Ultrasound-mediated blockade of nociceptive transmission by targeted liposomes for efficient cancer pain therapy

The lack of pain management for advanced pancreatic cancer resulted in severe suffering for patients at the final stage of life. Pain relief can be achieved through local injection of nerve-blocking agents, but the efficiency was attenuated by perineural barriers due to drug could hardly penetrate into peripheral nerves. To address this challenge, we here proposed a strategy of ultrasound-mediated blockade of nociceptive transmission for treating the cancer pain. To demonstrate the feasibility and effectiveness of the method, a kind of transferrin-modified liposome (TLAP) loaded with AZ23 (a TrkA inhibitor) and perfluoropentane was developed and capable of ultrasound imaging guidance and ultrasonic cavitation. After local injection around the pancreatic cancer, TLAP targets the nerves via recognizing transferrin receptor, and transforms from nanosized liposome into microbubble via liquid-to-gas phase transition when exposed to ultrasound irradiation. The following ultrasonic cavitation opens the perineural barriers, and facilitates AZ23 delivery into the nerve interior, which can be visualized under ultrasound imaging, and leads to superior efficacy of pain relief in mouse cancer pain model of pancreatic cancer. In addition, sustained retention at the injection site can be maintained for over two days, and analgesia is further reinforced through repeated ultrasound exposures, enabling effective and intensity-tunable pain control. Meanwhile, no significant systemic or local tissue damage was observed after treatment. This study presents an effective strategy to tackle the perineural barriers and provides an effective nanoplatform for cancer pain management using ultrasound. STATEMENT OF SIGNIFICANCE: Pain relief of pancreatic cancer patients can be achieved through local injection of nerve-blocking agents, but the efficiency is attenuated by perineural barriers due to drug could hardly penetrate into peripheral nerves. This study developed a kind of transferrin-modified liposome (TLAP) loaded with a TrkA inhibitor and perfluoropentane to achieve ultrasonic cavitation-induced perineural barriers destruction, and ultrasound-guided cancer pain management, which led to superior efficacy of pain relief in cancer pain model of pancreatic cancer. This study presents an effective strategy of ultrasound-mediated blockade of nociceptive transmission to tackle the perineural barriers and provides an effective nanoplatform for cancer pain management of pancreatic cancer using ultrasound.