2002 Fiscal Year Final Research Report Summary
DEVELOPMENT OF POLYAMINE-GLYCOPROTEIN CONJUGATES FOR INTRACELLULAR DELIVERY OF OLIGO-DNA AND THEIR APPLICATION TO MOLECULAR IMAGING
| Project/Area Number |
12470188
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KONISHI Junji KYOTO UNIVERSITY, GRADUATE SCHOOL OF MEDICINE DEPARTMENT OF NUCLEAR MEDICINE AND DIAGNOSTIC IMAGING PROFESSOR, 医学研究科, 教授 (70026970)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Hisataka KYOTO UNIVERSITY, GRADUATE SCHOOL OF MEDICINE DEPARTMENT OF NUCLEAR MEDICINE AND DIAGNOSTIC IMAGING INSTRUCTOR, 医学研究科, 助手 (60311734)
SAGA Tsuneo KYOTO UNIVERSITY, GRADUATE SCHOOL OF MEDICINE DEPARTMENT OF NUCLEAR MEDICINE AND DIAGNOSTIC IMAGING ASSOCIATE PROFESSOR, 医学研究科, 助教授 (40273445)
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| Project Period (FY) |
2000 – 2002
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| Keywords | antisense oligo DNA / dendrimer / avidin / indium-111 / poritoneal dissemination / imaging / internal radiation therapy |
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| Research Abstract |
Oligo-DNA (oligo)/carrier complexes were constructed using polyamine deudrimer (G4), which form electrostatic complex with oligo, and avidin (Av), which has the affinity to cancer cells. Oligo/G4 and oligo/G4-Av internalized into cancer cells more than oligo alone did.
In addition, G4-anti-cancer nonoclonal antibody conjugate was made as another carrier of oligo to the tumor. Formed G4-antobody conjugate retained its immunoreactivity and selectively localized in the tumor tissue of tumor-bearing mice.
Three ^<111>In-labeled oligo-carrier complexes were then prepared (oligo/G4, oligo/G4-Av, and oligo-Av), and were injected intraperitoneally (i.p.) into mice bearing i.p.-disseminated tumors. Compared to oligo alone, these complexes accumulated much more in disseminated tumors. Disseminated tumors could be imaged with the administration of large amount of ^<111>In-labeled oligo-carrier complexes, showing the possibility of these complexes to monitor the course of gene delivery.
Then, dual labeled complex (oligo labeled by ^<111>In, G4 labeled by ^<153>Gd) were constructed and i.p. injected into mice bearing disseminated tumors. Uptake of ^<153>Gd in tumors and organs was higher than ^<111>In except for blood and kidney, indicating that ^<111>In-oligo was detached from the complex in the tumors and organs, and went back to the bloodstream and then accumulated in the kidney.
Incorporating many chelating sites through G4 could make ^<111>In- labeled Av with extremely high specific activity. Formed ^<111>In-labeled Av rapidly internalized into cancer cells after binding, and i.p. administration of large amount of ^<111>In-labeled Av into mice bearing i.p.-disseminated tumors significantly elongated the survival of the mice. ^<111>In-labeled Av can be applied to the internal radiation therapy of i.p.-disseminated tumors by Auger and internal conversion electrons emitted by ^<111>In.
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