A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer

Abstract

Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs) and doxorubicin (DOX) was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU]) were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ∼180 nm, with a zeta potential of about −28∼−30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI) capability with a transverse relaxivity (r²) of about 58.5 mM^–1 · s^–1. Confocal microscopy showed more efficient uptake of M-PLDU in Panc-1 cells by antibody-mediated targeting. Methyl thiazolyl tetrazolium assay results showed significant inhibitory effect of M-PLDU against Panc-1 cells (half-maximal inhibitory concentration, 1.95 μM). The in vivo imaging study showed that the tumor signal intensity (SI) dropped significantly about 4 hours after intravenous injection of M-PLDU. The decrease in tumor SI induced by M-PLDUs (ΔSI = 145.98 ± 20.45) or PLDUs (ΔSI = 75.69 ± 14.53) was much more significant than that by free USPIOs (ΔSI = 42.78 ± 22.12; P < 0.01). The in vivo antitumor study demonstrated that compared with FD (free DOX) and PLDU, M-PLDU possessed higher inhibitory effect on tumor growth and the tissue distribution assay further proved that M-PLDUs could selectively accumulate in the tumor xenograft. These results indicated that M-PLDU not only well retained the inherent MRI capability of USPIOs, but significantly improved the targeting distribution of USPIOs and therapeutic agents in pancreatic tumor tissues. They may serve as a promising theranostic nanomedicine not only for early detection but also for MRI-monitored targeting therapy of human pancreatic cancer.

Keywords:

• theranostic nanomedicine
• nanoimmunoliposome
• mesothelin
• USPIO
• doxorubicin
• pancreatic cancer

Acknowledgements

This work was financially supported by National Natural Science Foundation of China (81101141) and the Science and Technology Foundation of Shanghai Municipality of China (grant no 1052 nm03300). We thank Xiaoxia Du PhD in Shanghai Key Laboratory of Magnetic Resonance for her technical assistance.

Disclosure

The authors report no conflicts of interest in this work.