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

Tendon–bone contact pressure and biomechanical evaluation of a modified suture-bridge technique for rotator cuff repair

The aim of the study was to evaluate the time-zero mechanical and footprint properties of a suture-bridge technique for rotator cuff repair in an animal model. Thirty fresh-frozen sheep shoulders were randomly assigned among three investigation groups: (1) cyclic loading, (2) load-to-failure testing, and (3) tendon–bone interface contact pressure measurement. Shoulders were cyclically loaded from 10 to 180 N and displacement to gap formation of 5- and 10-mm at the repair site. Cycles to failure were determined. Additionally, the ultimate tensile strength and stiffness were verified along with the mode of failure. The average contact pressure and pressure pattern were investigated using a pressure-sensitive film system. All of the specimens resisted against 3,000 cycles and none of them reached a gap formation of 10 mm. The number of cycles to 5-mm gap formation was 2,884.5 ± 96.8 cycles. The ultimate tensile strength was 565.8 ± 17.8 N and stiffness was 173.7 ± 9.9 N/mm. The entire specimen presented a unique mode of failure as it is well known in using high strength sutures by pulling them through the tendon. We observed a mean contact pressure of 1.19 ± 0.03 MPa, applied on the footprint area. The fundamental results of our study support the use of a suture-bridge technique for optimising the conditions of the healing biology of a reconstructed rotator cuff tendon. Nevertheless, an individual estimation has to be done if using the suture-bridge technique clinically. Further investigation is necessary to evaluate the cell biological healing process in order to achieve further sufficient advancements in rotator cuff repair