Phage Display Library Derived Peptides that Bind to Human Tumor Melanin as Potential Vehicles for Targeted Radionuclide Therapy of Metastatic Melanoma

详细信息    查看全文

• 作者：Robertha C. Howell ; Ekaterina Revskaya ; Valeria Pazo ; Joshua D. Nosanchuk ; Arturo Casadevall ; Ekaterina Dadachova
• 刊名：Bioconjugate Chemistry
• 出版年：2007
• 出版时间：November 2007
• 年：2007
• 卷：18
• 期：6
• 页码：1739 - 1748
• 全文大小：1962K
• 年卷期：v.18,no.6(November 2007)
• ISSN：1520-4812

文摘

Metastatic melanoma remains an incurable disease, and there is a great need for novel therapeutic modalities. We have recently identified melanin as a target for radionuclide therapy of melanoma and demonstrated the feasibility of this approach using a 188-rhenium (¹⁸⁸Re)-radiolabeled melanin-binding decapeptide to fungal melanin known as 4B4. Although the results indicated that radiolabeled melanin-binding decapeptide had activity against melanoma, that peptide also manifested high kidney uptake and this might become a concern during clinical trials. We hypothesized that by identifying peptides with different amino acid composition against tumor melanin we might be able to decrease their kidney uptake. Using the Heptapeptide Ph.D.-7 Phage Display Library, we identified three heptapeptides that bind to human tumor melanin. These peptides were radiolabeled with ¹⁸⁸Re via HYNIC ligand, and their comprehensive biodistribution in A2058 human metastatic melanoma tumor-bearing nude mice was compared to that of ¹⁸⁸Re-4B4 decapeptide. While tumor uptake of heptapeptides was quite similar to that of ¹⁸⁸Re-4B4 decapeptide, there was dramatically less uptake in the kidneys at both 3 h (6% ID/g vs 38%) and 24 h (2% ID/g vs 15%) postinjection. Administration of one of the generated heptapeptides, ¹⁸⁸Re-HYNIC-AsnProAsnTrpGlyProArg, to A2058 human metastatic melanoma-bearing nude mice resulted in significant retardation of the tumor growth. Immunofluorescence showed that in spite of their relatively small size heptapeptides were not able to penetrate through the membranes of viable melanoma cells and bound only to extracellular melanin, which provides assurance that they will be safe to healthy melanin-containing tissues during radionuclide therapy. Thus, these heptapeptides appear to have potentially significant advantages for targeted therapy of melanoma relative to existing melanin-binding peptides.