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The use of near-infrared or infrared photons is a promising approach for biomedical imaging in living tissue. This technology often requires exogenous contrast agents with combinations of hydrodynamic diameter, absorption, quantum yield and stability that are not possible with conventional organic fluorophores. Here we show that the fluorescence emission of type II quantum dots can be tuned into the near infrared while preserving absorption cross-section, and that a polydentate phosphine coating renders them soluble, disperse and stable in serum. We then demonstrate that these quantum dots allow a major cancer surgery, sentinel lymph node mapping, to be performed in large animals under complete image guidance. Injection of only 400 pmol of near-infrared quantum dots permits sentinel lymph nodes 1 cm deep to be imaged easily in real time using excitation fluence rates of only 5 mW/cm(2). Taken together, the chemical, optical and in vivo data presented in this study demonstrate the potential of near-infrared quantum dots for biomedical imaging.

SUMMARYThe field of nanotechnology holds great promise for the diagnosis and treatment of human disease. However, the size and charge of most nanoparticles preclude their efficient clearance from the body as intact nanoparticles. Without such clearance or their biodegradation into biologically benign components, toxicity is potentially amplified and radiological imaging is hindered. Using quantum dots (QDs) as a model system, we have precisely defined the requirements for renal filtration and urinary excretion of inorganic, metal-containing nanoparticles. Zwitterionic or neutral organic coatings prevented adsorption of serum proteins, which otherwise increased hydrodynamic diameter (HD) by over 15 nm and prevented renal excretion. A final HD smaller than 5.5 nm resulted in rapid and efficient urinary excretion, and elimination of QDs from the body. This study provides a foundation for the design and development of biologically targeted nanoparticles for biomedical applications. KeywordsNanotechnology; Quantum Dots; Biodistribution; Clearance; Fluorescence Imaging Although targeted nanoparticles hold promise for the detection and treatment of human disease, toxicity -either potential or real -remains the major roadblock to clinical translation. 1 Historically, the U.S. Food and Drug Administration (FDA) has required that agents injected into the human body, especially diagnostic agents, be cleared completely, in a reasonable amount of time. This policy makes sense in that total body clearance minimizes the area under the exposure curve. It also minimizes the chance that the agent will interfere with other diagnostic tests. For example, gold, used extensively in the nanotechnology literature, has a linear attenuation coefficient 150-fold higher than even bone, and at doses injected intravenously would likely preclude accurate computed tomographic (CT) scanning, especially in organs such as the liver, where it eventually accumulates. Against this backdrop is the inherent stability of most nanoparticles. Indeed, a recent study suggests that quantum dots (QDs) with the appropriate organic coating are retained in the body for at least two years and remain fluorescent. 2 When considering that many nanometer-sized objects proposed for clinical use contain heavy metals, regulatory approval of such stable particles is unlikely, and the type of long-term toxicity studies that would be required for such approval will continue to discourage clinical translation.A potential solution to this conundrum is to focus on the physiology underlying biodistribution and clearance of agents injected intravenously into the body. For globular proteins, a hydrodynamic diameter (HD) of approximately 5-6 nm is associated with the ability to be cleared rapidly from the body via renal filtration and urinary excretion (Table 1). Nanoparticle toxicity would be minimized, if not eliminated, if there were a way to clear them from the body. However, currently it is unknown what the renal filtration threshold is for metal-based nanometer-sized objec...

Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better, and/or less expensively. Optical imaging that exploits invisible near-infrared fluorescent light has the potential to improve cancer surgery outcomes while minimizing anesthesia time and lowering healthcare costs. Because of this, the last few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this review, we introduce the concept of near-infrared fluorescence imaging for cancer surgery, review the clinical trial literature to date, outline the key issues pertaining to imaging system and contrast agent optimization, discuss limitations and leverage, and provide a framework for making the technology available for the routine care of cancer patients in the near future.

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Background-Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE™ imaging system overcomes this major obstacle.

Optical imaging using near-infrared (NIR) fluorescence provides new prospects for general and oncologic surgery. ICG is currently utilised in NIR fluorescence cancer-related surgery for three indications: sentinel lymph node (SLN) mapping, intraoperative identification of solid tumours, and angiography during reconstructive surgery. Therefore, understanding its advantages and limitations is of significant importance. Although non-targeted and non-conjugatable, ICG appears to be laying the foundation for more widespread use of NIR fluorescence-guided surgery.

Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defense against cold and obesity1. PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) is a 140 kDa zinc finger protein that robustly induces brown fat determination and differentiation2. Recent data suggests that brown fat cells arise in vivo from a myf5-positive, myoblastic lineage through the action of PRDM163; however, the molecular mechanisms responsible for this developmental switch is unclear. Here we show that PRDM16 forms a transcriptional complex with the active form of C/EBP-β (LAP), serving as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/EBP-β is sufficient to induce a fully functional brown fat program in naïve fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these two factors into mice gives rise to an ectopic fat pad with the morphological and biochemical characteristics of brown fat. As with endogenous brown fat, this synthetic brown fat tissue serves as a sink for glucose uptake, as determined by 18FDG-PET scanning. These data indicate that the PRDM16-C/EBP-β complex initiates brown fat development from myoblastic precursors, and may provide opportunities for the development of novel therapeutics for obesity and type-2 diabetes.