Efficient delivery of the Bcl-2 antisense oligonucleotide G3139 via nucleus-targeted aCD33-NKSN nanoparticles
Efficient delivery of the Bcl-2 antisense oligonucleotide G3139 via nucleus-targeted aCD33-NKSN nanoparticles
复制标题
通过核靶向 aCD33-NKSN 纳米粒子有效递送 Bcl-2 反义寡核苷酸 G3139
DOI：
10.1016/j.ijpharm.2022.122074
复制
发表时间：
2022-08-06
影响因子：
5.8
通讯作者：
Lee，Robert J.
中科院分区：
文献类型：
--
作者：
Yan，Chengyun;Gu，Jiwei;Lee，Robert J.
G3139是一种反义寡脱氧核糖核苷酸（ODN），作为Bcl-2下调剂被开发用于治疗急性髓性白血病（AML）。然而，由于G3139的血浆清除率快，渗透性低，临床疗效有限。为了提高G3139的有效递送，本文制备了一种由CD33抗体（aCD33）、核定位信号（NLS）、基因融合肽（KALA）和硬脂酸（SA）组成的新型纳米基因递送载体（aCD33- nksn），用于CD33抗原靶向和核定位。制备的aCD33-NKSN/G3139纳米颗粒呈球形，粒径均匀，具有正电荷和缓释特性。它们具有优异的G3139负载能力和胶体稳定性。与游离G3139相比，aCD33-NKSN/G3139能更有效地抑制Kasumi-1细胞中Bcl-2的表达和诱导凋亡。与游离G3139相比，aCD33-NKSN/G3139给药更有效地抑制肿瘤生长，并显著延长小鼠的生存时间。结果表明，aCD33- nksn /G3139纳米颗粒可通过aCD33靶向和核定位能力提高包封G3139的抗肿瘤活性，为治疗急性髓系白血病提供了良好的临床应用前景。
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.