DataVXACS NanoPaper
journal article·2023-07-25

Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment

Yukun Huang, Yu Chen, Songlei Zhou, Laozhi Xie, Kaifan Liang, Jianpei Xu, Qian Zhang, Huan Chen, Dayuan Wang, Qingxiang Song, Gan Jiang, Ni Mei, Fenfen Ma, Huiping Lu, Xiaoling Gao, Jun Chen

ACS Nano· Volume 17· Issue 14
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Source abstract

Abstract

Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic "Nutri-hijacker" with "Trojan horse" design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.
Source: openalex_inverted_index · Quality: baseline

Research context

Nanomaterials

OpenAlex topics: Pancreatic function and diabetes · Pancreatic and Hepatic Oncology Research · Autophagy in Disease and Therapy

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Shanghai Pudong Hospital & Department of Pharmaceutics, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, People’s Republic of China

Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China

Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, People’s Republic of China

Shanghai Center for Drug Evaluation and Inspection, Lane 58, HaiQv Road, Shanghai 201210, People’s Republic of China

Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai 201399, People’s Republic of China

Funding

Postdoctoral Research Foundation of China · Postdoctoral Science Foundation of Shanghai Municipality · National Key Research and Development Program of China · Science and Technology Commission of Shanghai Municipality · National Natural Science Foundation of China · Program of Shanghai Academic Research Leader · Zhangjiang mRNA innovation and translation center, Shanghai

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