Tumor-Associated Fibroblast-Targeted Regulation and Deep Tumor Delivery of Chemotherapeutic Drugs with a Multifunctional Size-Switchable Nanoparticle

摘要

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)/[email?protected]/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/[email?protected]/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/[email?protected]/GA displayed significant and long-term antitumor effect in stroma-rich pancreatic cancer and breast cancer models.