Therapeutic Remodeling of the Tumor Microenvironment Enhances Nanoparticle Delivery

作者：Yuanxin Chen, Xiujie Liu, Hengfeng Yuan, Zhaogang Yang, Christina A. Von Roemeling, Yaqing Qie, Zhao Hai, Yifan Wang, Wen Jiang, Betty Y.S. Kim · 发表于：Advanced Science · 年份：2019 · DOI：10.1002/advs.201802070 · 被引用次数：128 · 研究领域：Nanoparticle-Based Drug Delivery、3D Printing in Biomedical Research、Angiogenesis and VEGF in Cancer

A major challenge in the development of cancer nanomedicine is the inability for nanomaterials to efficiently penetrate and deliver therapeutic agents into solid tumors. Previous studies have shown that tumor vasculature and extracellular matrix regulate the transvascular and interstitial transport of nanoparticles, both critical for successfully delivering nanomedicine into solid tumors. Within the malignant tumor microenvironment, blood vessels are morphologically abnormal and functionally exhibit substantial permeability. Furthermore, the tumor extracellular matrix (ECM), unlike that of the normal tissue parenchyma, is densely packed with collagen. These pathophysiological properties greatly impede intratumoral delivery of nanomaterials. By using an antivascular endothelial growth factor receptor antibody, DC101, and an antitransforming growth factor β1 (TGF-β1) antibody, normalization of the tumor vasculature and ECM is achieved, respectively, in a syngeneic murine glioma model. This normalization effect results in a more organized vascular network, improves tissue perfusion, and reduces collagen density, all of which contribute to enhanced nanoparticle delivery and distribution within tumors. These findings suggest that combined vascular and ECM normalization strategies can be used to remodel the tumor microenvironment and improve nanomedicine delivery into solid tumors, which has significant implications for developing more effective combinational therapeutic strategies...