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Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide bi-DTPA-[F3]2 into the nucleus of tumor cells.

Drecoll E, Gaertner FC, Miederer M, Blechert B, Vallon M, Müller JM, Alke A, Seidl C, Bruchertseifer F, Morgenstern A, Senekowitsch-Schmidtke R, Essler M - PLoS ONE (2009)

Bottom Line: No toxicity of the treatment was observed.In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion.In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine, Klinikum-rechts-der-Isar, München, Germany.

ABSTRACT

Background: Alpha-particle emitting isotopes are effective novel tools in cancer therapy, but targeted delivery into tumors is a prerequisite of their application to avoid toxic side effects. Peritoneal carcinomatosis is a widespread dissemination of tumors throughout the peritoneal cavity. As peritoneal carcinomatosis is fatal in most cases, novel therapies are needed. F3 is a tumor homing peptide which is internalized into the nucleus of tumor cells upon binding to nucleolin on the cell surface. Therefore, F3 may be an appropriate carrier for alpha-particle emitting isotopes facilitating selective tumor therapies.

Principal findings: A dimer of the vascular tumor homing peptide F3 was chemically coupled to the alpha-emitter (213)Bi ((213)Bi-DTPA-[F3](2)). We found (213)Bi-DTPA-[F3](2) to accumulate in the nucleus of tumor cells in vitro and in intraperitoneally growing tumors in vivo. To study the anti-tumor activity of (213)Bi-DTPA-[F3](2) we treated mice bearing intraperitoneally growing xenograft tumors with (213)Bi-DTPA-[F3](2). In a tumor prevention study between the days 4-14 after inoculation of tumor cells 6x1.85 MBq (50 microCi) of (213)Bi-DTPA-[F3](2) were injected. In a tumor reduction study between the days 16-26 after inoculation of tumor cells 6x1.85 MBq of (213)Bi-DTPA-[F3](2) were injected. The survival time of the animals was increased from 51 to 93.5 days in the prevention study and from 57 days to 78 days in the tumor reduction study. No toxicity of the treatment was observed. In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion.

Conclusions/significance: In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology.

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Tumor reduction study.(a) The scheme depicts the time points when 213Bi-DTPA-[F3]2 was injected and the time points when optical imaging was performed. (b) Assessment of the tumor growth by optical imaging in mice treated with 213Bi-DTPA-[F3]2 or in control mice treated with PBS or 213Bi-DTPA. (c) Kaplan-Meier analysis of the survival of mice with intra-peritoneal tumors treated with 213Bi-DTPA-[F3]2 (red), 213Bi-DTPA (green) or PBS (black).
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pone-0005715-g005: Tumor reduction study.(a) The scheme depicts the time points when 213Bi-DTPA-[F3]2 was injected and the time points when optical imaging was performed. (b) Assessment of the tumor growth by optical imaging in mice treated with 213Bi-DTPA-[F3]2 or in control mice treated with PBS or 213Bi-DTPA. (c) Kaplan-Meier analysis of the survival of mice with intra-peritoneal tumors treated with 213Bi-DTPA-[F3]2 (red), 213Bi-DTPA (green) or PBS (black).

Mentions: In a tumor reduction study we tested whether 213Bi-DTPA-[F3]2 is also effective in the treatment of large intraperitoneal tumors. Between the days 16 and 26 after inoculation of tumor cells we i.p. injected 6×1.85 MBq 213Bi-DTPA-[F3]2, 6×1.85 MBq 213Bi-DTPA or 6×100 µl PBS were (Figure 5a). Again, optical imaging confirmed lower tumor loads after treatment with 213Bi-DTPA-[F3]2 (Figure 5b). In this study the mean survival of mice was 57 days in the PBS group, 48 days in the group treated with 213Bi-DTPA and 78 days in the 213Bi-DTPA-[F3]2-group, i.e. there was a trend of increased survival which was statistically significant (p = 0.04; Figure 5c).


Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide bi-DTPA-[F3]2 into the nucleus of tumor cells.

Drecoll E, Gaertner FC, Miederer M, Blechert B, Vallon M, Müller JM, Alke A, Seidl C, Bruchertseifer F, Morgenstern A, Senekowitsch-Schmidtke R, Essler M - PLoS ONE (2009)

Tumor reduction study.(a) The scheme depicts the time points when 213Bi-DTPA-[F3]2 was injected and the time points when optical imaging was performed. (b) Assessment of the tumor growth by optical imaging in mice treated with 213Bi-DTPA-[F3]2 or in control mice treated with PBS or 213Bi-DTPA. (c) Kaplan-Meier analysis of the survival of mice with intra-peritoneal tumors treated with 213Bi-DTPA-[F3]2 (red), 213Bi-DTPA (green) or PBS (black).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682652&req=5

pone-0005715-g005: Tumor reduction study.(a) The scheme depicts the time points when 213Bi-DTPA-[F3]2 was injected and the time points when optical imaging was performed. (b) Assessment of the tumor growth by optical imaging in mice treated with 213Bi-DTPA-[F3]2 or in control mice treated with PBS or 213Bi-DTPA. (c) Kaplan-Meier analysis of the survival of mice with intra-peritoneal tumors treated with 213Bi-DTPA-[F3]2 (red), 213Bi-DTPA (green) or PBS (black).
Mentions: In a tumor reduction study we tested whether 213Bi-DTPA-[F3]2 is also effective in the treatment of large intraperitoneal tumors. Between the days 16 and 26 after inoculation of tumor cells we i.p. injected 6×1.85 MBq 213Bi-DTPA-[F3]2, 6×1.85 MBq 213Bi-DTPA or 6×100 µl PBS were (Figure 5a). Again, optical imaging confirmed lower tumor loads after treatment with 213Bi-DTPA-[F3]2 (Figure 5b). In this study the mean survival of mice was 57 days in the PBS group, 48 days in the group treated with 213Bi-DTPA and 78 days in the 213Bi-DTPA-[F3]2-group, i.e. there was a trend of increased survival which was statistically significant (p = 0.04; Figure 5c).

Bottom Line: No toxicity of the treatment was observed.In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion.In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology.

View Article: PubMed Central - PubMed

Affiliation: Department of Nuclear Medicine, Klinikum-rechts-der-Isar, München, Germany.

ABSTRACT

Background: Alpha-particle emitting isotopes are effective novel tools in cancer therapy, but targeted delivery into tumors is a prerequisite of their application to avoid toxic side effects. Peritoneal carcinomatosis is a widespread dissemination of tumors throughout the peritoneal cavity. As peritoneal carcinomatosis is fatal in most cases, novel therapies are needed. F3 is a tumor homing peptide which is internalized into the nucleus of tumor cells upon binding to nucleolin on the cell surface. Therefore, F3 may be an appropriate carrier for alpha-particle emitting isotopes facilitating selective tumor therapies.

Principal findings: A dimer of the vascular tumor homing peptide F3 was chemically coupled to the alpha-emitter (213)Bi ((213)Bi-DTPA-[F3](2)). We found (213)Bi-DTPA-[F3](2) to accumulate in the nucleus of tumor cells in vitro and in intraperitoneally growing tumors in vivo. To study the anti-tumor activity of (213)Bi-DTPA-[F3](2) we treated mice bearing intraperitoneally growing xenograft tumors with (213)Bi-DTPA-[F3](2). In a tumor prevention study between the days 4-14 after inoculation of tumor cells 6x1.85 MBq (50 microCi) of (213)Bi-DTPA-[F3](2) were injected. In a tumor reduction study between the days 16-26 after inoculation of tumor cells 6x1.85 MBq of (213)Bi-DTPA-[F3](2) were injected. The survival time of the animals was increased from 51 to 93.5 days in the prevention study and from 57 days to 78 days in the tumor reduction study. No toxicity of the treatment was observed. In bio-distribution studies we found (213)Bi-DTPA-[F3](2) to accumulate in tumors but only low activities were found in control organs except for the kidneys, where (213)Bi-DTPA-[F3](2) is found due to renal excretion.

Conclusions/significance: In conclusion we report that (213)Bi-DTPA-[F3](2) is a novel tool for the targeted delivery of alpha-emitters into the nucleus of tumor cells that effectively controls peritoneal carcinomatosis in preclinical models and may also be useful in oncology.

Show MeSH
Related in: MedlinePlus