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首页> 外文期刊>Bioconjugate Chemistry >Phage Display Library Derived Peptides that Bind to Human Tumor Melanin as Potential Vehicles for Targeted Radionuclide Therapy of Metastatic Melanoma
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Phage Display Library Derived Peptides that Bind to Human Tumor Melanin as Potential Vehicles for Targeted Radionuclide Therapy of Metastatic Melanoma

机译：噬菌体展示库衍生的肽结合人肿瘤黑色素作为转移性黑色素瘤靶向放射性核素治疗的潜在载体

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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.
机译：转移性黑素瘤仍然是无法治愈的疾病，并且迫切需要新颖的治疗方法。我们最近将黑素确定为放射性核素治疗黑素瘤的靶标，并证明了使用188-（（〜（188）Re）的方法的可行性。 -放射性标记的黑色素结合十肽对真菌黑色素的作用称为4B4。尽管结果表明，放射性标记的黑色素结合十肽对黑色素瘤具有活性，但该肽也表现出较高的肾脏摄取，这在临床试验中可能引起关注。具有针对氨基酸黑色素的不同氨基酸组成的多肽，我们可能能够减少其肾脏摄取。使用七肽Ph.D.-7噬菌体展示库，我们鉴定了三种与人肿瘤黑色素结合的七肽。这些肽用〜（ 188）通过HYNIC配体进行的Re及其在A2058人转移性黑色素瘤荷瘤裸鼠中的全面生物分布与〜（188）Re-4B4十肽的摄取非常相似，尽管七肽的肿瘤摄取与〜（188）Re-4B4十肽的摄取非常相似，但肾脏在两个3小时的摄取显着减少（6％ID /注射后24 h（g vs 38％）和24 h（2％ID / g vs 15％）。将产生的七肽之一〜（188）Re-HYNIC-AsnProAsnTrpGlyProArg施用给A2058人转移性黑色素瘤裸鼠导致显着免疫荧光表明，尽管七肽的大小相对较小，但它们却无法穿透活的黑色素瘤细胞的膜，仅与细胞外的黑色素结合，从而确保它们对含有健康黑色素的组织是安全的。因此，相对于现有的黑色素结合肽，这些七肽似乎对黑色素瘤的靶向治疗具有潜在的显着优势。

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