Fibrotic elements within the tumor microenvironment and its implications for nano-drug delivery systems

The passage of nano―drug delivery systemsnanoDDS through the tumor tissue, after extravasation via the enhanced permeability and retentionEPR effect, is often hindered by the presence of various stromal barriers. These barriers are formed by the complex interaction of tumor cells and various “normal” stromal cells within the tumor microenvironment. In particular, fibrotic elements within the tumor microenvironment, mainly comprising fibroblasts that have acquired abnormal phenotypes and the abundant extracellular matrix components that these cells secrete, constitute a formidable barrier to nanoDDS delivery. While targeting fibrosis is considered a promising strategy, the heterogeneity of fibroblasts and the complex functional consequences of fibrosis on tumor progression and therapeutic response have rendered the establishment of anti―fibrotic treatment strategies especially difficult. In this review, we provide a general overview of our current understanding of the fibrotic elements within the tumor microenvironment and discuss implications toward establishing a more efficacious nanoDDS treatment strategy.