Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.
Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.
复制标题
DOI：
10.1073/pnas.2113180119
复制
发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
我们报告了一种基于分子刷的寡核苷酸治疗平台，其独特地提供具有结合选择性、改善的药理学性质和不寻常的生物分布特征的缀合反义寡核苷酸。与KRASMUT驱动的非小细胞肺癌小鼠模型的最新技术水平相比，这些改进导致了上级体内性能，副作用最小，并可能最终扩大可以开发基于核酸的治疗的疾病领域。鸟苷三磷酸酶（GT3）KRAS的突变形式是人类肿瘤的关键驱动因素，但仍然是一个具有挑战性的治疗靶点，使KRASMUT癌症成为一个高度未满足的临床需求。在这里，我们报告了一类瓶刷聚乙二醇（PEG）结合的反义寡核苷酸（ASO），有效的体内KRAS耗竭。由于其高度分支的结构，这些分子纳米构建体抑制了几乎所有与DNA-蛋白质相互作用相关的副作用，并显著增强了阿索的药理学性质，如血浆药代动力学和肿瘤摄取。全身递送至携带人非小细胞肺癌异种移植物的小鼠导致KRAS水平和肿瘤生长的显著降低，并且抗肿瘤性能远远超过当前流行的阿索范例，例如化学修饰的寡核苷酸和使用线性或略微支化的PEG的PEG化。重要的是，这些缀合物放宽了对阿索化学的要求，允许未修饰的天然磷酸二酯ASO实现与化学修饰的ASO相当的功效。瓶刷聚合物及其阿索缀合物在小鼠中似乎是安全的且耐受良好。总之，这些数据表明，分子刷-ASO缀合物是用于治疗KRAS驱动的人类癌症的有前景的治疗平台，并保证进一步的临床前和临床开发。
We report a molecular brush-based oligonucleotide therapeutics platform which uniquely provides conjugated antisense oligonucleotides with binding selectivity, improved pharmacological properties, and an unusual biodistribution profile. These improvements lead to superior in vivo performance compared with the state of the art in KRASMUT-driven non–small-cell lung carcinoma mouse models with minimal side effects and may eventually broaden the disease areas where a nucleic acid–based treatment can be developed. The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA–protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non–small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush–ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.
登录
查看更多内容
影响因子：
14.9
作者：
Koller E;Vincent TM;Chappell A;De S;Manoharan M;Bennett CF
通讯作者：
Bennett CF
影响因子：
4.5
作者：
Henry, SP;Bolte, H;Kornbrust, DJ
通讯作者：
Kornbrust, DJ
吸毒不良的RA：任务可能吗？
影响因子：
120.1
作者：
Cox, Adrienne D.;Fesik, Stephen W.;Kimmelman, Alec C.;Luo, Ji;Der, Channing J.
通讯作者：
Der, Channing J.
有效递送反义和siRNA寡核苷酸的机制和策略。
影响因子：
14.9
作者：
Juliano, Rudy;Alam, Md. Rowshon;Dixit, Vidula;Kang, Hyumin
通讯作者：
Kang, Hyumin
影响因子：
14.9
作者：
Juliano RL
通讯作者：
Juliano RL