Abstract
Multidisciplinary research efforts in the field of drug delivery have led to the development of a variety of drug delivery systems (DDS) designed for site-specific delivery of diagnostic and therapeutic agents. Since efficient uptake of drug carriers into target cells is central to effective drug delivery, a comprehensive understanding of the biological pathways for cellular internalization of DDS can facilitate the development of DDS capable of precise tissue targeting and enhanced therapeutic outcomes. Diverse methods have been applied to study the internalization mechanisms responsible for endocytotic uptake of extracellular materials, which are also the principal pathways exploited by many DDS. Chemical inhibitors remain the most commonly used method to explore endocytotic internalization mechanisms, although genetic methods are increasingly accessible and may constitute more specific approaches. This review highlights the molecular basis of internalization pathways most relevant to internalization of DDS, and the principal methods used to study each route. This review also showcases examples of DDS that are internalized by each route, and reviews the general effects of biophysical properties of DDS on the internalization efficiency. Finally, options for intracellular trafficking and targeting of internalized DDS are briefly reviewed, representing an additional opportunity for multi-level targeting to achieve further specificity and therapeutic efficacy.