Focus on Fundamentals: Achieving Effective Nanoparticle Targeting

Successful molecular targeting of nanoparticle drug carriers can enhance therapeutic specificity and reduce systemic toxicity. Typically, ligands specific for cognate receptors expressed on the intended target cell type are conjugated to the nanoparticle surface. This approach, often called active targeting, seems to imply that the conjugated ligand imbues the nanoparticle with homing capacity. However, ligand-receptor interactions are mediated by short-range forces and cannot produce magnetic-like attraction over larger distances. Successful targeting actually involves two key characteristics: contact of the nanoparticle with the intended target cell and subsequent ligand-mediated retention at the site. Here we propose a conceptual framework, based on recent literature combined with basic principles of molecular interactions, to guide rational design of nanoparticle targeting strategies. In spite of much effort, ligand-targeted nanoparticles have yet to achieve significant clinical impact. The primary approach thus far to optimizing nanoparticle targeting has been largely based on empirical studies. However, fundamental principles of ligand–receptor interactions can be used to guide a more rational-design approach. The basic principles of binding were developed in vitro under simple conditions with complete control over all relevant binding parameters. Adapting these for in vivo drug delivery requires understanding the specific challenges present in vivo. Nanoparticle delivery in vivo is highly dynamic and, consequently, targeting should be viewed as a kinetic competition between target site and off-target accumulation. Site-specific retention can be maximized by focusing on the two steps that drive local retention: (i) close contact between nanoparticle and target cell; and (ii) effective ligand–receptor engagement upon contact.