Fan Ruyu, He Shipeng, Wang Yongqing, Qiao Jiaming, Liu Hongcheng, Galstyan Levon, Ghazaryan Arman, Cai Hui, Feng Shini, Ni Pinyue, Dong Guoqiang, Li Huafei
School of Lifesciences, Shanghai University 333 Nanchen Road, Shanghai 200444, China.
Institute of Translational Medicine, Shanghai University 333 Nanchen Road, Shanghai 200444, China.
Am J Cancer Res. 2022 Mar 15;12(3):1027-1041. eCollection 2022.
Pancreatic carcinoma (PC) has one of the highest mortality-to-incidence ratios of any solid tumor worldwide. Although KRAS mutation is commonly found in 95% of PCs, directly targeting KRAS remains to be a highly challenging task because of its lacking catalytic pockets where molecule inhibitors can bind with. Proteolysis-targeting chimeric (PROTAC) represents an effective approach for specific degradation of disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system (UPS). Previously, we designed a first-in-class PROTAC induced PDEδ degrader (PIPD), which demonstrated improved anti-tumor efficacy against KRAS mutant malignancies. However, translating cellular degradative effects from bench to beside remains a highly challenging task because of PROTAC's poor penetration efficiency across target cytomembranes and non-targeting delivery induced undesired "off target" side-effects. Herein, a smart nano-drug delivery system (CM8988-PIPD) was successfully constructed by biomimetic strategy for targeted delivery of PIPD. The biomimetic nanoparticle showed well-defined regular spherical structure with an average particle size of approximately 124.8 nm. Cancer cytomembrane camouflage endows CM8988-PIPD with excellent serum stability, controlled drug release profile, favorable biocompatibility & immunocompatibility, and prominent targeting ability to homologous PC cells. Owing to these advantages, the smart DDS significantly enhanced PDEδ degrading efficacy, resulting in induced cellular apoptosis (more than 50% for both PC cells) and suppressed cell proliferation via the inhibition of RAS signaling. studies illustrated that CM8988-PIPD hold great potential for the treatment of PC, which merits further investigation in both pre-clinical and clinical investigations in the future.
胰腺癌（PC）是全球所有实体瘤中死亡率与发病率之比最高的癌症之一。尽管95%的胰腺癌中普遍存在KRAS突变，但直接靶向KRAS仍然是一项极具挑战性的任务，因为它缺乏可供分子抑制剂结合的催化口袋。蛋白酶靶向嵌合体（PROTAC）代表了一种通过劫持内源性泛素-蛋白酶体系统（UPS）特异性降解致病蛋白的有效方法。此前，我们设计了一种一流的PROTAC诱导的PDEδ降解剂（PIPD），它对KRAS突变恶性肿瘤显示出更高的抗肿瘤疗效。然而，由于PROTAC跨靶细胞膜的穿透效率低以及非靶向递送会引发不良的“脱靶”副作用，将细胞降解作用从实验室转化到临床应用仍然是一项极具挑战性的任务。在此，我们通过仿生策略成功构建了一种智能纳米药物递送系统（CM8988-PIPD）用于PIPD的靶向递送。该仿生纳米颗粒呈现出明确的规则球形结构，平均粒径约为124.8nm。癌细胞膜伪装赋予CM8988-PIPD优异的血清稳定性、可控的药物释放曲线、良好的生物相容性和免疫相容性，以及对同源胰腺癌细胞突出的靶向能力。由于这些优势，这种智能药物递送系统显著提高了PDEδ的降解效率，导致细胞凋亡（两种胰腺癌细胞均超过50%），并通过抑制RAS信号传导抑制细胞增殖。研究表明，CM8988-PIPD在胰腺癌治疗方面具有巨大潜力，值得在未来的临床前和临床研究中进一步探索。
