Subcellular Drug Depots as Reservoirs for Small-Molecule Drugs

Abstract

Therapeutic nanoparticles (TNP) have been developed to more efficiently and safely deliver medicines, especially for the treatment of solid cancers. TNP can deliver drugs through extended systemic payload release while TNP circulate in blood, through direct TNP uptake by target cells, and indirectly through cellular TNP uptake followed by gradual payload redistribution to neighboring cells. In the latter, cells that accumulate TNP can act as reservoirs from which nanoencapsulated small-molecule drugs are slowly released to act on other cells. Recent studies have highlighted this “drug depot” mechanism, particularly via TNP uptake by tumor-associated macrophages, as an important component of TNP drug action. Similar effects have been suggested for other classes of therapies, including antibody drug conjugates. In this report, we highlight evidence for the drug depot effect and describe experimental strategies to quantify it, with a particular focus on subcellular-resolution microscopy performed in vitro and in live animal xenografts. We describe proof-of-principle application of this approach to a model TNP based on clinically relevant polymeric micelle formulations of small-molecule cytotoxic chemotherapies.