Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs Targeting Mutated BRAF and MEK in Melanoma.
Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs Targeting Mutated BRAF and MEK in Melanoma.
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合理设计聚谷氨酸，提供针对黑色素瘤中突变 BRAF 和 MEK 的优化药物组合。
DOI：
10.1002/adtp.202000028
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发表时间：
2020
影响因子：
4.6
通讯作者：
Satchi-
中科院分区：
文献类型：
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作者：
Pisarevsky,Evgeni;Blau,Rachel;Epshtein,Yana;Ben-Shushan,Dikla;Eldar-Boock,Anat;Tiram,Galia;Koshrovski-Michael,Shani;Scomparin,Anna;Pozzi,Sabina;Krivitsky,Adva;Shenbach-Koltin,Gal;Yeini,Eilam;Fridrich,Lidar;White,Richard;Satchi-
针对癌症的靶向治疗可以缓解症状和诱导缓解，但它们通常表现为疾病控制时间有限，引起副作用，并可能诱导获得性耐药。因此，开发一种针对肿瘤的独特的递送系统是非常有动力的，其中可以将几个活性实体结合在一起，通过减少全身暴露来增加治疗指数，并可以增强它们的协同活性。为了实现这些目标，生物相容性和生物可降解性的聚(α，L-谷氨酸)(PGA)被选为促进外渗依赖的肿瘤靶向递送的纳米载体。当RAS/RAF/MEK/ERK通路在黑色素瘤中异常激活时，可导致细胞增殖失控，诱导侵袭，减少细胞凋亡。在这里，我们选择了两种针对该通路的药物：一种MEK1/2抑制剂(selumetinib，SLM)和一种改良的BRAF抑制剂(改良的达普拉非尼，mDBF)，它们在体外显示出协同作用。合成了PGA-SLM-mDBF(PGA-SLM-mDBF)，并对其进行了表征。PGA-SLM-mDBF抑制黑色素瘤细胞的增殖，降低其迁移和发芽能力，而不诱导溶血作用。此外，在小鼠原发黑色素瘤模型中，它表现出了优越的抗肿瘤活性，并在较低剂量下比游离药物延长了生存时间。
Targeted therapies against cancer can relieve symptoms and induce remission; however, they often present limited duration of disease control, cause side effects, and may induce acquired resistance. Therefore, there is great motivation to develop a unique delivery system, targeted to the tumor, in which several active entities can be combined, the therapeutic index can be increased by reducing systemic exposure, and their synergistic activity can be enhanced. To meet these goals, the biocompatible and biodegradable poly(α,l‐glutamic acid) (PGA) is chosen as a nanocarrier that facilitates extravasation‐dependent tumor targeting delivery. The RAS/RAF/MEK/ERK pathway when aberrantly activated in melanoma, can lead to uncontrolled cell proliferation, induced invasion, and reduced apoptosis. Here, two drugs targeting this pathway are selected: a MEK1/2 inhibitor (selumetinib, SLM) and a modified BRAF inhibitor (modified dabrafenib, mDBF) that exhibit synergism in vitro. The combination of PGA conjugated to SLM and mDBF (PGA–SLM–mDBF) is synthesized and characterized. PGA–SLM–mDBF inhibits the proliferation of melanoma cells and decreases their migratory and sprouting abilities without inducing a hemolytic effect. Moreover, it exhibits superior antitumor activity in a mouse model of primary melanoma and prolonged survival at a lower dose than the free drugs.