Renal clearance of quantum dots

Abstract

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...

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