Fu Yige, Saraswat Aishwarya, Wei Zenghui, Agrawal Manas Yogendra, Dukhande Vikas V, Reznik Sandra E, Patel Ketan
College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Pharmaceutics. 2021 Jul 1;13(7):1005. doi: 10.3390/pharmaceutics13071005.
A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.
在维莫非尼耐药的黑色素瘤中探索了一种通过共同靶向c-Myc和肿瘤基质的新型治疗策略。开发了BRD4蛋白酶解靶向嵌合体（ARV-825）和尼达尼布共载聚乙二醇化纳米脂质体（ARNIPL）以纳入协同细胞毒性比率。这两种分子的水溶性都极差。采用柠檬酸修饰的水化方法来提高这两种分子在脂质体中的载药量。平均粒径为111.1±6.55nm的ARNIPL对两种药物的包封率均超过90%，并且在4℃下可物理稳定保存一个月。这两种分子和ARNIPL在维莫非尼耐药细胞系（A375R）中均表现出显著更高的细胞毒性、凋亡以及靶蛋白BRD4和c-Myc的下调。ARNIPL显著抑制了A375R的血管生成拟态和克隆形成潜力。用ARNIPL处理观察到三维球体中的肿瘤生长受到抑制，同时TGF-β1减少。因此，ARNIPL可能是治疗维莫非尼耐药黑色素瘤的一种有前景的治疗方法。
