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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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Anti-tumor-activity of 213Bi-DTPA-[F3]2 in vitro.MDA-MB-435 tumor cells were incubated for 12 h with different activities of 213Bi-DTPA-[F3]2 as indicated. The number of malignant cell clones growing in soft agar was determined after 14 days and compared to untreated cells. Values±SEM are shown (n = 6, p<0.01). The inset shows that cell death is induced by 213Bi-DTPA-[F3]2, as detected by Trypan blue staining of cells (solid line). 213Bi induced significantly lower numbers of dead cells (dashed line) (n = 3, * = p<0.01).
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pone-0005715-g002: Anti-tumor-activity of 213Bi-DTPA-[F3]2 in vitro.MDA-MB-435 tumor cells were incubated for 12 h with different activities of 213Bi-DTPA-[F3]2 as indicated. The number of malignant cell clones growing in soft agar was determined after 14 days and compared to untreated cells. Values±SEM are shown (n = 6, p<0.01). The inset shows that cell death is induced by 213Bi-DTPA-[F3]2, as detected by Trypan blue staining of cells (solid line). 213Bi induced significantly lower numbers of dead cells (dashed line) (n = 3, * = p<0.01).

Mentions: As F3 was shown to be internalized into the nucleus of tumor cells and therefore may be an appropriate carrier for α-particle emitting isotopes, we investigated the potential of 213Bi-DTPA-[F3]2 to effectively reduce the number of cells in a tumor cell population. For this purpose we performed colony formation assays (Figure 2). We found that 213Bi-DTPA-[F3]2 significantly reduced the number of clones resulting from MDA-MB-435 cells in a dose dependent manner (p<0.01). Furthermore, 213Bi-DTPA-[F3]2 was found to be effective on a variety of tumor cells from different tumor types frequently causing peritoneal carcinomatosis including pancreas carcinoma (MIAPACA), colon carcinoma (CMT 93) and ovarian cancer (OvCAR3). Table 1 indicates the ID50 values for these cell lines, i.e. the 213Bi-activity concentration reducing the number of malignant clones by 50% compared to a control. We also tested the cytotoxic effect of 213Bi-DTPA-[F3]2 by staining dead cells. The inset to figure 3 indicates that 213Bi-DTPA-[F3]2 induced cell death in a dose dependent manner. In contrast, free 213Bi is less active. These findings show that 213Bi-DTPA-[F3]2 has a specific anti-tumor activity in vitro. DTPA-[F3]2 not labelled with 213Bi did not block cell growth and did not induce cell death (10 pg/ml to 100 ng/ml; data not shown).


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)

Anti-tumor-activity of 213Bi-DTPA-[F3]2 in vitro.MDA-MB-435 tumor cells were incubated for 12 h with different activities of 213Bi-DTPA-[F3]2 as indicated. The number of malignant cell clones growing in soft agar was determined after 14 days and compared to untreated cells. Values±SEM are shown (n = 6, p<0.01). The inset shows that cell death is induced by 213Bi-DTPA-[F3]2, as detected by Trypan blue staining of cells (solid line). 213Bi induced significantly lower numbers of dead cells (dashed line) (n = 3, * = p<0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005715-g002: Anti-tumor-activity of 213Bi-DTPA-[F3]2 in vitro.MDA-MB-435 tumor cells were incubated for 12 h with different activities of 213Bi-DTPA-[F3]2 as indicated. The number of malignant cell clones growing in soft agar was determined after 14 days and compared to untreated cells. Values±SEM are shown (n = 6, p<0.01). The inset shows that cell death is induced by 213Bi-DTPA-[F3]2, as detected by Trypan blue staining of cells (solid line). 213Bi induced significantly lower numbers of dead cells (dashed line) (n = 3, * = p<0.01).
Mentions: As F3 was shown to be internalized into the nucleus of tumor cells and therefore may be an appropriate carrier for α-particle emitting isotopes, we investigated the potential of 213Bi-DTPA-[F3]2 to effectively reduce the number of cells in a tumor cell population. For this purpose we performed colony formation assays (Figure 2). We found that 213Bi-DTPA-[F3]2 significantly reduced the number of clones resulting from MDA-MB-435 cells in a dose dependent manner (p<0.01). Furthermore, 213Bi-DTPA-[F3]2 was found to be effective on a variety of tumor cells from different tumor types frequently causing peritoneal carcinomatosis including pancreas carcinoma (MIAPACA), colon carcinoma (CMT 93) and ovarian cancer (OvCAR3). Table 1 indicates the ID50 values for these cell lines, i.e. the 213Bi-activity concentration reducing the number of malignant clones by 50% compared to a control. We also tested the cytotoxic effect of 213Bi-DTPA-[F3]2 by staining dead cells. The inset to figure 3 indicates that 213Bi-DTPA-[F3]2 induced cell death in a dose dependent manner. In contrast, free 213Bi is less active. These findings show that 213Bi-DTPA-[F3]2 has a specific anti-tumor activity in vitro. DTPA-[F3]2 not labelled with 213Bi did not block cell growth and did not induce cell death (10 pg/ml to 100 ng/ml; data not shown).

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