title: 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 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.forename: Xingfa
authors.initials: X
authors.lastname: Ke
authors.forename: Zhiying
authors.initials: Z
authors.lastname: He
authors.forename: Daoqiu
authors.initials: D
authors.lastname: Yang
authors.forename: Hai
authors.initials: H
authors.lastname: Gong
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Jing
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Jianming
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D003287:Contrast Media; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D058851:GPI-Linked Proteins / Q000627:therapeutic use*; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods*; D008081:Liposomes / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D008297:Male; D000090204:Mesothelin; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D058851:GPI-Linked Proteins; D008081:Liposomes; C000715527:MSLN protein, human; D058185:Magnetite Nanoparticles; C000715528:Msln protein, mouse; D053769:Nanocapsules; D004317:Doxorubicin; D000090204:Mesothelin