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Tc-99m-labeled RGD-conjugated alpha-melanocyte stimulating hormone hybrid peptides with reduced renal uptake

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Abstract

The purpose of this study was to examine whether the replacement of the positively-charged Lys or Arg linker with a neutral linker could reduce the renal uptake of Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (α-MSH) hybrid peptide. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys3,4,10, D-Phe7, Arg11]α-MSH3-13 {(Arg11)CCMSH} through the neutral βAla or Ahx {aminohexanoic acid} linker (replacing the Lys or Arg linker) to generate novel RGD-βAla-(Arg11)CCMSH and RGD-Ahx-(Arg11)CCMSH hybrid peptides. The receptor-binding affinity and cytotoxicity of RGD-βAla-(Arg11)CCMSH and RGD-Ahx-(Arg11)CCMSH were determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of 99mTc-RGD-βAla-(Arg11)CCMSH and 99mTc-RGD-Ahx-(Arg11)CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The replacement of the Lys or Arg linker with the βAla or Ahx linker retained nanomolar receptor-binding affinities and remarkable cytotoxicity of RGD-βAla-(Arg11)CCMSH and RGD-Ahx-(Arg11)CCMSH. The receptor-binding affinities of RGD-βAla-(Arg11)CCMSH and RGD-Ahx-(Arg11)CCMSH were 0.8 ± 0.05 and 1.3 ± 0.1 nM. Three-hour incubation with 0.1 µM of RGD-βAla-(Arg11)CCMSH and RGD-Ahx-(Arg11)CCMSH decreased the survival percentages of B16/F1 cells by 71 and 67 % as compared to the untreated control cells 5 days post the treatment. The replacement of the Arg linker with the βAla or Ahx linker reduced the non-specific renal uptake of 99mTc-RGD-βAla-(Arg11)CCMSH and 99mTc-RGD-Ahx-(Arg11)CCMSH by 62 and 61 % at 2 h post-injection. 99mTc-RGD-βAla-(Arg11)CCMSH displayed higher melanoma uptake than 99mTc-RGD-Ahx-(Arg11)CCMSH at 0.5, 2, 4, and 24 h post-injection. Enhanced tumor to kidney uptake ratio of 99mTc-RGD-βAla-(Arg11)CCMSH warranted the further evaluation of 188Re-labeled RGD-βAla-(Arg11)CCMSH as a novel MC1 receptor-targeting therapeutic peptide for melanoma treatment in the future.

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Acknowledgments

We appreciate Dr. Fabio Gallazzi for his technical assistance. This work was supported by the NIH grant NM-INBRE P20RR016480/P20GM103451. The SPECT/CT images in this article were generated by the Keck-UNM Small Animal Imaging Resource established with funding from the W.M. Keck Foundation and the University of New Mexico Cancer Research and Treatment Center (NIH P30 CA118100).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy, University of New Mexico, Albuquerque, NM, 87131, USA

    Jianquan Yang & Yubin Miao

  2. Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA

    Chien-An A. Hu

  3. Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM, 87131, USA

    Chien-An A. Hu & Yubin Miao

  4. Department of Dermatology, University of New Mexico, Albuquerque, NM, 87131, USA

    Yubin Miao

  5. College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM, 87131-0001, USA

    Yubin Miao

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  1. Jianquan Yang
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Correspondence to Yubin Miao.

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Handling Editor: F. Albericio.

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Yang, J., Hu, CA.A. & Miao, Y. Tc-99m-labeled RGD-conjugated alpha-melanocyte stimulating hormone hybrid peptides with reduced renal uptake. Amino Acids 47, 813–823 (2015). https://doi.org/10.1007/s00726-014-1911-z

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  • DOI: https://doi.org/10.1007/s00726-014-1911-z

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