Tumor-associated fibroblasts (TAFs), which form a predominant stromal cellular component of the tumor microenvironment, hinder the delivery of nanomedicine to deep
tumor cells and lead to poor prognosis of
tumors. However, depletion of TAFs by therapeutic agents results in the secretion of damage response program (DRP) molecules to weaken the efficacy of
tumor treatment. This paper reports a multifunctional size-switchable nanoparticle (denoted DGL (dendrigraft poly-
l-lysine) (DGL)/GEM@PP/GA) for TAF-targeted regulation and deep
tumor penetration. After accumulation at the
tumor site, in response to overexpressed
matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment,
gemcitabine (GEM)-conjugated small nanoparticles (DGL/GEM) are released from DGL/GEM@PP/GA, leaving 18β-glycyrrhetinic
acid (GA)-loaded large nanoparticles (PP/GA). The released DGL/GEM can penetrate to the deep region of the
tumor as well as intracellularly release GEM to kill
tumor cells. However, residual GA-loaded nanoparticles with lower
tumor penetration ability could accumulate around
tumor vessels and be preferentially absorbed by TAFs to regulate the secretion of Wnt 16, which is an important DRP molecule. By taking actions on both
tumor cells and TAFs, DGL/GEM@PP/GA displayed significant and long-term antitumor effect in stroma-rich
pancreatic cancer and
breast cancer models.