Nanomedicines with high drug availability and drug sensitivity overcome hypoxia-associated drug resistance

Yi Liu; Wang Dong; Yinchu Ma; Jiaxiang Dou; Wei Jiang; Li Wang; Qin Wang; Shuya Li; Yucai Wang; Min Li

doi:10.1016/j.biomaterials.2023.122023

Nanomedicines with high drug availability and drug sensitivity overcome hypoxia-associated drug resistance

Biomaterials. 2023 Mar:294:122023. doi: 10.1016/j.biomaterials.2023.122023. Epub 2023 Jan 22.

Authors

Yi Liu¹, Wang Dong², Yinchu Ma², Jiaxiang Dou², Wei Jiang², Li Wang², Qin Wang², Shuya Li², Yucai Wang³, Min Li⁴

Affiliations

¹ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
² The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
³ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, 230601, China. Electronic address: [email protected].
⁴ Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. Electronic address: [email protected].

PMID: 36708621
DOI: 10.1016/j.biomaterials.2023.122023

Abstract

Tumor hypoxia heterogeneity, a hallmark of the tumor microenvironment, confers resistance to conventional chemotherapy due to insufficient drug availability and drug sensitivity in hypoxic regions. To overcome these challenges, we develope a nanomedicine, NP_HPaPN, constructed with hyaluronic acid (HA) grafted with cisplatin prodrug and PEG-azobenzene for hypoxia-responsive PEG shell deshielding and loaded with a DNA damage repair inhibitor (NERi). After arriving at the tumor site, NP_HPaPN deshields the PEG shell in response to hypoxia due to the enzymolysis of azobenzene and thus exposes HA. The exposed HA binds to the highly expressed CD44 on cisplatin-resistant tumor cells and mediates drug internalization, thus increasing drug availability to hypoxic tumor cells. After intracellular hyaluronidase-mediated cleavage, the HA NPs release the cisplatin prodrug and NERi, and cause enhanced DNA damage and consequent cell death, thus enhancing the drug sensitivity of hypoxic tumor cells. Eventually, NP_HPaPN achieves distinct tumor growth suppression with an ∼84.4% inhibition rate.

Keywords: Cisplatin resistance; Drug delivery; Hypoxia-responsive nanoparticle; Nucleotide excision repair; Tumor hypoxia heterogeneity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cisplatin / pharmacology
Cisplatin / therapeutic use
Drug Resistance
Humans
Hyaluronic Acid / pharmacology
Hypoxia / drug therapy
Nanomedicine
Nanoparticles* / therapeutic use
Neoplasms* / pathology
Prodrugs* / metabolism
Prodrugs* / pharmacology
Prodrugs* / therapeutic use
Tumor Microenvironment

Substances

azobenzene
Cisplatin
Prodrugs
Hyaluronic Acid