Howell Robertha C, Revskaya Ekaterina, Pazo Valeria, Nosanchuk Joshua D, Casadevall Arturo, Dadachova Ekaterina
Department of Nuclear Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.
Bioconjug Chem. 2007 Nov-Dec;18(6):1739-48. doi: 10.1021/bc060330u. Epub 2007 Oct 2.
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 ( (188)Re)-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 (188)Re via HYNIC ligand, and their comprehensive biodistribution in A2058 human metastatic melanoma tumor-bearing nude mice was compared to that of (188)Re-4B4 decapeptide. While tumor uptake of heptapeptides was quite similar to that of (188)Re-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, (188)Re-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.
转移性黑色素瘤仍然是一种无法治愈的疾病，因此迫切需要新的治疗方法。我们最近将黑色素确定为黑色素瘤放射性核素治疗的靶点，并使用一种188-铼（188Re）标记的与真菌黑色素结合的十肽（称为4B4）证明了这种方法的可行性。尽管结果表明放射性标记的黑色素结合十肽对黑色素瘤有活性，但该肽在肾脏中的摄取量也很高，这在临床试验中可能会成为一个问题。我们推测，通过鉴定针对肿瘤黑色素具有不同氨基酸组成的肽，或许能够降低它们在肾脏中的摄取。利用七肽Ph.D.-7噬菌体展示文库，我们鉴定出三种与人肿瘤黑色素结合的七肽。这些肽通过HYNIC配体用188Re进行放射性标记，并将它们在A2058人转移性黑色素瘤荷瘤裸鼠体内的全面生物分布与188Re-4B4十肽进行比较。虽然七肽在肿瘤中的摄取与188Re-4B4十肽相当，但在注射后3小时（6%ID/g对38%）和24小时（2%ID/g对15%），肾脏中的摄取量显著减少。将生成的一种七肽（188Re-HYNIC-AsnProAsnTrpGlyProArg）给予A2058人转移性黑色素瘤荷瘤裸鼠，导致肿瘤生长明显迟缓。免疫荧光显示，尽管七肽相对较小，但它们无法穿透活的黑色素瘤细胞膜，仅与细胞外黑色素结合，这确保了它们在放射性核素治疗期间对含黑色素的健康组织是安全的。因此，相对于现有的黑色素结合肽，这些七肽在黑色素瘤的靶向治疗中似乎具有潜在的显著优势。
