The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90-95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α-targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α-targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.

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Gold nanorods excited at 830 nm on a far-field laser-scanning microscope produced strong two-photon luminescence (TPL) intensities, with a cos 4 dependence on the incident polarization. The TPL excitation spectrum can be superimposed onto the longitudinal plasmon band, indicating a plasmon-enhanced two-photon absorption cross section. The TPL signal from a single nanorod is 58 times that of the two-photon fluorescence signal from a single rhodamine molecule. The application of gold nanorods as TPL imaging agents is demonstrated by in vivo imaging of single nanorods flowing in mouse ear blood vessels.in vivo imaging ͉ plasmon resonance ͉ multiphoton ͉ nonlinear optics P hotoluminescence from noble metals was first reported in 1969 by Mooradian (1) and later observed as a broad background in surface-enhanced Raman scattering (2). Singlephoton luminescence from metals has been described as a three-step process as follows: (i) excitation of electrons from the d-to the sp-band to generate electron-hole pairs, (ii) scattering of electrons and holes on the picosecond timescale with partial energy transfer to the phonon lattice, and (iii) electron-hole recombination resulting in photon emission (1). Two-photon luminescence (TPL) was characterized by Boyd et al. (3) and is considered to be produced by a similar mechanism as singlephoton luminescence, but the relatively weak TPL signal can be amplified by several orders of magnitude when produced from roughened metal substrates. This amplification is due to a resonant coupling with localized surface plasmons, which are well known to enhance a variety of linear and nonlinear optical properties (4-9).Metal nanoparticles are also capable of photoluminescence, which has been shown to correlate strongly with their welldefined plasmon resonances (10-16). For example, Mohamed et al. (11) have observed that the quantum efficiency of singlephoton luminescence from gold nanorods is enhanced by a factor of Ͼ1 million under plasmon-resonant conditions. Plasmonresonant TPL is attractive for nonlinear optical imaging of biological samples with 3D spatial resolution (17). Gold nanorods are particularly appealing as TPL substrates because their longitudinal plasmon modes are resonant at near-infrared, where the absorption of water and biological molecules are minimized. Moreover, nanorods have larger local field enhancement factors than nanoparticles due to reduced plasmon damping (18). A scanning near-field optical microscopy study of TPL from single nanorods (diameter Ϸ 40 nm) has recently been reported by Imura et al. (16), who observed that the luminescence is greatest at their tips. However, further characterization of TPL from single gold nanorods is needed: the polarization dependence of TPL excitation and emission from nanorods has yet to be defined, as well as the relationship between TPL enhancement and the longitudinal and transverse plasmon modes. These studies can provide a deeper understanding of single-particle TPL and its potential application in nonlinear optical imag...

In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.