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Theranostics 2020; 10(11):4885-4899. doi:10.7150/thno.43932 This issue Cite

Research Paper

Combination therapy with ropivacaine-loaded liposomes and nutrient deprivation for simultaneous cancer therapy and cancer pain relief

Jiqian Zhang^1✉*, Shasha Zhu^2*, Qilian Tan^3*, Dan Cheng³, Qingqing Dai¹, Zhilai Yang¹, Lei Zhang¹, Fenfen Li⁴, Youmei Zuo¹, Wei Dai¹, Lihai Chen³, Erwei Gu¹, Guanghong Xu¹, Zhaolian Wei², Yunxia Cao^2✉, 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
2. Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Anhui Province Key Laboratory of Reproductive Health and Genetics, Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University
3. Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University
4. Centre for Biomedical Engineering, Department of Electronic Science and Technology, University of Science and Technology of China
*These authors contributed equally to the study

✉ Corresponding authors: Xuesheng Liu: Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Anhui Province, 20032, Hefei, China, (0086)0551-62922057, liuxueshengedu.cn. Yunxia Cao: Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Anhui Province Key Laboratory of Reproductive Health and Genetics, Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230022, China, caoyunxia6com. Jiqian Zhang: Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Anhui Province, 20032, Hefei, China, jiqianzhustc.edu.cn More

Abstract

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse.

Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy.

Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A.

Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

Keywords: autophagy, cancer, cancer pain, VEGF-A, STAT3, ropivacaine, liposome

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