Theranostics 2016; 6(10):1573-1587. doi:10.7150/thno.15164

Research Paper

Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer

Lingxi Xing1*, Qiusheng Shi1*, Kailiang Zheng2, Ming Shen3, Jing Ma1, Fan Li1, Yang Liu1, Lizhou Lin1, Wenzhi Tu4, Yourong Duan3✉, Lianfang Du1✉

1. Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China
2. Engineering Department, Crop Science Division of Bayer, Institute, WV, 25112, USA
3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, P. R. China
4. The Comprehensive Cancer Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, P. R. China
*Co-first Authors

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.

Keywords: Ultrasound-mediated microbubble destruction, nanoparticles, controlled release, tumor target, pancreatic cancer.

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How to cite this article:
Xing L, Shi Q, Zheng K, Shen M, Ma J, Li F, Liu Y, Lin L, Tu W, Duan Y, Du L. Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer. Theranostics 2016; 6(10):1573-1587. doi:10.7150/thno.15164. Available from http://www.thno.org/v06p1573.htm