Combinatorial targeting for the treatment of B-cell acute lymphoblastic leukemia

b细胞急性淋巴细胞白血病（ALL）占所有ALL诊断的75%。具体来说，治疗b细胞ALL的费城（Ph）染色体亚群（产生一种名为BCR-ABL的新基因）具有挑战性，复发率高，生存率低。最近越来越多的证据表明，信号换能器和转录激活因子S {STATS)信号是治疗高危b细胞ALL的一个有希望的治疗靶点。利用STAT5 siRNA可以有效靶向STATS5单向信号，精确敲低STATS5基因，抑制b细胞ALL细胞的增殖。另一方面，与线粒体蛋白MitoNEET相互作用的小分子配体NL-1在b细胞ALL中显示出抗白血病活性。我们假设同时使用STATS siRNA和NL-1靶向STATS和MITONEET的组合治疗策略！可增强抗白血病活性。STATS siRNA是带负电的亲水核酸，体内稳定性较差，NL-1不溶于水溶液。这些挑战迫切需要开发一种合适的输送系统，可以将这两种治疗方法精确地封装并输送到细胞中。我们的初步数据表明，利用可电离脂质纳米颗粒方法不仅可以有效地封装核酸和小分子治疗药物，还可以在体外将它们递送到b细胞ALL细胞。提出了两个独立的目标来优化和验证可电离脂质纳米颗粒作为b细胞ALL治疗的细胞内递送平台。目的1：开发含有STATS siRNA和NL-1的可电离脂质纳米颗粒，并优化其细胞内释放动力学。目的2：确定STATS siRNA-NL-1可电离脂质纳米颗粒是否允许细胞内靶向，从而增强抗白血病活性。这一应用在多个方面都是创新的，包括可翻译脂质纳米颗粒平台的开发，核酸和小分子治疗药物的细胞内双重递送，以及可电离脂质纳米颗粒技术b细胞ALL模型的测试。据我们所知，这是第一个利用可电离唇纳米颗粒靶向b细胞ALL的策略。我们期望，一旦这项应用完成，我们将确定合适的可电离脂质纳米颗粒平台，诱导核酸和小分子治疗的双重细胞内释放。此外，我们将确定组合靶向治疗是否为减少b细胞ALL肿瘤负荷的最佳选择。

B-cell acute IympnooIast1c IeuKemIa (ALL) accounts for 75% of all ALL diagnoses. Specifically, treating the Philadelphia {Ph) chromosome subgroup (which creates a new gene called BCR-ABL) of B-cell ALL challenging and has high relapse rates and poor survival. Mounting evidence from recent findings suggest that Signal Transducer and Activator of Transcription S {STATS) signaling is a promising therapeutic targE for treating high-risk B-cell ALL. One-way STATS5 signaling can be efficiently targeted is by utilizing STAT5 siRNA, which can precisely knock down the STATS gene and inhibit the proliferation of B-cell ALL cells. C the other hand, a small molecule ligand, NL-1, which interacts with mitochondrial protein, MitoNEET he demonstrated its anti-leukemic activity in B-cell ALL. We hypothesize that a combinatorial treatment strategy that simultaneously targets STATS and MITONEET using STATS siRNA and NL-1, respective! may show enhanced anti-leukemic activity. STATS siRNA is a negatively charged hydrophilic nucleic ac with poor in vivo stability, and NL-1 is insoluble in aqueous solvents. These challenges necessitate significant need to develop a suitable delivery system that can encapsulate and deliver both of these therapeutics precisely to cells. Our preliminary data show that utilizing an ionizable lipid nanoparticle approach not only efficiently encapsulates nucleic acids and small molecules therapeutics but als intracellularly delivers them to B-cell ALL cells in vitro. Two independent aims are proposed to optimize and validate ionizable lipid nanoparticles as an intracellular delivery platform for B-cell ALL treatment. Aim 1: To develop ionizable lipid nanoparticles containing STATS siRNA and NL-1 and optimize their intracellular, release kinetics. Aim 2: Determine if STATS siRNA-NL-1 ionizable lipid nanoparticles will allow du intracellular targeting, leading to enhanced anti-leukemic activity. This application is innovative in multiple ways, including the development of translatable lipid nanoparticle platforms, the dual intracellular delive1 of nucleic acid and small molecule therapeutics, and the testing of ionizable lipid nanoparticle technology B-cell ALL models. To the best of our knowledge, this is the first strategy that utilizes ionizable lip nanoparticles to target B-cell ALL. We expect that once this application is complete, we will have identified the suitable ionizable lipid nanoparticle platform that induces the dual intracellular release of nucleic acid and small molecule therapeutics. Furthermore, we will have determined if combinatorial targeting is optimal, for reducing tumor burden in B-cell ALL.