Attempts to strengthen and simplify the tumor vascular normalization strategy using tumor vessel normalization promoting nanomedicines.

Tumor vascular normalization theory opened the door for the rational use of antiangiogenic agents and chemotherapeutics. However, efforts to seize the normalization window have constrained the development of vascular normalization therapy in clinical applications owing to the lack of circulating biomarkers and the tedious dosage regimes. Applying "Occam's Razor" to therapeutic design inspired us to construct an effective and simple tumor vascular normalization prompting strategy. Herein, we developed tumor vessel normalization prompting nanomedicine lipid derivative conjugates (LGCs) made of anti-angiogenic agents with low molecular weight heparin (LMWH) and gemcitabine (Gem). This treatment exploits the complementary action of anti-vascular endothelial growth factor (VEGF) therapy and metronomic chemotherapy (MET) to strengthen the tumor vascular normalization effect. Furthermore, by loading cytotoxic drugs, such as paclitaxel (PTX), into the LGCs we constructed a "nano-community" to simultaneously restore the tumor vasculature and deliver the loaded drugs. Accordingly, improved drug delivery and therapeutic outcomes were achieved with no need to identify the precise time of the normalization window. Overall, our studies suggest that tumor vessel normalization therapy and nanomedicine design could be combined in one entity, using two waves of normalization strategies to achieve optimal chemo drug delivery into solid tumors.