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WIREs Syst Biol Med
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Systems approaches to design of targeted therapeutic delivery

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Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems‐inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well‐defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large‐scale high‐throughput combinatorial synthesis and selection of lipid‐ and polymer‐based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems‐based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain. WIREs Syst Biol Med 2015, 7:253–265. doi: 10.1002/wsbm.1304 This article is categorized under: Laboratory Methods and Technologies > Macromolecular Interactions, Methods Laboratory Methods and Technologies > Proteomics Methods Translational, Genomic, and Systems Medicine > Therapeutic Methods
Schematic of work flow for development of nanoparticles via chemical library techniques as employed by Anderson et al. Libraries of chemical components with targeted variation of properties (e.g., lipid‐like molecules, cell‐penetrating peptides, epoxy‐containing polymers, and amines) (a) are combined in arrays under conditions conducive to nanoparticle formation (b). Nanoparticles are evaluated in physical and analytical techniques (e.g., gel‐permeation chromatography, dynamic light scattering, and atomic force microscopy) to assess stability, size, and surface chemistry as a function of component properties. With consideration for capacity to carry therapeutic agents, nanoparticles evaluated in the initial array are applied in analogous arrays in vitro via automated cell culture (c). For the case of siRNA delivery, two‐color luciferase assays evaluated gene knockdown in arrayed assays . Nanoparticles selected via success in cell and biophysical assays are applied in animal models, where, in addition to therapeutic readout, image‐based tracking (e.g., via bioluminescence, CT, and fluorescence) enables evaluation of in vivo performance and distribution (d).
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Method of isolating the ‘membranome’ of pulmonary endothelial cells. The pulmonary vasculature is accessed by cannulating the right ventricle (top left) and then injecting a solution of poly‐cationic silica nanoparticles (circles with ‘+’ symbols in the center). The positively charged nanoparticles bind to the negatively charged glycocalyx of the pulmonary endothelial cells (top right). The lungs are then minced and homogenized. The homogenate is then subjected to multiple rounds of centrifugation, after which the nanoparticles are pelleted, along with the endothelial membranes they are bound to (bottom left). Electron micrographs have confirmed the beads are associated with sheets of plasma membranes, studded with membrane‐associated proteins (blue shapes, bottom right). The resulting protein mixture can then be cleared of lipid and nanoparticles, and subjected to gel separation, liquid chromatography, mass spectrometry, or directly used as antigens for antibody generation.
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Laboratory Methods and Technologies > Proteomics Methods
Laboratory Methods and Technologies > Macromolecular Interactions, Methods
Translational, Genomic, and Systems Medicine > Therapeutic Methods

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