新生血管化能够为肿瘤提供必要的营养和氧气，并维持肿瘤细胞生长的微环境。在本研究中，我们结合抗血管生成治疗和基因治疗实现协同的抗肿瘤治疗。我们使用1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)]和pH响应性苯甲亚胺连接键(DSPE-Hyd-mPEG)与聚乙烯亚胺-聚(丙内酯) (PEI-PDLLA) 纳米复合物共递送血管内皮生长因子受体抑制剂 fruquintinib (Fru) 和抑制上皮-间充质转化的小干扰RNA CCAT1 (siCCAT1) (Fru和siCCAT1共递送纳米粒子，FCNP)。由于pH响应的特性，DSPE-Hyd-mPEG会在富集在肿瘤部位之后从FCNP中移除并具有体内保护作用。同时，Fru作用于肿瘤周围的血管上快速释放，然后纳米粒子负载的siCCAT1（CNP）被癌细胞吞噬，并促进siCCAT1的成功溶酶体逃逸，发挥了抑制CCAT1的作用。我们观察到FCNP对CCAT1的高效沉默，并同时下调了VEGFR-1的表达。此外，FCNP通过抗血管生成和基因治疗在SW480皮下异种移植模型中显示出显著的协同的抗肿瘤活性，并在治疗过程中具有良好的生物安全性和生物相容性。总之，FCNP被认为是针对结直肠癌的联合抗血管生成和基因治疗的一种有前途的策略。Copyright © 2023 Elsevier B.V. All rights reserved.

Neovascularization can provide tumors with essential nutrients and oxygen, as well as maintain a microenvironment for tumor cell growth. In this study, we combined anti-angiogenic therapy and gene therapy for synergistic anti-tumor therapy. We co-delivered the vascular endothelial growth factor receptor inhibitor fruquintinib (Fru) and small interfering RNA CCAT1 (siCCAT1) inhibiting epithelial-mesenchymal transition using 1,2-distearoyl-snglycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol)] with a pH-responsive benzoic imine linker bond (DSPE-Hyd-mPEG) and polyethyleneimine-poly (d, l-lactide) (PEI-PDLLA) nanocomplex (Fru and siCCAT1 co-delivery NP, FCNP). Due to the characteristics of pH-response, DSPE-Hyd-mPEG removed from FCNP after enrichment at the tumor site, which had a protective effect in the body. Meanwhile, Fru acting on the peritumor blood vessels was rapidly released, and then the nanoparticles loaded with siCCAT1 (CNP) was engulfed by cancer cells and facilitate the successful lysosomal escape of siCCAT1 in, playing the role of silencing CCAT1. Efficient silencing of CCAT1 by FCNP was observed, and simultaneously, the expression of VEGFR-1 was also down-regulated. Furthermore, FCNP elicited significant synergistic antitumor efficacy via anti-angiogenesis and gene therapy in the SW480 subcutaneous xenograft model with favorable biosafety and biocompatibility during the treatment. Overall, FCNP was considered a promising strategy for the combined anti-angiogenesis-gene treatment against colorectal cancer.Copyright © 2023 Elsevier B.V. All rights reserved.