Vascular normalization with pegylated emulsion of SU5416 enhances anti-tumor effect of liposomal paclitaxel in 4T1 breast cancer-bearing mice: Analysis of intratumoral vessels and microenvironment

Therapeutic efficacy of vascular normalization strategy was investigated in mice bearing 4T1 cells, a triplenegative breast cancer. The strategy is to enhance the tumor distribution of anti-tumor drugs by partly normalizing tumor vessels and thereby to improve the anti-tumor effect. SU5416, an angiogenesis inhibitor, was pre-administered as a polyethylene glycol (PEG)-modified emulsion (PE-SU5416) to normalize tumor vessels. Subsequent administration of PEG-modified liposomal paclitaxel (PL-PTX) successfully suppressed the growth of 4T1 tumors to approximately 62% of group treated with PE-SU5416 or PL-PTX alone. The pre-administration of PE-SU5416 significantly increased the tumor distribution of PEG-liposomes and PTX. Additionally, PE-SU5416 treatment also significantly increased normalized vessels covered with pericytes and tumor vessels with blood flow, and significantly decreased the hypoxic area in tumor tissues. Furthermore, cancer-associated fibroblasts (CAFs) and collagen levels were significantly decreased by PE-SU5416 treatment, which would have facilitated the diffusion of PEG-liposomes and/or PTX within tumor tissues. In conclusion, PE-SU5416 treatment not only structurally and functionally normalized tumor vessels but also improved the tumor microenvironment, i.e., reduced CAFs and collagen, leading to an improvement in tumor distribution and intratumoral diffusion of subsequently administered PL-PTX, which could be responsible for the significantly enhanced anti-tumor activity based on the vascular normalization theory.