Metabolism of nanomaterials in vivo: blood circulation and organ clearance.

Before researchers apply nanomaterials (NMs) in biomedicine, they need to understand the blood circulation and clearance profile of these materials in vivo. These qualities determine the balance between nanomaterial-induced activity and unwanted toxicity. NMs have heterogeneous characteristics: they combine the bulk properties of solids with the mobility of molecules, and their highly active contact interfaces exhibit diverse functionalities. Any new and unexpected circulation features and clearance patterns are of great concern in toxicological studies and pharmaceutical screens. A number of studies have reported that NMs can enter the bloodstream directly during their application or indirectly via inhalation, ingestion, and dermal exposure. Due to the small size of NMs, the blood can then transport them throughout the circulation and to many organs where they can be stored. In this Account, we discuss the blood circulation and organ clearance patterns of NMs in the lung, liver, and kidney. The circulation of NMs in bloodstream is critical for delivery of inhalable NMs to extrapulmonary organs, the delivery of injectable NMs, the dynamics of tissue redistribution, and the overall targeting of drug carriers to specific cells and organs. The lung, liver, and kidney are the major distribution sites and target organs for NMs exposure, and the clearance patterns of NMs in these organs are critical for understanding the in vivo fate of NMs. Current studies suggest that multiple factors control the circulation and organ clearance of NMs. The size, shape, surface charge, surface functional groups, and aspect ratio of NMs as well as tissue microstructures strongly influence the circulation of NMs in bloodstream, their site-specific extravasation, and their clearance profiles within organs. Therefore structure design and surface modification can improve biocompatibility, regulate the in vivo metabolism, and reduce the toxicity of NMs. The biophysicochemical interactions occurring between NMs and between NMs and the biological milieu after the introduction of NMs into living systems may further influence the blood circulation and clearance profiles of NMs. These interactions can alter properties such as agglomeration, phase transformations, dissolution, degradation, protein adsorption, and surface reactivity. The physicochemical properties of NMs change dynamically in vivo thereby making the metabolism of NMs complex and difficult to predict. The development of in situ, real-time, and quantitative techniques, in vitro assays, and the adaptation of physiologically-based pharmacokinetic (PBPK) and quantitative structure-activity relationship (QNSAR) modeling for NMs will streamline future in vivo studies.

[1]  B. Jarrar,et al.  Gold nanoparticles administration induced prominent inflammatory, central vein intima disruption, fatty change and Kupffer cells hyperplasia , 2011, Lipids in Health and Disease.

[2]  Mark E. Davis,et al.  Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements , 2009, Proceedings of the National Academy of Sciences.

[3]  Yuliang Zhao,et al.  Exosomes as extrapulmonary signaling conveyors for nanoparticle-induced systemic immune activation. , 2012, Small.

[4]  R. Zhou,et al.  Binding of blood proteins to carbon nanotubes reduces cytotoxicity , 2011, Proceedings of the National Academy of Sciences.

[5]  Maxine J McCall,et al.  Durability and inflammogenic impact of carbon nanotubes compared with asbestos fibres , 2011, Particle and Fibre Toxicology.

[6]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[7]  P. Choyke,et al.  Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. , 2008, Nanomedicine.

[8]  Magnus Bergkvist,et al.  Paradoxical glomerular filtration of carbon nanotubes , 2010, Proceedings of the National Academy of Sciences.

[9]  Mark E. Davis,et al.  Targeting kidney mesangium by nanoparticles of defined size , 2011, Proceedings of the National Academy of Sciences.

[10]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.

[11]  A. Tropsha,et al.  Quantitative nanostructure-activity relationship modeling. , 2010, ACS nano.

[12]  H. Makino,et al.  Molecular sieve in glomerular basement membrane as revealed by electron microscopy. , 1979, Journal of electron microscopy.

[13]  Tonghua Wang,et al.  Translocation and fate of multi-walled carbon nanotubes in vivo , 2007 .

[14]  Meng Wang,et al.  Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats. , 2008, Toxicology.

[15]  Iseult Lynch,et al.  Protein-nanoparticle interactions: What does the cell see? , 2009, Nature nanotechnology.

[16]  Ick Chan Kwon,et al.  In vivo targeted delivery of nanoparticles for theranosis. , 2011, Accounts of chemical research.

[17]  Ya‐Ping Sun,et al.  Covalently PEGylated carbon nanotubes with stealth character in vivo. , 2008, Small.

[18]  Weibo Cai,et al.  Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy , 2008, Proceedings of the National Academy of Sciences.

[19]  Feng Zhao,et al.  Bio-distribution and metabolic paths of silica coated CdSeS quantum dots. , 2008, Toxicology and applied pharmacology.

[20]  Rebekah Drezek,et al.  In vivo biodistribution of nanoparticles. , 2011, Nanomedicine.

[21]  Judith Klein-Seetharaman,et al.  Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation. , 2010, Nature nanotechnology.

[22]  Sean Callanan,et al.  Internal benchmarking of a human blood-brain barrier cell model for screening of nanoparticle uptake and transcytosis. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[23]  M. Bawendi,et al.  Renal clearance of quantum dots , 2007, Nature Biotechnology.

[24]  B. Hyman,et al.  Nanoparticles enhance brain delivery of blood–brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging , 2011, Proceedings of the National Academy of Sciences.

[25]  Yunlong Zhou,et al.  Chirality of glutathione surface coating affects the cytotoxicity of quantum dots. , 2011, Angewandte Chemie.

[26]  Lang Tran,et al.  Evaluating the uptake and intracellular fate of polystyrene nanoparticles by primary and hepatocyte cell lines in vitro. , 2010, Toxicology and applied pharmacology.

[27]  V. Rasche,et al.  Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes. , 2010, Biomaterials.

[28]  Z. Gu,et al.  Biodistribution of carbon single-wall carbon nanotubes in mice. , 2004, Journal of nanoscience and nanotechnology.

[29]  Wei Bai,et al.  Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation , 2010, Nanotechnology.

[30]  Feng Zhao,et al.  Acute toxicological effects of copper nanoparticles in vivo. , 2006, Toxicology letters.

[31]  Ying Liu,et al.  Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. , 2011, Small.

[32]  Judith Klein-Seetharaman,et al.  Mechanistic investigations of horseradish peroxidase-catalyzed degradation of single-walled carbon nanotubes. , 2009, Journal of the American Chemical Society.

[33]  Marianne Geiser,et al.  Update on macrophage clearance of inhaled micro- and nanoparticles. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[34]  Håkan Wallin,et al.  Protracted elimination of gold nanoparticles from mouse liver. , 2009, Nanomedicine : nanotechnology, biology, and medicine.

[35]  B. Haraldsson,et al.  A gel-membrane model of glomerular charge and size selectivity in series. , 2001, American journal of physiology. Renal physiology.

[36]  Gaurav Sahay,et al.  Endocytosis of nanomedicines. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[37]  Filip Braet,et al.  Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review , 2002, Comparative hepatology.

[38]  Daniel A. Heller,et al.  Treating metastatic cancer with nanotechnology , 2011, Nature Reviews Cancer.

[39]  Sébastien Laurent,et al.  Volatility forecasts evaluation and comparison: Volatility forecasts evaluation and comparison , 2012 .

[40]  Meng Wang,et al.  Particokinetics and extrapulmonary translocation of intratracheally instilled ferric oxide nanoparticles in rats and the potential health risk assessment. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  Stephanie E. A. Gratton,et al.  The effect of particle design on cellular internalization pathways , 2008, Proceedings of the National Academy of Sciences.

[42]  David Y Lai,et al.  Toward toxicity testing of nanomaterials in the 21st century: a paradigm for moving forward. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[43]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[44]  Wendelin J. Stark,et al.  Nanoparticles in biological systems. , 2011, Angewandte Chemie.

[45]  Jing Wang,et al.  Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice , 2008 .

[46]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[47]  A. El-Ansary,et al.  On the Toxicity of Therapeutically Used Nanoparticles: An Overview , 2009, Journal of toxicology.

[48]  Kostas Kostarelos,et al.  Physiologically based pharmacokinetic modeling of nanoparticles. , 2010, ACS nano.

[49]  C. Casals,et al.  Uptake of nanoparticles by alveolar macrophages is triggered by surfactant protein A. , 2011, Nanomedicine : nanotechnology, biology, and medicine.