Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma†,RSC Medicinal Chemistry

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Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-03-06 00:00:00 , DOI: 10.1039/c7md00638a
Raghuvir H Gaonkar ₁ , Rinku Baishya ₂ , Brahamacharry Paul ₁ , Saikat Dewanjee ₃ , Shantanu Ganguly ₄ , Mita C Debnath ₁ , Soumya Ganguly ₁

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The cytotoxic drug gemcitabine (GEM) has been conjugated to receptor-binding peptides to target melanoma tumors. A hexapeptide having a Lys–Gly–His–Lys sequence (pep-1), an octapeptide with an Arg–Gly–Asp–Lys–Gly–His–Lys sequence (pep-2), a GEM-conjugated Lys–Gly–His–Lys peptide (GEM–pep-3) and a GEM-conjugated Asp–Gly–Arg peptide (GEM–pep-4) were synthesized and characterized. In vitro uptake of fluorescently labeled GEM–pep-3 and GEM–pep-4 on B16F10 cells was investigated. Fluorescence microscopy studies demonstrated significant uptake of GEM–pep-3 in the B16F10 mouse melanoma cell line. The peptides and GEM-coupled peptides were radiolabeled with [^99mTc(CO)₃(H₂O)₃]⁺ and examined for in vitro cell binding in the B16F10 melanoma cell line and in vivo biodistribution and scintigraphic studies in a B16F10 melanoma tumor-bearing mice model. In vitro cellular uptake studies and biological evaluation confirmed significant deposition of GEM–pep-3 at the melanoma tumor site. The MTT assay depicted higher cytotoxic behaviour of GEM–pep-3 than free GEM. A considerable amount of cell apoptosis was also observed in B16F10 cells. Finally, the in vivo therapeutic efficacy study revealed a significant decrease in tumor growth in the GEM–pep-3-treated animal model. These studies reveal enough potentiality of GEM–pep-3 to treat melanoma and underline the need for further evaluation.

中文翻译：

开发与细胞毒性药物缀合的基于肽的双功能螯合剂，用于治疗黑色素瘤†

细胞毒性药物吉西他滨 (GEM) 已与受体结合肽结合以靶向黑色素瘤。具有 Lys–Gly–His–Lys 序列的六肽 (pep-1)、具有 Arg–Gly–Asp–Lys–Gly–His–Lys 序列的八肽 (pep-2)、GEM 缀合的 Lys–Gly–合成并表征了 His-Lys 肽 (GEM-pep-3) 和 GEM 缀合的 Asp-Gly-Arg 肽 (GEM-pep-4)。研究了 B16F10 细胞对荧光标记的 GEM-pep-3 和 GEM-pep-4 的体外摄取。荧光显微镜研究表明 B16F10 小鼠黑色素瘤细胞系显着摄取 GEM-pep-3。肽和 GEM 偶联肽用 [ ^99m Tc(CO) ₃ (H ₂ O) ₃ ] ⁺进行放射性标记，并检查 B16F10 黑色素瘤细胞系中的体外细胞结合以及 B16F10 黑色素瘤肿瘤中的体内生物分布和闪烁扫描研究小鼠模型。体外细胞摄取研究和生物学评估证实了 GEM-pep-3 在黑色素瘤肿瘤部位的显着沉积。 MTT 测定显示 GEM-pep-3 比游离 GEM 具有更高的细胞毒性行为。在 B16F10 细胞中也观察到大量细胞凋亡。最后，体内治疗效果研究表明，GEM-pep-3 治疗的动物模型中肿瘤生长显着减少。这些研究揭示了 GEM-pep-3 治疗黑色素瘤的足够潜力，并强调了进一步评估的必要性。

更新日期：2018-03-06

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