Aberrant tumor vasculature leads to the malignant tumor microenvironment (TME) for tumor progression. Research has found temporary tumor vascular normalization after treated with low-dose anti-angiogenic agents, however, has paid little attention to prolonging the normalization window and its further influence on tumor tissue. Based on the dose- and time-dependent effect of anti-angiogenic agents, we developed V@LDL NPs, a nano-delivery system sustainedly releasing Vandetanib, an anti-VEGFR2 inhibitor, to control the dose of drug to the normalizing level, and prove its stable tumor vascular normalizing effect in 4 T1 breast cancer model. Furthermore, long-term normalized vasculature could improve tumor perfusion, then provide a circulation to reverse abnormalities in TME, such as hypoxia and heterogeneity, and also inhibit tumor progression. Our findings demonstrate that stable tumor vascular normalization could be a considerable strategy for long-term change to remodel TME and probably result in a therapeutic benefit to anti-cancer treatment, which could be achieved by anti-angiogenic nano-delivery system.

异常的肿瘤脉管系统导致肿瘤进展的恶性肿瘤微环境（TME）。研究发现用低剂量抗血管生成剂治疗后肿瘤血管暂时正常化，然而，很少关注延长正常化窗口及其对肿瘤组织的进一步影响。基于抗血管生成药物的剂量和时间依赖性效应，我们开发了 V@LDL NPs，一种纳米递送系统，可持续释放抗 VEGFR2 抑制剂 Vandetanib，以将药物剂量控制在正常水平，以及在 4 T1 乳腺癌模型中证明其稳定的肿瘤血管正常化作用。此外，长期正常化的脉管系统可以改善肿瘤灌注，然后提供循环以逆转 TME 中的异常，例如缺氧和异质性，并抑制肿瘤进展。