Synthetic Peptide Drugs for Targeting Skin Cancer: Malignant Melanoma and Melanotic Lesions

Abstract

Peptides play decisive roles in the skin, ranging from host defense responses to various forms of neuroendocrine regulation of cell and organelle function. Synthetic peptides conjugated to radionuclides or photosensitizers may serve to identify and treat skin tumors and their metastatic forms in other organs of the body. In the introductory part of this review, the role and interplay of the different peptides in the skin are briefly summarized, including their potential application for the management of frequently occurring skin cancers. Special emphasis is given to different targeting options for the treatment of melanoma and melanotic lesions. Radionuclide Targeting: α-Melanocyte-stimulating hormone (α-MSH) is the most prominent peptide for targeting of melanoma tumors via the G protein-coupled melanocortin-1 receptor that is (over-)expressed by melanoma cells and melanocytes. More than 100 different linear and cyclic analogs of α-MSH containing chelators for 111In, 67/68Ga, 64Cu, 90Y, 212Pb, 99mTc, 188Re were synthesized and examined with experimental animals and in a few clinical studies. Linear Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH2 (NAP-amide) and Re-cyclized Cys- Cys-Glu-His-D-Phe-Arg-Trp-Cys-Arg-Pro-Val-NH2 (Re[Arg11]CCMSH) containing different chelators at the N- or C-terminus served as lead compounds for peptide drugs with further optimized characteristics. Alternatively, melanoma may be targeted with radiopeptides that bind to melanin granules occurring extracellularly in these tumors. Photosensitizer targeting: A more recent approach is the application of photosensitizers attached to the MSH molecule for targeted photodynamic therapy using LED or coherent laser light that specifically activates the photosensitizer. Experimental studies have demonstrated the feasibility of this approach as a more gentle and convenient alternative compared to radionuclides.

Specific Targeting of Melanotic Cells with Peptide Ligated Photosensitizers for Photodynamic Therapy

“…3e,f ) indicate targeting and binding nature of the different peptides and their photosensitizer derivatives to the MC1 receptor at sub-micromolar concentrations. The increase in cellular uptake is due to the targeting ability of the peptides with its balanced lipophilicity/hydrophilicity nature as demonstrated with radiolabelled DOTA ligands which supports the melanin production results 62 , 63 : Significant melanin production using α-MSH with B16 melanoma cell line is observed at 72 h, whereas negligible amount of melanin was produced in first 36–48 h 62 . This safe time-window of first 48 h without considerable melanin production is important in our study, because this allowed us to do light induced cytotoxicity measurement within 24 h without much interference by melanin, a stable protein-complex with a wide absorption spectrum from 400–650 nm.…”

“…subcutaneous melanoma). The newly designed photosensitive peptide can be used for very targeted and personalized treatments of benign and malign pigmented lesions 63 .…”

Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging

“…12–18 Its naturally occurring ligand is a 13-amino acid peptide, alpha melanocyte stimulating hormone (αMSH), which is involved in the regulation of skin pigmentation, as well as immune and anti-inflammatory responses. 19 Numerous structure-activity studies have identified linear and cyclic peptide agonists and antagonists with nanomolar and subnanomolar binding affinities.…”

Cell cycle regulatory markers in melanoma: New strategies in diagnosis and treatment

“…In their study, 2 groups of sun-sensitive and sun-resistance phenotypes were investigated, which varied in susceptibility to ulceration and Breslow thickness of melanoma. Their results indicated that the former group was more in danger than the latter (2,3). Also, Taylor et al in another study found a direct relationship between melanoma and haplotypes.…”

“…Melanocotin1 receptor (MC1R) is a transmembrane G protein receptor, located in cell membrane that can control melanogenesis (1). This mentioned biomolecule is upregulated in metastasis of melanoma tumors (2). Taylor et al have mentioned several variants of MC1R as risk factors in melanoma.…”