Figure 3. Strategies to overcome heterogeneity in EPR-based tumor targeting.

Several strategies can be employed to improve nanomedicine-based anticancer therapy. From left: Enhancing: Pharmacological and physical means, such as radiotherapy (RT), hyperthermia (HT) (adapted from [101]) and sonoporation (adapted from [133]) can be used to enhance the EPR effect in tumors. Combining: Synergism between nanomedicine-based chemotherapy and clinically relevant fractionated radiotherapy leads to increased nanomedicine accumulation and enhanced efficacy (adapted from [99]). Active targeting with pharmacologically active ligands (e.g. anti-EGFR nanobodies) synergizes with the drug molecules entrapped within a given nanomedicine formulation (adapted from [173]). Bypassing: In case of tumors with low or no EPR, vascular targeting (e.g. via RGD-targeted nanocarriers; adapted from [188]) or the use of triggerable nanocarriers that release their payload intravascularly (e.g. from drug-loaded microbubbles; adapted from [125]) can be used to improve drug delivery in spite of low/no EPR effect. Imaging: The heterogeneity in EPR-based tumor targeting can be addressed via direct or indirect imaging approaches, employing either nanotheranostics and companion nanodiagnostics to monitor the biodistribution and target site accumulation of nanomedicines, or employing the use of established images probes and protocols to visualize tumor blood vessels and the microenvironment. Imaging tumor blood vessels and EPR-based tumor targeting can help to pre-select patients for more personalized nanomedicine treatments (adapted from [210] and [205]).