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Demonstration of biocompatible quantum dots ten years ago [1,2] spurred interest in various nanomaterials with fascinating optical, electronic and magnetic properties, and their potential for medical applications. [3] Plasmon resonance, an optical phenomenon associated with metal nanoparticles, is currently investigated for biomedical imaging and intervention at the cellular level (Table 1). However, requirements of complete elimination from the body may limit the clinical utility of nanoparticles of these sizes. [18] Here we report preparation and testing of biodegradable plasmon resonant nanoshells of 63 nm diameter. Rather than a continuous metallic shell, this composite nanostructure is formed as a shell-shaped array of gold clusters supported on a spherical biodegradable core. This fundamentally new class of materials maintains optical tunability characteristic of solid metallic shells, yet upon degradation yields individual clusters of 5.7 nm diameter, compatible with the requirements of renal clearance. Biodegradable metallic nanoparticles may enable clinical translation of many research-stage technologies.In the Rayleigh approximation of small non-interacting spherical particles, plasmon resonance occurs when ε= −2ε m where ε is the dielectric function of the particles and ε m is that of the medium, and results in intense absorption and scattering of electromagnetic radiation. [19] Gold is of particular interest to biomedical applications because, in addition to being bioinert, its refractive index satisfies the plasmon resonance condition in the visible range, around 530 nm. With a departure from restrictions of the Rayleigh approximation, particle shape and size further control the spectral position of the plasmon resonance, leading to the optical tunability of such particles throughout the visible to near-infrared range, with opportunities for imaging and therapeutic applications. However, concerns regarding unknown toxicities and elimination routes of nanoparticles [20] led to investigation of the hydrodynamic diameter as a critical parameter in design of diagnostic and therapeutic nanoparticles. Consequently proposed criteria of nanoparticles' clinical utility include "degradability to clearable components", i.e., to particles having hydrodynamic diameter of 5-6 nm or less, clearable by renal filtration. [18] Currently investigated plasmon resonant nanostructures do not meet these criteria (Table 1).In response to this challenge we demonstrate preparation of plasmon resonant nanoshells comprised of an array of gold clusters that upon degradation yield components of a clearable size ( Figure 1a) The optical properties of this composite shell are no longer that of solid

Successful integration of diagnostic and therapeutic actions at the level of individual cells requires new materials that combine biological compatibility with functional versatility. This review focuses on the development of liposome-based functional materials, where payload release is activated by light. Methods of sensitizing liposomes to light have progressed from the use of organic molecular moieties to the use of metallic plasmon resonant structures. This development has facilitated application of near infrared light for activation, which is preferred for its deep penetration and low phototoxicity in biological tissues. Presented mechanisms of light-activated liposomal content release enable precise in vitro manipulation of minute amounts of reagents, but their use in clinical diagnostic and therapeutic applications will require demonstration of safety and efficacy.

We explored plasmon resonant nanorods of gold as a contrast agent for optical coherence tomography (OCT). Nanorod suspensions were generated through wet chemical synthesis and characterized with spectrophotometry, transmission electron microscopy, and OCT. Polyacrylamide-based phantoms were generated with appropriate scattering and anisotropy coefficients (30 cm(-1) and 0.89, respectively) to image distribution of the contrast agent in an environment similar to that of tissue. The observed signal was dependent on whether the plasmon resonance peak overlapped the source bandwidth of the OCT, confirming the resonant character of enhancement. Gold nanorods with plasmon resonance wavelengths overlapping the OCT source yielded a signal-to-background ratio of 4.5 dB, relative to the tissue phantom. Strategies for OCT imaging with nanorods are discussed.

Biodegradable, spectrally tunable plasmon resonant nanocapsules are created via the deposition of gold onto the surface of 100 nm diameter thermosensitive liposomes. These nanocapsules demonstrate selective release of encapsulated contents upon illumination with light of a wavelength matching their distinct resonance bands, which correspond to 760 and 1210 nm in this study. Spectrally selective release is accomplished through the use of multiple, low intensity laser pulses delivered over a period of less than four minutes, ensuring that illumination affects only the gold-coated liposomes and avoids heating the surrounding media. The result of this illumination scheme for selective release using multiple wavelengths of light is a biologically safe mechanism for realizing drug delivery, microfluidic, and sensor applications.

Molecularly targeted gold nanorods were investigated for applications in both diagnostic imaging and disease treatment with cellular resolution. The nanorods were tested in two genetically engineered cell lines derived from the human colon carcinoma HCT-116, a model for studying ligand-receptor interactions. One of these lines was modified to express delta opioid receptor (deltaOR) and green fluorescent protein, whereas the other was receptor free and expressed a red fluorescent protein, to serve as the control. Deltorphin, a high-affinity ligand for deltaOR, was stably attached to the gold nanorods through a thiol-terminated linker. In a mixed population of cells, we demonstrated selective imaging and destruction of receptor-expressing cells while sparing those cells that did not express the receptor. The molecularly targeted nanorods can be used as an in vitro ligand-binding and cytotoxic treatment assay platform and could potentially be applied in vivo for diagnostic and therapeutic purposes with endoscopic technology.

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Control of the two strongest upconversion emission lines in NaYF4:Yb3+, Er3+ nanoparticles is demonstrated by varying the excitation repetition rate. This technique may enable new multiplexed sensing modalities based on multicolor luminescent nanoparticles, currently contemplated for biomedical imaging and diagnostics.