Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine

Abstract

// Cheng Wang 1 , Biao Liu 2, * , Xuelian Xu 1 , Bo Zhuang 1 , Hongxia Li 1 , Jiaqi Yin 1 , Mengyi Cong 1 , Wei Xu 3, 4 , Aiping Lu 2 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China 2 Institute for Advancing Translational Medicine in Bone and Joint Diseases, Jockey Club School of Chinese Medicine Building, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong 3 Department of Pharmacy, Shandong Provincial Qian Foshan Hospital, Jinan, China 4 Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA * Co-first author, the author contributed equally to this work Correspondence to: Cheng Wang, e-mail: cheng13980029671@163.com Wei Xu, e-mail: wei1@email.unc.edu Aiping Lu, e-mail: aipinglu@hkbu.edu.hk Keywords: chemoresistance, pancreatic cancer, triptolide, AS1411, PEG-PDLLA Received: September 24, 2015      Accepted: January 13, 2016      Published: January 29, 2016 ABSTRACT Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro . Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar ® in vivo . Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer.