Real-time multiple-particle tracking: applications to drug and gene delivery Junghae Suh a , Michelle Dawson b , Justin Hanes a,b, * a Department of Biomedical Engineering, The Johns Hopkins University, 3400 N. Charles St., Baltimore MD, 21218, USA b Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles St., Baltimore MD, 21218, USA Received 12 May 2004; accepted 5 August 2004 Abstract Complex biological environments, such as the cell cytoplasm or the mucus lining the airways of the lungs, can pose significant barriers to efficient therapeutic drug and gene delivery. Biological barriers are particularly important in controlled drug delivery applications that utilize a large carrier particle, such as a liposome or a polymer micro- or nanosphere. The dynamic transport of particulate drug and gene delivery vehicles through these barriers is poorly understood, having been primarily studied with static methods in the past. Recently, the transport of synthetic drug and gene carriers has been investigated quantitatively with real-time particle tracking technology, providing new insight into particle behavior in complex biological environments that is guiding rational improvements in particle design. This review briefly highlights basic principles of particle tracking and its application to elucidate important phenomena that limit effective particulate drug and gene delivery. D 2004 Elsevier B.V. All rights reserved. Keywords: Drug delivery; Gene delivery; Multiple-particle tracking; Intracellular; Mucus; Diffusion; Transport; Rheology Contents 1. Introduction...................................................... 64 2. Intracellular barriers ................................................. 65 2.1. Properties of cell cytoplasm.......................................... 65 2.2. Active transport of nonviral vectors...................................... 66 2.3. Subdiffusive and immobile vectors ...................................... 66 2.4. Rapid perinuclear accumulation of gene vectors ............................... 67 0169-409X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2004.06.001 * Corresponding author. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles St., Baltimore MD, 21218, USA. Tel.: +1 410 516 3484; fax: +1 410 516 5510. E-mail address: hanes@jhu.edu (J. Hanes). Advanced Drug Delivery Reviews 57 (2005) 63 – 78 www.elsevier.com/locate/addr