Image-guided strategies to improve drug delivery to tumors beyond using the enhanced permeability and retention (EPR) effect.

Immature and hyperpermeable vessels and active transport through endothelial cells, combined with impaired lymphatic clearance and uptake by tumor-associated macrophages, contribute to the accumulation of anticancer drugs in tumors. These so-called "Enhanced Permeability and Retention" (EPR) and "Active Transport and Retention" (ATR) effects are pronounced for nanomedicines. However, while little is known about ATR, EPR is heterogeneous within tumors and patients, limiting the therapeutic efficacy of EPR-based drug delivery systems (DDS). This review discusses strategies to refine and complement EPR-based drug delivery. One possibility is to better stratify patients for therapy using histological and omics biomarkers as well as via companion diagnostics and theranostics. Active targeting of DDS could be used to improve retention and internalization by tumor cells. In addition, active targeting of endothelial cells is increasingly being discussed to promote drug accumulation in tumors by transcytosis. Other strategies include pharmacological or (image-guided) physical priming of the tumor microenvironment. Pharmacological priming has been successfully demonstrated with angiogenic factors to increase vascular maturity, erythropoietin to increase perfusion, and corticosteroids to remodel vessels and the associated extracellular matrix (ECM). Physical priming has been carried out using heat, radiation and ultrasound. The latter is often used in combination with microbubbles that oscillate or burst upon stimulation, mechanically untightening the vessel walls and adjacent ECM. Clinically, this strategy is being evaluated in particular for brain tumors. Thus, EPR-dependent drugs may greatly benefit from patient pre-selection strategies and complementary interventions targeting biological barriers between the injection site and the target.