Tumor targeting and imaging of intraperitoneal tumors by use of antisense oligo-DNA complexed with dendrimers and/or avidin in mice.

Abstract

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 (111)In labeled through a diethylenetriaminepentaacetic acid chelate. (111)In-oligo was mixed with generation 4 polyamidoamine dendrimer (G4) or with biotinylated G4 (G4-Bt), which are positively charged to form electrostatic complexes. (111)In-oligo/G4-Bt and (111)In-oligo-Bt were conjugated to avidin ((111)In-oligo/G4-Av and (111)In-oligo-Av, respectively). (111)In-oligo/G4, (111)In-oligo/G4-Av, (111)In-oligo-Av, and carrier-free (111)In-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 (111)In-oligo-carrier complexes or (111)In-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 (111)In-oligo-carrier complex or (111)In-oligo (1.85 MBq/2.2 ng). (111)In-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 (111)In-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 (111)In-oligo delivered to the i.p.-disseminated tumors by the carriers were successfully obtained. In conclusion, G4, G4-Av, and Av can effectively deliver (111)In-oligo to i.p.-disseminated tumors. (111)In-oligo-carrier complexes also have potential as tracers for imaging and monitoring of gene delivery.

• Authors: N Sato, H Kobayashi, T Saga, Y Nakamoto, T Ishimori, K Togashi, Y Fujibayashi, J Konishi, M W Brechbiel
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 11 Pg. 3606-12 (Nov 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11705883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Antisense
• Indium Radioisotopes
• Oligonucleotides
• Avidin
• Receptor, ErbB-2

Topics

• Animals
• Avidin (chemistry, pharmacokinetics)
• Biological Transport
• DNA, Antisense (chemistry, genetics, pharmacokinetics)
• Endocytosis
• Female
• Gene Transfer Techniques
• Indium Radioisotopes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Oligonucleotides (chemistry, genetics, pharmacokinetics)
• Peritoneal Neoplasms (genetics, pathology)
• Radionuclide Imaging (methods)
• Receptor, ErbB-2 (genetics)
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured