The purpose of our study was to optimize melanoma tumor uptake of 188 Re-CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of 188 Re-CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co-infusion were investigated as strategies to improve the tumor/kidney uptake ratio of 188 Re-CCMSH. The substitution of Lys 11 with Arg 11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake.

The purpose of this study was to evaluate the human MC1 receptor-mediated melanoma targeting properties of two metal cyclized alpha-MSH peptide analogues, (188)Re-(Arg(11))CCMSH and (188)Re-CCMSH. Initially, the presence and density of the MC1 receptor were determined on a bank of human melanoma cell lines. All eight human melanoma cell lines tested in this study displayed the MC1 receptor at a density of 900 to 5700 receptors per cell. Receptor affinity and biodistribution properties of (188)Re-(Arg(11))CCMSH and (188)Re-CCMSH were evaluated in a cultured TXM13 human melanoma-xenografted Scid mouse model. Biodistribution results demonstrated that 3.06 +/- 0.68 %ID/g of (188)Re-(Arg(11))CCMSH accumulated in the tumors 1 h postinjection and greater than 65% of the activity at 1 h postinjection remained in the tumors at 4 h after dose administration. Whole body clearance of (188)Re-(Arg(11))CCMSH was very rapid, with approximately 82% of injected dose cleared through urinary system at 4 h postinjection. There was very little activity in blood and major organs such as liver, lung, and muscle except for the kidney. (188)Re-CCMSH exhibited similar tumor uptake and retention in TXM13 human melanoma-xenografted Scid mice as (188)Re-(Arg(11))CCMSH. However, the kidney uptake value of (188)Re-CCMSH was two times higher than that of (188)Re-(Arg(11))CCMSH. The results of this study indicate that the MC1 receptor is present on the surface of a large number of human melanoma cells, which makes the MC1 receptor a good imaging or therapeutic target. Moreover, the biodistribution properties of (188)Re-(Arg(11))CCMSH and (188)Re-CCMSH highlight their potential as therapeutic agents for human melanoma.

Tears in the avascular portion of the knee meniscus are commonplace and are frequently incapable of healing spontaneously. Delivery of synovial cells from the meniscal periphery to avascular injuries can result in an effective healing response but is difficult to accomplish surgically. This report describes the development of a novel in vitro model comprised of three-dimensionally cultured cells in agarose used to assess the proof of concept that a cellular conduit device could be used to facilitate the delivery of synovial fibroblasts from a cell source to a remote acellular recipient site. The results indicate that synovial fibroblasts are capable of migrating through a cellular conduit more optimally than a created trephined channel over a clinically relevant distance in response to a chemotactic gradient. This model proved to be a reliable way to assess fibroblast-like synoviocyte migration in a clinically relevant fashion for application to avascular meniscal tear healing methodologies, and provided mechanistic information regarding the successful in vivo testing of this specific biomedical device.

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