Metabolic Intervention Liposome Boosted Lung Cancer Radio‐Immunotherapy via Hypoxia Amelioration and PD‐L1 Restraint

Author:

Wang Saijun1,Zhou Zaigang234ORCID,Hu Rui1,Dong Mingyue1,Zhou Xiaobo1,Ren Siyan1,Zhang Yi1,Chen Chengxun1,Huang Ruoyuan1,Zhu Man1,Xie Wanying1,Han Ling1,Shen Jianliang2345ORCID,Xie Congying1346

Affiliation:

1. Medical and Radiation Oncology Department of the Second Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 China

2. State Key Laboratory of Ophthalmology, Optometry and Vision Science School of Ophthalmology and Optometry, School of Biomedical Engineering Wenzhou Medical University Wenzhou 325027 China

3. Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang 325000 China

4. Wenzhou Key Laboratory of Basic Science and Translational Research of Radiation Oncology Wenzhou Zhejiang 325000 China

5. Wenzhou Institute University of Chinese Academy of Sciences Wenzhou Zhejiang 325000 China

6. Zhejiang‐Hong Kong Precision Theranostics of Thoracic Tumors Joint Laboratory The Second Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang 325000 China

Abstract

AbstractAt present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand‐1 (PD‐L1) expression. Incredibly, intracellular PD‐L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD‐L1function still limits the effectiveness of radio‐immunotherapy. Therefore, better PD‐L1 regulation strategies are still urgently needed to better sensitize radio‐immunotherapy. Hence, for this purpose, TPP‐LND is synthesized by linking mitochondrial‐targeted triphenylphosphine cations (TPP+) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 µM). Then, TPP‐LND is wrapped with liposomes to form TPP‐LND@Lip nanoparticles. By doing this, TPP‐LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD‐L1 via enhancing the adenosine 5′‐monophosphate‐activated protein kinase activation. As expected, these well‐designed economical TPP‐LND@Lip nanoparticles are more effective than conventional anti‐PD‐L1 antibodies to some extent.

Funder

National Natural Science Foundation of China

Wenzhou Municipal Science and Technology Bureau

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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