Figure 4. Pharmacological and physical means to enhance tumor accumulation.

Heterogeneity in EPR-based tumor targeting can be overcome by using different pharmacological and physical means. A-B: Accumulation of radiolabeled liposomes in tumors was increased after TNF-α application, which enhances vascular permeability and tumor penetration. The concentration of liposomes was substantially higher in TNF-α-treated tumors than in control tumors (adapted from [70]). C-D: Losartan, an angiotensin II receptor blocker, decompresses tumor blood vessels and leads to improved vessel perfusion. This results in enhanced accumulation of 5-fluorouracil (5-FU; adapted from [77]). E: Extravasation of liposomes from tumor blood vessels upon applying hyperthermia at different temperatures (adapted from [120]). F: CT-FMT images showing enhanced accumulation of fluorophore-labeled liposomes in tumors after sonoporation (adapted from [123]). G: Sonoporation in combination with gemcitabine has a positive impact on the survival of patients suffering from inoperable pancreatic cancer (adapted from [131]). H: Site-specific sonoporation in combination with liposomal doxorubicin inhibits the growth of rat glioma (FUS+DOX; indicated by yellow circles) more efficiently compared to treatment with liposomal doxorubicin alone (DOX only; adapted from [136]).