Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer

• Published in: Acta pharmaceutica Sinica. B Vol. 10; no. 8; pp. 1563 - 1575
• Main Authors: Zhou, Yu, Zhou, Wenxi, Chen, Xinli, Wang, Qingbing, Li, Chao, Chen, Qinjun, Zhang, Yu, Lu, Yifei, Ding, Xiaoyi, Jiang, Chen
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-08-2020; Elsevier
• Subjects: Drug delivery; Exosomes; Original; Pancreatic cancer; Penetration; Target therapy; Drug delivery; Penetration; Exosomes; Pancreatic cancer; Target therapy
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2019.11.013

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix (ECM). Based on the theory that bone marrow mesenchymal stem cells (BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes (Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel (PTX) and gemcitabine monophosphate (GEMP)—an intermediate product of gemcitabine metabolism—were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy in vivo and in vitro, plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance (Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.
We constructed an exosome co-delivery system with gemcitabine monophosphate (GEMP) in the cavity and paclitaxel (PTX) coating on the membrane. The exosome platform showed superiorities in targeting pancreatic cancer, performing triple functions on excellent penetrating, anti-matrix and overcoming chemoresistance. [Display omitted]