Abstract
Abstract Chemotherapy-induced peripheral neuropathy is a dose-limiting debilitating symptom that can affect many patients treated with anticancer treatments. The resulting neuropathic pain is thought to be a peripheral symptom, however, central sensitization has recently been suggested as a possible causal mechanism for chronic pain conditions; nociceptive neurons in the dorsal horns of the spinal cord become sensitized by a neuroinflammatory response through chronic peripheral tissue damage or inflammation [Zhuo, 2012]. Centrally active anti-inflammatory therapies, such as methylprednisolone (MP), may therefore have beneficial therapeutic properties, but its effective use is limited by several (severe) acute and chronic side effects or highly invasive local delivery routes. Systemic administrations of encapsulated MP in glutathione PEGylated liposomes (2B3-201) have recently resulted in superior efficacy and reduced side effects compared to the free MP in rodent models with neuroinflammation [Gaillard, 2012]. Therefore, 2B3-201 was hypothesized to have therapeutic value in preventing chemo-induced neuropathic pain as well. 2B3-201 was initially investigated in a pharmacokinetic and biodistribution study and compared to free MP, showing an enhanced plasma circulation (half life of ∼7 hours vs. several minutes for free MP), and higher sustained levels of 2B3-201 in brain and spinal cord. Furthermore, 2B3-201 did not result in psychotic-like behavioral effects in rats, as were caused by free MP. Also, repeated weekly administrations of 2B3-201 were well tolerated in rats, while the same weekly doses of free MP were causing side effects. The efficacy of 2B3-201 was investigated at WuXi AppTec (Shanghai, China) in two chemo-induced neuropathic pain models with demonstrated spinal cord pathology as a consequence of repeated bortezomib or paclitaxel administrations. Rats received paclitaxel (1 mg/kg/day, 8x) or bortezomib (0.2 mg/kg/day, 8x), and the effect of 2B3-201 on mechanical allodynia was evaluated at three dose levels (10, 20, or 30 mg/kg). Rats were monitored daily and allodynic measurements were taken at baseline and from days 4 to 8 after treatment start. The body weight gain of the rats was slightly inhibited by paclitaxel and bortezomib, and co-therapy with 2B3-201 showed a dose-dependent larger inhibition of weight gain. Despite the increased signs of chemotherapeutic side effects on body weight, 2B3-201 dose-dependently relieved neuropathic pain in both models. At the highest dose, the significant effect of 2B3-201 on neuropathic pain was no longer observed, which was probably due to the more severe chemotherapeutic side effects. In conclusion, the positive treatment effect of 2B3-201 against chemotherapy-induced neuropathic pain, in combination with a good PK, biodistribution and safety profile, warrant the further development of 2B3-201 for this indication. Citation Format: Pieter J. Gaillard, Rick Dorland, Chantal C. Appeldoorn. 2B3-201, glutathione pegylated liposomal methylprednisolone, prevents chemotherapy-induced neuropathic pain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2013-4342
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