Smart Hypoxia-Responsive Transformable and Charge-Reversible Nanoparticles for Deep Penetration and Tumor Microenvironment Modulation of Pancreatic Cancer
Recently, our group has developed a hypoxia-responsive transformable and charge-reversible nanoparticle, which can deliver gemcitabine monophosphate and STAT3 inhibitor, and achieved deep penetration and tumor microenvironment modulation of pancreatic cancer. The relevant studies were published online in Biomaterials, named “Smart Hypoxia-Responsive Transformable and Charge-Reversible Nanoparticles for Deep Penetration and Tumor Microenvironment Modulation of Pancreatic Cancer”.
The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control.
Hence, we design and construct an aptamer-decorated hypoxia-responsive nano-particle s(DGL)n@Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment.
Hongyi Chen, the PhD fellow of 2019 from the School of Pharmacy, Fudan University, is the first author, while Professor Chen Jiang is the corresponding author. The work was supported by grants from the National Natural Science Foundation of China, Key Projects of Shanghai Science Foundation, Shanghai Municipal Science and Technology Major Project, and ZJLab.
For more information: https://doi.org/10.1016/j.biomaterials.2022.121599
