Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice

To improve vascular normalization strategy for intractable triple-negative breast cancer 4T1, we examined the anti-tumor effects of repeated sequential administration of polyethylene glycol (PEG)-modified emulsion of SU5416 (PE-SU5416), a vascular endothelial growth factor (VEGF) receptor-2 kinase inhibitor, and PEGmodified liposomal paclitaxel (PL-PTX) in mice bearing 4T1 cells. Three sequential administrations (Seqx3) of PE-SU5416 and PL-PTX exhibited significantly higher anti-tumor activity than a single sequential administration (Seqx1). The tumor vasculatures were structurally normalized until after two PE-SU5416 (PESU5416x2) or sequential (Seqx2) administrations, while the improvement in vascular function, such as oxygen supply, blood flow, and PEG-liposomal distribution, was evident until after three administrations of PE-SU5416 (PE-SU5416x3) and Seqx3. Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416x3 and Seqx3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416x2, PE-SU5416x3, Seqx2, and Seqx3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416x2, PE-SU5416x3, Seqx2, and Seqx3 significantly decreased tumor growth factor-(3 (TGF-(3), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-(3 levels by PE-SU5416 suppresses CAF activation.