title: Systems approaches to design of targeted therapeutic delivery.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Myerson
authors.affiliation: Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Brenner
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D015195:Drug Design; D006801:Humans; D053758:Nanoparticles; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D049490:Systems Biology / Q000379:methods*