耐药性黑色素瘤的新型基因疗法:PTEN 质粒与 BRD4 PROTAC 脂质纳米载体的协同组合

IF 6.5 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy. Nucleic Acids Pub Date : 2024-07-31 DOI:10.1016/j.omtn.2024.102292
Aishwarya Saraswat, Hari Priya Vemana, Vikas Dukhande, Ketan Patel
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引用次数: 0

摘要

BRAF突变黑色素瘤患者在接受强效BRAF抑制剂(BRAFi)(如维莫非尼)治疗仅7个月后,肿瘤就会复发。事实证明,在黑色素瘤中,驱动BRAFi耐药性的多种分子通路都汇聚到了c-Myc的激活上。因此,我们发现了一种新的组合治疗策略,即针对10号染色体上缺失的磷酸酶和缺失的天丝同源物(PTEN)肿瘤抑制基因和上调的BRD4肿瘤蛋白,将其作为耐药黑色素瘤的Myc依赖性弱点。作为有希望的治疗靶点,我们决定同时提供 PTEN 质粒和 BRD4 靶向 PROteolysis-TArgeting Chimera(ARV),以治疗 BRAF 抗性黑色素瘤中 "无法治疗 "的 c-Myc。由于 PTEN 质粒和 ARV 的理化性质不同,我们制作了负载 PTEN 质粒的脂质纳米粒子(PL-NANO)和负载 ARV-825 的纳米脂质体(AL-NANO),使每种治疗载荷的平均粒径小于 100 纳米,封装效率大于 99%。在二维和三维模型中,PL-NANO 和 AL-NANO 的组合显示出协同的肿瘤生长抑制作用和显著的细胞凋亡作用。重要的是,PL-NANO 和 AL-NANO 的同时给药可显著上调 PTEN 的表达水平,并降解 BRD4 蛋白,最终下调 BRAFi 抗性黑色素瘤细胞中 c-Myc 的水平。总之,脂质纳米载体可提供这种新型致命鸡尾酒,是针对BRAF耐药黑色素瘤中无法治疗的c-Myc癌基因的独一无二的基因疗法。
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Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers
Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation of c-Myc in melanoma. Therefore, we identified a novel combinatorial therapeutic strategy by targeting loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities of drug-resistant melanoma. Being promising therapeutic targets, we decided to concomitantly deliver PTEN plasmid and BRD4 targeted PROteolysis-TArgeting Chimera (ARV) to drug the “undruggable” c-Myc in BRAFi-resistant melanoma. Since PTEN plasmid and ARV are distinct in their physicochemical properties, we fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) and ARV-825-loaded nanoliposomes (AL-NANO) to yield a mean particle size of less than 100 nm and greater than 99% encapsulation efficiency for each therapeutic payload. Combination of PL-NANO and AL-NANO displayed synergistic tumor growth inhibition and substantial apoptosis in two-dimensional and three-dimensional models. Importantly, simultaneous delivery of PL-NANO and AL-NANO achieved significant upregulation of PTEN expression levels and degradation of BRD4 protein to ultimately downregulate c-Myc levels in BRAFi-resistant melanoma cells. Altogether, lipid nanocarriers delivering this novel lethal cocktail stands as one-of-a-kind gene therapy to target undruggable c-Myc oncogene in BRAFi-resistant melanoma.
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来源期刊
Molecular Therapy. Nucleic Acids
Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
15.40
自引率
1.10%
发文量
336
审稿时长
20 weeks
期刊介绍: Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.
期刊最新文献
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