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Tumor Targeting and Imaging of Intraperitoneal Tumors by Use of Antisense Oligo-DNA Complexed with Dendrimers and/or Avidin in Mice¹

Department of Nuclear Medicine and Diagnostic Imaging [N. S., T. S., Y. N., T. I., J. K.], and Hitachi Medical Co. chaired Department of Diagnostic and Interventional Imagiology [H. K., K. T.], Kyoto University, Kyoto 606-8507, Japan; Molecular Imaging Division, Biomedical Imaging Research Center, Fukui Medical University, Fukui 910-1193, Japan [Y. F.]; and Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892 [M. W. B.]

To establish an effective nonviral gene delivery and a corresponding imaging method for i.p.-disseminated tumors, various oligonucleotide-carrier complexes were synthesized, and their in vitro and in vivo properties were examined.

The 20-mer multiamino-linked oligonucleotide (oligo), synthesized as antisense against the c-erbB-2 sequence, and the 3'-biotinylated form of the same oligonucleotide (oligo-Bt) were ¹¹¹In labeled through a diethylenetriaminepentaacetic acid chelate. ¹¹¹In-oligo was mixed with generation 4 polyamidoamine dendrimer (G4) or with biotinylated G4 (G4-Bt), which are positively charged to form electrostatic complexes. ¹¹¹In-oligo/G4-Bt and ¹¹¹In-oligo-Bt were conjugated to avidin (¹¹¹In-oligo/G4-Av and ¹¹¹In-oligo-Av, respectively). ¹¹¹In-oligo/G4, ¹¹¹In-oligo/G4-Av, ¹¹¹In-oligo-Av, and carrier-free ¹¹¹In-oligo (2.96 kBq/22.4–45.9 ng of oligo) were examined for internalization in vitro in human ovarian cancer cells (SHIN3). Biodistribution of ¹¹¹In-oligo-carrier complexes or ¹¹¹In-oligo was examined in normal (n = 4–7) or i.p. SHIN3 tumor-bearing (n = 6–10) mice 2–24 h after i.p. injection (74 kBq/125–300 ng). Scintigraphy of i.p. tumor-bearing and normal mice was performed at various times postinjection of ¹¹¹In-oligo-carrier complex or ¹¹¹In-oligo (1.85 MBq/2.2 ng).

¹¹¹In-oligo-carrier complexes bound to the tumor cells were internalized at a rate of 34–56% at 24 h. In vivo, G4, G4-Av, and Av significantly enhanced tumor delivery of ¹¹¹In-oligo [9.1, 14.5, and 24.4% of injected dose per g of tissue (ID/g) at 24 h; P < 0.05, < 0.01, and < 0.0001, respectively] compared with delivery without carrier (0.8% ID/g). Scintigrams of ¹¹¹In-oligo delivered to the i.p.-disseminated tumors by the carriers were successfully obtained.

In conclusion, G4, G4-Av, and Av can effectively deliver ¹¹¹In-oligo to i.p.-disseminated tumors. ¹¹¹In-oligo-carrier complexes also have potential as tracers for imaging and monitoring of gene delivery.

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