4.7 Article

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

期刊

INTERNATIONAL JOURNAL OF NANOMEDICINE
卷 7, 期 -, 页码 5053-5065

出版社

DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S34801

关键词

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

资金

  1. National Natural Science Foundation of China [81101141]
  2. Science and Technology Foundation of Shanghai Municipality of China [1052 nm03300]

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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 similar to 180 nm, with a zeta potential of about -28 similar to-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 (r(2)) 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 mu M). 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 (Delta SI = 145.98 +/- 20.45) or PLDUs (Delta SI = 75.69 +/- 14.53) was much more significant than that by free USPIOs (Delta SI = 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.

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