Abstract：
G3139 is an antisense oligodeoxyribonucleotide (ODN) developed as a Bcl-2 down-regulating agent for the treatment of acute myelogenous leukemia (AML). However, the clinical efficacy of G3139 has been shown to be limited due to its rapid plasma clearance and low permeability. To enhance the effective delivery of G3139, this work prepared a novel nano gene delivery vector (aCD33-NKSN) consisting of a CD33 antigbody (aCD33), a nuclear localization signal (NLS), gene fusion peptides (KALA), and stearic acid (SA) for CD33 antigen targeting and nuclear localization. The aCD33-NKSN/G3139 nanoparticles were spherical and uniformly sized with a positive charge and sustained release. They had an excellent G3139 loading capacity and colloidal stability. The aCD33-NKSN/G3139 delivered G3139 into the nucleus of Kasumi-1 cells and aCD33-NKSN/G3139 could more effectively inhibited Bcl-2 expression and induced apoptosis in Kasumi-1 cells versus free G3139. The aCD33-NKSN/G3139 administration was more effective at inhibiting tumor growth, and significantly prolonged the survival time of mice in contrast to free G3139. The results illustrate that aCD33-NKSN/G3139 nanoparticles could improve the antitumor activity of encapsulated G3139 due to aCD33 targeting and the ability to perform nuclear localization, The results offer a promising clinical application potential for the treatment of acute myeloid leukemia.
摘要：
G3139是一种反义寡脱氧核糖核苷酸（ODN），可作为Bcl-2下调剂用于治疗急性髓细胞性白血病（AML）。然而,G3139的临床疗效已被证明是有限的，由于其快速的血浆清除和低通透性。为了增强G3139的有效递送，这项工作制备了一种由CD33抗体（aCD33）组成的新型纳米基因递送载体（aCD33-NKSN），核定位信号(NLS)，基因融合肽（KALA），和硬脂酸（SA）用于CD33抗原靶向和核定位。aCD33-NKSN/G3139纳米颗粒是球形的并且尺寸均匀,具有正电荷和持续释放。它们具有优异的G3139负载能力和胶体稳定性。aCD33-NKSN/G3139将G3139递送到Kasumi-1细胞核中，与游离G3139相比，aCD33-NKSN/G3139可以更有效地抑制Bcl-2表达并诱导Kasumi-1细胞凋亡。aCD33-NKSN/G3139给药更有效地抑制肿瘤生长，与游离G3139相比，小鼠的存活时间明显延长。结果表明，aCD33-NKSN/G3139纳米颗粒可以提高封装的G3139的抗肿瘤活性，这是由于aCD33靶向和进行核定位的能力。该结果为急性髓系白血病的治疗提供了有希望的临床应用潜力。
