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Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer

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The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5 μg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity.

In this work, Ara-C encapsulated with hyaluronic acid–tyramine conjugates (HA–Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No.81201682), the Scientific Research Foundation of the Luzhou Science and Technology Bureau (No.2016LZXNYD-J05), and the Southwest Medical University Foundation (No.201617).

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  1. Juan Tang and Na Wang have contributed equally to this work

Authors and Affiliations

  1. Department of Oncology, Affiliated Hospital of Southwest Medical University, 25 TaiPing Rd, Luzhou, 646000, China

    Juan Tang, Na Wang, JingBo Wu, PeiRong Ren, JunYang Li, LiShi Yang, XiangXiang Shi, ShaoZhi Fu & Sheng Lin

  2. Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China

    Yue Chen & Sheng Lin

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Highlights

• Cytarabine has radio-sensitizing abilities on Lewis lung cancer cells.

• Hyaluronic acid–tyramine conjugates as a cytarabine carrier for intratumoral injection.

• The complexes exhibited radiotherapy sensitization and prolonged the survival time.

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Tang, J., Wang, N., Wu, J. et al. Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer. Invest New Drugs 37, 1146–1157 (2019). https://doi.org/10.1007/s10637-019-00740-4

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