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 (r 2 ) of about 58.5 mM -1 ⋅ s -1 . Confocal microscopy showed more efficient uptake of M-PLDU in Panc-1 cells by antibodymediated 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 (∆SI = 145.98 ± 20.45) or PLDUs (∆SI = 75.69 ± 14.53) was much more significant than that by free USPIOs (∆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.

Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

“…Polydispersity index (PDI) of 0.10 suggested a very narrow size distribution range of this formulation. Encapsulation of MNPs into the liposomes was proved to be difficult task and a maximum of 15% EE had been shown earlier [36]. We here reported EE of 60.0% which could possibly be attributed to the ultrasmall sized MNPs.…”

“…[36] 7:2:0.5 molar ratios of EPC, Cholesterol, and mPEG2000-DSPE was thoroughly mixed in chloroform and evaporated under vacuum. 1.0 mg of ultrasmall MNPs was added onto the resultant thin lipid film for rehydration.…”

Liposomes and Nanotechnology in Drug Development: Focus On Pancreatic Cancer

“…The results of this study showed that M-PLDU controlled advanced inhibitory effect on the growth of the cancer and distribution assay of tissue further more verified that M-PLDUs might selectively collect in the tumor xenograft. This study shows that M-PLDU not only well retains the inherent MRI capability of USPIO, but also significantly enhances the targeted delivery of USPIO and therapeutic agents in pancreatic tumor cells [70].…”

Targeted nanotechnology for cancer imaging

“…Similar approaches have also been evaluated using nanoparticles with MR capabilities [226–234]. These studies used various types of nanoparticles, which include ultrasmall superparamagnetic iron oxide (USPIO) particles, iron oxide nanoworms, liposomes and dendrimers.…”

“…The therapeutic strategies have ranged from chemotherapy ( e.g. taxanes and anthracyclines) [226, 229, 230] and small interfering RNA [233] to antiangiogenic approaches using the CREKA polypeptide and vascular blockade [232], while the target sites included the folate receptor [227, 229], urokinase plasminogen activator receptor [231], integrins [228, 234], prostate-specific membrane antigen [228]. In addition to MR, theranostic agents have been developed using radioisotopes for SPECT and PET imaging [235–237].…”