PDF(Pubmed)
Abstract：
Cancer treatment with vascular disrupting agents (VDAs) causes rapid and extensive necrosis in solid tumors. However, these agents fall short in eliminating all malignant cells, ultimately leading to tumor regrowth. Here, we investigated whether the molecular changes in the tumor microenvironment induced by VDA treatment sensitize the tumors for secondary nanotherapy enhanced by clinical-stage tumor penetrating peptide iRGD. Treatment of peritoneal carcinomatosis (PC) and breast cancer mice with VDA combretastatin A-4 phosphate (CA4P) resulted in upregulation of the iRGD receptors αv-integrins and NRP-1, particularly in the peripheral tumor tissue. In PC mice treated with CA4P, coadministration of iRGD resulted in an approximately threefold increase in tumor accumulation and a more homogenous distribution of intraperitoneally administered nanoparticles. Notably, treatment with a combination of CA4P, iRGD, and polymersomes loaded with a novel anthracycline Utorubicin (UTO-PS) resulted in a significant decrease in the overall tumor burden in PC-bearing mice, while avoiding overt toxicities. Our results indicate that VDA-treated tumors can be targeted therapeutically using iRGD-potentiated nanotherapy and warrant further studies on the sequential targeting of VDA-induced molecular signatures.
摘要：
使用血管破坏剂(VDA)的癌症治疗在实体瘤中引起快速和广泛的坏死。然而,这些药物不足以消除所有恶性细胞，最终导致肿瘤再生。这里,我们研究了VDA治疗诱导的肿瘤微环境的分子变化是否使肿瘤对临床阶段肿瘤穿透肽iRGD增强的二次纳米治疗敏感.用VDAcombrestatinA-4磷酸盐（CA4P）治疗腹膜癌（PC）和乳腺癌小鼠导致iRGD受体αv-整合素和NRP-1上调，特别是在周围肿瘤组织中。在用CA4P处理的PC小鼠中，iRGD的共同给药导致肿瘤积聚增加约三倍，腹膜内给药的纳米颗粒分布更均匀。值得注意的是,用CA4P联合治疗，IRGD,和装载有新型蒽环类阿霉素（UTO-PS）的聚合物囊泡导致携带PC的小鼠的总体肿瘤负荷显着降低，同时避免明显的毒性。我们的结果表明，VDA治疗的肿瘤可以使用iRGD增强的纳米疗法进行靶向治疗，并需要对VDA诱导的分子特征的顺序靶向进行进一步研究。
