Gaonkar Raghuvir H, Baishya Rinku, Paul Brahamacharry, Dewanjee Saikat, Ganguly Shantanu, Debnath Mita C, Ganguly Soumya
Infectious Diseases and Immunology Division , CSIR-Indian Institute of Chemical Biology , Kolkata , India . Email:
Natural Product Chemistry Group , Chemical Science and Technology Division , North East Institute of Science and Technology , Assam , India.
Medchemcomm. 2018 Mar 6;9(5):812-826. doi: 10.1039/c7md00638a. eCollection 2018 May 1.
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. 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 [Tc(CO)(HO)] and examined for cell binding in the B16F10 melanoma cell line and biodistribution and scintigraphic studies in a B16F10 melanoma tumor-bearing mice model. 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 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.
细胞毒性药物吉西他滨（GEM）已与受体结合肽偶联，以靶向黑色素瘤肿瘤。合成并表征了具有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）、吉西他滨偶联的Lys-Gly-His-Lys肽（GEM-pep-3）和吉西他滨偶联的Asp-Gly-Arg肽（GEM-pep-4）。研究了荧光标记的GEM-pep-3和GEM-pep-4在B16F10细胞上的摄取情况。荧光显微镜研究表明，GEM-pep-3在B16F10小鼠黑色素瘤细胞系中有显著摄取。用[Tc(CO)(HO)]对这些肽和吉西他滨偶联肽进行放射性标记，并在B16F10黑色素瘤细胞系中检测细胞结合情况，以及在荷B16F10黑色素瘤肿瘤的小鼠模型中进行生物分布和闪烁显像研究。细胞摄取研究和生物学评估证实，GEM-pep-3在黑色素瘤肿瘤部位有显著沉积。MTT分析表明，GEM-pep-3的细胞毒性行为比游离吉西他滨更高。在B16F10细胞中也观察到相当数量的细胞凋亡。最后，治疗效果研究显示，在GEM-pep-3治疗的动物模型中肿瘤生长显著减少。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。
