title: In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy.
abstract: The purpose of our study was to optimize melanoma tumor uptake of 188Re-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 188Re-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 188Re-CCMSH. The substitution of Lys11 with Arg11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of 188Re-CCMSH and 188Re-(Arg(11))CCMSH were determined in B16/F1 murine melanoma-bearing C57 mice. Tumor uptake values of (188)Re-CCMSH and 188Re-(Arg(11))CCMSH were 15.03 +/- 5.20% ID/g and 20.44 +/- 1.91% ID/g at 1 hr postinjection and 1.94 +/- 0.47% ID/g and 3.50 +/- 2.32% ID/g at 24 hr postinjection. Renal retention of 188Re-(Arg(11))CCMSH was 11.79 +/- 1.29 ID/g and 3.67 +/- 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to 188Re-CCMSH. The Arg for Lys substitution in 188Re-(Arg(11))CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both 188Re-CCMSH and 188Re-(Arg(11))CCMSH were significantly reduced by co-injection of 20 mg of L-lysine, L-arginine and a combination of L-lysine:L-arginine. Tumor/kidney uptake values for 188Re-CCMSH and 188Re-(Arg(11))CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co-injection, the tumor/kidney ratio of 188Re-CCMSH was lower than that of 188Re-(Arg(11))CCMSH. Improved tumor uptake and reduced kidney retention of 188Re-(Arg(11))CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys.
authors.affiliation: Department of Biochemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
authors.forename: Nellie K
authors.initials: NK
authors.lastname: Owen
authors.forename: Donna
authors.initials: D
authors.lastname: Whitener
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hoffman
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Quinn
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008545:Melanoma / Q000532:radiotherapy*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012211:Rhenium / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D009842:Oligopeptides; D019275:Radiopharmaceuticals; D000521:alpha-MSH; D012211:Rhenium