15 research outputs found
Treatment of Peritoneal Carcinomatosis by Targeted Delivery of the Radio-Labeled Tumor Homing Peptide 213Bi-DTPA-[F3]2 into the Nucleus of Tumor Cells
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
Intrinsic functional connectivity underlying successful emotion regulation of angry faces
Imaging the up’s and down’s of emotion regulation in lifetime depression
Reappraisal is a particularly effective strategy for influencing emotional experiences, specifically for reducing the impact of negative stimuli. Although depression has repeatedly been linked to dysfunctional behavioral and neural emotion regulation, prefrontal and amygdala engagement seems to vary with clinical characteristics and the specific regulation strategy used. Whereas previous neuroimaging research has focused on down-regulating reactions to emotionally evocative scenes, the current study compared up- and down-regulation in response to angry facial expressions in patients with depression and healthy individuals. During the initial viewing of faces, patients with depression showed hypoactivation particularly in areas implicated in emotion generation, i.e., amygdala, insula and putamen. In contrast, up-regulating negative emotions yielded stronger recruitment of core face processing areas and posterior medial frontal cortex in patients than in controls. However, group differences did not extend to resting-state functional connectivity. Recurrent depression was inversely associated with amygdala activation specifically during down-regulation, but differences in medication status may limit the current findings. Despite a pattern of reduced neural emotional reactivity in mainly medicated patients, their ‘successful’ recruitment of the regulation network for up-regulation might point toward an effective use of reappraisal when increasing negative emotions. Future studies need to address how patients might benefit from transferring this ability to adaptive goals, such as improving interpersonal emotion regulation
IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G 2
Molecular Design of <sup>68</sup>Ga- and <sup>89</sup>Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors
Anticalin proteins directed against the prostate-specific
membrane
antigen (PSMA), optionally having tailored plasma half-life using
PASylation technology, show promise as radioligands for PET-imaging
of xenograft tumors in mice. To investigate their suitability, the
short-circulating unmodified Anticalin was labeled with 68Ga (Ï„1/2 = 68 min), using the NODAGA chelator, whereas
the half-life extended PASylated Anticalin was labeled with 89Zr (Ï„1/2 = 78 h), using either the linear chelator
deferoxamine (Dfo) or a cyclic derivative, fusarinine C (FsC). Different
PSMA targeting Anticalin versions (optionally carrying the PASylation
sequence) were produced carrying a single exposed N- or C-terminal
Cys residue and site-specifically conjugated with the different radiochelators via maleimide chemistry. These protein conjugates were labeled
with radioisotopes having distinct physical half-lives and, subsequently,
applied for PET-imaging of subcutaneous LNCaP xenograft tumors in
CB17 SCID mice. Uptake of the protein tracers into tumor versus healthy
tissues was assessed by segmentation of PET data as well as biodistribution
analyses. PET-imaging with both the 68Ga-labeled plain
Anticalin and the 89Zr-labeled PASylated Anticalin allowed
clear delineation of the xenograft tumor. The radioligand A3A5.1-PAS(200)-FsC·89Zr, having an extended plasma half-life, led to a higher
tumor uptake 24 h p.i. compared to the 68Ga·NODAGA-Anticalin
imaged 60 min p.i. (2.5% ID/g vs 1.2% ID/g). Pronounced
demetallation was observed for the 89Zr·Dfo-labeled
PASylated Anticalin, which was ∼50% lower in the case of the
cyclic radiochelator FsC (p < 0.0001). Adjusting
the plasma half-life of Anticalin radioligands using PASylation technology
is a viable approach to increase radioisotope accumulation within
the tumor. Furthermore, 89Zr-ImmunoPET-imaging using the
FsC radiochelator is superior to that using Dfo. Our strategy for
the half-life adjustment of a tumor-targeting Anticalin to match the
physical half-life of the applied radioisotope illustrates the potential
of small binding proteins as an alternative to antibodies for PET-imaging
Tumor reduction study.
<p>(a) The scheme depicts the time points when <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> was injected and the time points when optical imaging was performed. (b) Assessment of the tumor growth by optical imaging in mice treated with <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> or in control mice treated with PBS or <sup>213</sup>Bi-DTPA. (c) Kaplan-Meier analysis of the survival of mice with intra-peritoneal tumors treated with <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> (red), <sup>213</sup>Bi-DTPA (green) or PBS (black).</p
The table shows the ID50 values of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub>, i.e. the activity concentration reducing the number of clones in a colony formation assay by 50% in different cell lines (EMT6, CMT93, MIAPACA, OVCAR3, MDA-MD-435).
<p>The table shows the ID50 values of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub>, i.e. the activity concentration reducing the number of clones in a colony formation assay by 50% in different cell lines (EMT6, CMT93, MIAPACA, OVCAR3, MDA-MD-435).</p
(a) Biodistribution of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub>.
<p>3.7 MBq of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> were injected i.p. into mice bearing intra-peritoneal MDA-MB-435 xenograft tumors. After 45 minutes the <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> activity present in individual organs, the tumors and the blood was measured. Values represent the percentage of the injected dose/g tissue (%ID/g)±SEM. The inset depicts a mouse with peritoneal carcinomatosis imaged with <sup>68</sup>Ga-DOTA-F3-PET. The asterics (*) indicates the location of the kidneys. b) Autoradiography studies were performed using histological sections of MDA-MB-435 xenograft tumors or muscle tissue. <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> was found in tumors 45 minutes after i. p. injection. <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> was found in the periphery of the tumor as well as in spots within the tumor tissue. H&E-staining and microscopy (100fold magnification) of the sections revealed that the intra-tumoral accumulation of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> occurs in the perivascular region. The H&E-stained picture represents the area within the white box in the autoradiography picture. Negligible activities were found in autoradiography pictures of control organs such as muscle.</p
Internalization of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> into MDA-MB-435 tumor cells.
<p>The radioactivity concentration present in the cytoplasm and the nuclei of cells incubated with 3.7 kBq/ml <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> for the indicated time periods was measured and compared to the radioactivity concentration in the supernatant. The bars represent the radioactivity in the nuclei (black, p<0.01, * = p<0.02) or the cytoplasm (white, p<0.01) compared to the supernatant. Values±SEM are shown. The inset shows binding of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> to tumor cells grown on glass cover slips in presence or absence of unlabelled DTPA-[F3]<sub>2</sub>, visualized by a micro imager.</p
Anti-tumor-activity of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> in vitro.
<p>MDA-MB-435 tumor cells were incubated for 12 h with different activities of <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub> 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 <sup>213</sup>Bi-DTPA-[F3]<sub>2</sub>, as detected by Trypan blue staining of cells (solid line). <sup>213</sup>Bi induced significantly lower numbers of dead cells (dashed line) (n = 3, * = p<0.01).</p