Figure 1.

Schematic representation of TSL (A) and CTSL (B) tumor targeting approach in combination with focused HT. TSL circulate through the vasculature after i.v. administration with negligible payload release at body temperature (37°C, NT) (A, I). External active targeting is mediated via local HT to release high concentrations of drug at tumor vascular level leading to drug extravasation (A, II). CTSL circulate in the blood stream and accumulate in tumor vasculature by means of electrostatic interaction with over-expressed negatively charged membrane proteins (B, I and II). After binding, nanoparticles are internalized into tumor endothelial cells (B, III). Regional HT applied via an external device focused on a tumor, triggers drug release from endothelium associated CTSL, delivering high concentrations of the drug intracellularly (B, IV and V).