title: Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer.
abstract: Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer.
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Lingxi
authors.initials: L
authors.lastname: Xing
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Qiusheng
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Engineering Department, Crop Science Division of Bayer, Institute, WV, 25112, USA.
authors.forename: Kailiang
authors.initials: K
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Lizhou
authors.initials: L
authors.lastname: Lin
authors.affiliation: The Comprehensive Cancer Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, P. R. China.
authors.forename: Yourong
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China.
authors.forename: Lianfang
authors.initials: L
authors.lastname: Du
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D018395:CA-19-9 Antigen / Q000378:metabolism*; D002470:Cell Survival; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D045423:Microbubbles; D053758:Nanoparticles / Q000008:administration & dosage*; D017239:Paclitaxel / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011091:Polyesters / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014463:Ultrasonography
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018395:CA-19-9 Antigen; D004337:Drug Carriers; D011091:Polyesters; C558447:methoxypolyethyleneglycol-poly(lactic-co-glycolic acid); D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: Ultrasound-mediated microbubble destruction; controlled release; nanoparticles; pancreatic cancer.; tumor target