the sensor to air (40% humidity) vs. dry N2 (g). These measurements significantly expand the applications space and characterization tools for plasmonic nanosensors.

A chemical warfare agent (CWA) gas detector based on surface-enhanced Raman spectroscopy (SERS) using robust nanostructured substrates and a portable Raman spectrometer is a promising alternative to existing modalities. A gas-dosing apparatus was constructed to simulate chemical gas exposure and provide a platform for quantitative analysis of SERS detection. As a first step toward characterizing SERS detection from the gas phase, benzenethiol (BT) has been chosen as the test analyte. SERS spectra were monitored during BT adsorption onto a silver film over a nanosphere (AgFON) substrate. The SERS detection limit time (DLt) for BT on a AgFON at 356 K is found to be 6 ppm-s (30 mg-s m(-3)) for a data acquisition time (t(acq)) of 1 s. The DLt for this kinetically controlled sensor is fundamentally determined by the low sticking probability of BT on AgFONs which is determined to be approximately 2 x 10(-5) at 356 K. The sticking probability increases with increasing temperature consistent with an adsorption activation barrier of approximately 13 kJ mol(-1). Although the DLts found in the present study for BT are in the low ppm-s, a theoretical model of SERS detection indicates DLts below 1 ppb s(-1) for t(acq)= 1 s are, in fact, achievable using existing portable Raman instrumentation and AgFON surfaces. Achieving this goal requires the sticking probability be increased 3 orders of magnitude, illuminating the importance of appropriate surface functionalization.

We have developed magnetically modulated optical nanoprobes ͑MagMOONs͒ to magnetically modulate the signal from fluorescent probes and thus separate it from autofluorescence, electronic offsets, and other background signals. These micro-and nanosized particles emit fluorescence signals, indicating chemical concentrations, and blink in response to rotating magnetic fields. Demodulating the signal dramatically enhances the probe's signal to background ratio. The probes and methods promise to improve immunoassays, intracellular chemical sensing, and fundamental biochemical research.

Sensors based upon surface-enhanced Raman spectroscopy (SERS) are attractive because they have narrow, vibrationally specific spectral peaks that can be excited using red and near-infrared light which avoids photobleaching, penetrates tissue, and reduces autofluorescence. Several groups have fabricated pH nanosensors by functionalizing silver or gold nanoparticle surfaces with an acidic molecule and measuring the ratio of protonated to deprotonated Raman bands. However, a limitation of these sensors is that macromolecules in biological systems can adsorb onto the nanoparticle surface and interfere with measurements. To overcome this interference, we encapsulated pH SERS sensors in a 30 nm thick silica layer with small pores which prevented bovine serum albumin (BSA) molecules from interacting with the pH-indicating 4-mercaptobenzoic acid (4-MBA) on the silver surfaces but preserved the pH-sensitivity. Encapsulation also improved colloidal stability and sensor reliability. The noise level corresponded to less than 0.1 pH units from pH 3 to 6. The silica-encapsulated functionalized silver nanoparticles (Ag-MBA@SiO(2)) were taken up by J774A.1 macrophage cells and measured a decrease in local pH during endocytosis. This strategy could be extended for detecting other small molecules in situ.

One of the greatest challenges in cancer therapy is to develop methods to deliver chemotherapy agents to tumor cells while reducing systemic toxicity to non-cancerous cells. A promising approach to localizing drug release is to employ drug-loaded nanoparticles with coatings that release the drugs only in the presence of specific triggers found in the target cells such as pH, enzymes, or light. However, many parameters affect the nanoparticle distribution and drug release rate and it is difficult to quantify drug release in situ. In this work, we show proof of principle for a “smart” radioluminescent nanocapsule with X-ray excited optical luminescence (XEOL) spectrum that changes during release of the optically absorbing chemotherapy drug, doxorubicin. XEOL provides an almost background-free luminescent signal for measuring drug release from particles irradiated by a narrow X-ray beam. We study in vitro pH triggered release rates of doxorubicin from nanocapsules coated with a pH responsive polyelectrolyte multilayer using HPLC and XEOL spectroscopy. The doxorubicin was loaded to over 5 % by weight, and released from the capsule with a time constant in vitro of ~ 36 days at pH 7.4, and 21.4 hr at pH 5.0, respectively. The Gd2O2S:Eu nanocapsules are also paramagnetic at room temperature with similar magnetic susceptibility and similarly good MRI T2 relaxivities to Gd2O3, but the sulfur increases the radioluminescence intensity and shifts the spectrum. Empty nanocapsules did not affect cell viability up to concentrations of at least 250 μ/ml. These empty nanocapsules accumulated in a mouse liver and spleen following tail vein injection, and could be observed in vivo using XEOL. The particles are synthesized with a versatile template synthesis technique which allows for control of particle size and shape. The XEOL analysis technique opens the door to non-invasive quantification of drug release as a function of nanoparticle size, shape, surface chemistry and tissue type.

Modulated optical nanoprobes (MOONs) are microscopic (spherical and aspherical) fluorescent particles designed to emit varying intensities of light in a manner that depends on particle orientation. MOONs can be prepared over a broad size range, allowing them to be tailored to applications including intracellular sensors, using submicrometer MOONs, and immunoassays, using 1−10 μm MOONs. When particle orientation is controlled remotely, using magnetic fields (MagMOONs), it allows modulation of fluorescence intensity in a selected temporal pattern. In the absence of external fields, or material that responds to external fields, the particles tumble erratically due to Brownian thermal forces (Brownian MOONs). These erratic changes in orientation cause the MOONs to blink. The temporal pattern of blinking reveals information about the local rheological environment and any forces and torques acting on the MOONs, including biomechanical forces as observed in macrophages. The rotational diffusion rate of Brownian MOONs is inversely proportional to the particle volume and hydrodynamic shape factor, for constant temperature and viscosity. Changes in the particle volume and shape due to binding, deformation, or aggregation can be studied using the temporal time pattern from the probes. The small size and the large number of MOONs that can be viewed simultaneously provide local measurements of physical properties, in both homogeneous and inhomogeneous media, as well as global statistical ensemble properties.