Enhancement of Antitumor Efficacy of Paclitaxel-Loaded PEGylated Liposomes by N,N-Dimethyl Tertiary Amino Moiety in Pancreatic Cancer

Yang Chen,1,* Li Wang,1,* Shi Luo,2 Jun Hu,3 Xing Huang,1 Pei-Wen Li,2 Yi Zhang,1 Chao Wu,1 Bo-Le Tian1 1Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 2Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China; 3Laboratory of Basic Scientific Research, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo-Le TianDepartment of Pancreatic Surgery, West China Hospital of Sichuan University, No. 37 Guo Xue Road, Chengdu, Sichuan Province 610041, People’s Republic of ChinaTel +86 13880683475Fax +86 28-85422475Email tianbolemed@163.comIntroduction: Pancreatic cancer, or pancreatic duct adenocarcinoma (PDAC), remains one of the most lethal cancers and features insidious onset, highly aggressive behavior and early distant metastasis. The dense fibrotic stroma surrounding tumor cells is thought to be a shield to resist the permeation of chemotherapy drugs in the treatment of PDAC. Thus, we synthesized a pancreas-targeting paclitaxel-loaded PEGylated liposome and investigated its antitumor efficacy in the patient-derived orthotopic xenograft (PDOX) nude mouse models of PDAC.Methods: The PTX-loaded PEGylated liposomes were prepared by film dispersion-ultrasonic method and modified by an N,N-dimethyl tertiary amino residue. Morphology characteristics of the PTX-loaded liposomes were observed by transmission electron microscope (TEM). The PDOX models of PDAC were established by orthotopic implantation and imaged by a micro positron emission tomography/computed tomography (PET/CT) imaging system. The in vivo distribution and antitumor study were then carried out to observe the pancreas-targeting accumulation and the antitumor efficacy of the proposed PTX liposomes.Results: PTX loaded well into both modified (PTX-Lip2N) and unmodified (PTX-Lip) PEGylated liposomes with spherical shapes and suitable parameters for the endocytosis process. The PDOX nude mouse models were successfully created in which high 18F-FDG intaking regions were observed by micro-PET/CT. In addition to higher cellular uptakes of PTX-Lip2N by the BxPC-3 cells, the proposed nanoparticle had a notable penetrating ability towards PDAC tumor tissues, and consequently, the antitumor ability of PTX-Lip2N was significantly superior to the unmodified PTX-Lip in vivo PDOX models and even more effective than nab-PTX in restraining tumor growth.Conclusion: The modified pancreas-targeting PTX-loaded PEGylated liposomes provide a promising platform for the treatment of pancreatic cancer.Keywords: pancreas-targeting, tertiary amine, pancreatic duct adenocarcinoma, paclitaxel liposome, antitumor efficacy