Zhou Yu, Zhou Wenxi, Chen Xinli, Wang Qingbing, Li Chao, Chen Qinjun, Zhang Yu, Lu Yifei, Ding Xiaoyi, Jiang Chen
Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China.
Acta Pharm Sin B. 2020 Aug;10(8):1563-1575. doi: 10.1016/j.apsb.2019.11.013. Epub 2019 Nov 28.
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 and , 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.
胰腺导管腺癌（PDAC）是最难治疗的恶性肿瘤之一，其5年相对生存率仅为6%。这种令人沮丧的治疗效果归因于化疗耐药性以及独特的病理生理学，即存在大量炎性细胞因子和细胞外基质（ECM）异常增生。基于骨髓间充质干细胞（BM-MSCs）可影响PDAC肿瘤微环境和恶性生长这一理论，我们采用源自BM-MSCs的外泌体（Exos）作为PDAC归巢载体，以突破病理性ECM的限制并增加治疗药物在肿瘤部位的蓄积。为克服PDAC的化疗耐药性，将紫杉醇（PTX）和吉西他滨代谢的中间产物单磷酸吉西他滨（GEMP）负载于纯化的Exos内或表面。在这项研究中，Exo递送平台在归巢和穿透能力方面表现出优势，这在肿瘤球体和PDAC原位模型上得到了验证。同时，还发现其具有良好的抗肿瘤疗效以及相对较轻的全身毒性。得益于对PDAC天然的选择性，我们构建的负载GEMP和PTX的Exo平台在卓越的穿透、抗基质和克服化疗耐药性方面具有联合功能（方案1）。令人期待的是，Exo平台可能为PDAC的靶向治疗提供一种前瞻性方法。
