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A Hypoxia-Sensitive Drug Delivery System Constructed by Nitroimidazole and its Application in the Treatment of Hepatocellular Carcinoma

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Abstract

Hypoxia is an important pathological phenomenon, and it can induce many tumor microenvironment changes, such as accumulations of intracellular lactic acid, decrease of tumor microenvironment pH value, and regulate a series of physiological and pathological processes such as adhesion, metastasis, and immune escape. Hypoxic tumor cells act as a key target for treating tumor. In this research, we designed and prepared PEG-nitroimidazole grafts, PEG-NI, and FA-PEG-NI. We first explored their physical and chemical properties to serve as a drug carrier. Then, the hypoxia-sensitive properties such as particle size changes and drug release were investigated. Finally, the tumor targeting ability was studied in vitro and in vivo, and anti-tumor capacity was determined. Both grafts showed excellent property as a nanodrug carrier and showed favorable drug encapsulation ability of sorafenib with the help of the hydrophobic chain of 6-(BOC-amino) hexyl bromide. The micelles responded to the hypoxic tumor environment with chemical and spatial structure changes leading to sensitive and fast drug release. With the modification of folic acid, FA-PEG-NI gained tumor targeting ability in vivo. FA-PEG-NI graft proved a potential targeting drug delivery system in the treatment of hypoxic hepatocellular carcinoma.

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Funding

Tha study was financially supported by Zhejiang Provincial Natural Science Foundation of China (LQ20H300004) and the National Natural Science Foundation of China (81973267).

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Authors and Affiliations

  1. College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China

    Tingting Meng, Kequan Shi, Xuwei Shang, Hong Yuan & Fuqiang Hu

  2. Zhejiang Institute for Food and Drug Control, NMPA Key Laboratory for Testing and Warning of Pharmceutical Microbiology, Key Laboratory of Drug Contacting Materials Quality Control of Zhejiang Province, Hangzhou, People’s Republic of China

    Yinghong Li

  3. Department of Pharmacy, Qingdao Fifth People’s Hospital, Qingdao City, People’s Republic of China

    Ying Tian & Mingxing Ma

Authors
  1. Tingting Meng
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  2. Yinghong Li
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  8. Fuqiang Hu
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Contributions

Tingting Meng: conceptualization, methodology, formal analysis, investigation, writing (original draft), and funding acquisition. Yinghong Li: methodology and validation. Ying Tian: conceptualization, validation, and writing (review & editing). Mingxing Ma: methodology writing (original draft). Xuwei Shang: methodology and validation. Hong Yuan: resources, supervision, and project administration. Fuqiang Hu: conceptualization, resources, writing (review & editing), supervision, project administration, and funding acquisition.

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Correspondence to Fuqiang Hu.

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Meng, T., Li, Y., Tian, Y. et al. A Hypoxia-Sensitive Drug Delivery System Constructed by Nitroimidazole and its Application in the Treatment of Hepatocellular Carcinoma. AAPS PharmSciTech 23, 167 (2022). https://doi.org/10.1208/s12249-022-02316-7

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