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Theranostics 2023; 13(7):2226-2240. doi:10.7150/thno.81325 This issue Cite

Research Paper

Analgesic and potentiated photothermal therapy with ropivacaine-loaded hydrogels

Jiqian Zhang^1,2*✉, Shasha Zhu^4*, Mingxu Zhao^1*, Mengni Zhou⁴, Xiaoling Zhu¹, Xin Qing¹, Zhilai Yang¹, Pengfei Wei⁶, Guoying Zhang², Weiling He^5✉, Yongqiang Yu^3✉, Xuesheng Liu^1✉

1. Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesia and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, 230032, China.
2. CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230032, China.
3. Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
4. Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
5. Department of Gastrointestinal Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.
6. School of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, China.
^*Co-first author: Jiqian Zhang, Shasha Zhu and Mingxu Zhao contributed equally to this work.

✉ Corresponding authors: Yongqiang Yu (E-mail: yuyongqiangedu.cn); Xuesheng Liu (E-mail: liuxueshengedu.cn); Weiling He (E-mail: hewlingsysu.edu.cn); Jiqian Zhang (E-mail: jiqianzhustc.eud.cn)

Abstract

Rationale: Tumor ablation can cause severe pain to patients, but there is no satisfactory means of analgesia available. In addition, recurrence of residual tumors due to incomplete ablation threatens patient safety. Photothermal therapy (PTT), a promising approach for tumor ablation, also faces the aforementioned problems. Therefore, developing novel photothermal agents that can efficiently relieve PTT-associated pain and potentiate the PTT efficacy are urgently needed.

Methods: The Pluronic F127 hydrogel doped with indocyanine green (ICG) was served as photothermal agent for PTT. Mouse model that inoculation of tumor near the sciatic nerve was constructed to assess the PTT-evoked pain. Subcutaneous and sciatic nerve vicinal tumor-bearing mice were used to test the efficacy of PTT.

Results: PTT-evoked pain depends on an increase in tumor temperature and is accompanied by the activation of TRPV1. A simple introduction of local anesthetic (LA) ropivacaine into ICG-loaded hydrogels relieves PTT-induced pain and exerts long-lasting analgesia compared with opioid analgesia. More interestingly, ropivacaine upregulates major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-doped with ropivacaine, TLR7 agonist imiquimod and ICG was rationally designed. In the hydrogel system, imiquimod primes tumor-specific CD8⁺ T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8⁺ T cells through upregulating MHC-I. Consequently, the hydrogel maximumly increases CD8⁺ T cells infiltration into tumor and potentiates PTT efficacy.

Conclusion: This study for the first time provides an LA-dopped photothermal agents for painless PTT and innovatively proposes that a LA can be used as an immunomodulator to potentiate the PTT efficacy.

Keywords: cancer, cancer-related pain, Pluronic F127, photothermal therapy, local anesthetics

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