Fu Yige, Rathod Drishti, Patel Ketan
College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
Exp Cell Res. 2020 Nov 1;396(1):112275. doi: 10.1016/j.yexcr.2020.112275. Epub 2020 Sep 6.
Limited treatment options and development of resistance to targeted therapy within few months pose significant challenges in the treatment of BRAF-mutated malignant melanoma. Moreover, extensive angiogenesis and vasculogenic mimicry promote the rapid progression of disease. The purpose of this study was to develop a protein kinase C inhibitor anchored BRD4 PROTAC (ARV) loaded PEGylated nanoliposomes (LARPC). Palmitoyl-dl-carnitine chloride (PC) was used as a protein kinase C inhibitor to provide a cationic surface charge to LARPC. The formulation was characterized for particle size, zeta potential, drug release and various cell culture assays using HUVEC and vemurafenib resistant melanoma cells. The particle size of LARPC was found to be 105.25 ± 2.76 nm with a zeta potential of +26.6 ± 6.25 mV. Inhibition of angiogenesis was demonstrated by ARV and LARPC using human umbilical vein endothelial cells (HUVEC)-based matrigel basement membrane model. Additionally, LARPC demonstrated very low IC with promising inhibition of vasculogenic mimicry channel formation, cell migration as well as colony formation in vemurafenib-resistant melanoma cell lines. Hence, the outcome of this combination therapy indicated the suitability of LARPC as a potential and novel approach for eradicating vemurafenib-resistant melanoma.
治疗选择有限以及在短短几个月内就对靶向治疗产生耐药性，这给BRAF突变的恶性黑色素瘤的治疗带来了重大挑战。此外，广泛的血管生成和血管生成拟态促进了疾病的快速进展。本研究的目的是开发一种负载蛋白激酶C抑制剂锚定的BRD4 PROTAC（ARV）的聚乙二醇化纳米脂质体（LARPC）。棕榈酰 - dl - 肉碱氯化物（PC）用作蛋白激酶C抑制剂，为LARPC提供阳离子表面电荷。使用人脐静脉内皮细胞（HUVEC）和维莫非尼耐药黑色素瘤细胞对该制剂进行了粒径、zeta电位、药物释放和各种细胞培养测定的表征。发现LARPC的粒径为105.25±2.76nm，zeta电位为+26.6±6.25mV。使用基于人脐静脉内皮细胞（HUVEC）的基质胶基底膜模型，ARV和LARPC证明了对血管生成的抑制作用。此外，LARPC在维莫非尼耐药黑色素瘤细胞系中表现出非常低的半数抑制浓度（IC），对血管生成拟态通道形成、细胞迁移以及集落形成具有良好的抑制作用。因此，这种联合治疗的结果表明LARPC作为根除维莫非尼耐药黑色素瘤的一种潜在的新方法具有适用性。
