Exosomes and platinum-induced peripheral neuropathy

摘要： 以铂为基础的药物通常用于治疗癌症。铂类药物是卵巢疾病的一线治疗方法 和结直肠癌。然而，化疗引起的周围神经病变(CIPN)是最常见的 常见的并发症。接受奥沙利铂治疗的患者中，超过70%的患者受到神经病变的影响。 奥沙利铂导致两种外周感觉神经病症状：急性和短暂性感冒加重， 以及一种慢性形式，在多次接触药物后发病，不会随着药物的使用而消失 停止。神经毒性通常会导致铂类药物剂量减少，从而影响铂类药物的疗效。 抑制肿瘤进展的药物。化疗后平均6年，47%的女性仍然 报告的CIPN症状。到目前为止，开发神经保护剂的研究还没有成功 减少CIPN。迫切需要开发新的治疗CIPN的方法。开发此类产品所面临的挑战 治疗方法包括，一种治疗方法不需要阻碍抗肿瘤疗效，而是需要有效地抑制CIPN。我们的 初步数据显示，脑内皮细胞来源的外切体(CEC-exos)可取消奥沙利铂。 诱导荷瘤小鼠周围神经病变及增敏奥沙利铂对肿瘤细胞的杀伤作用。 外体是纳米囊泡，通过转运货物蛋白、脂类和 源细胞和靶细胞之间的基因组物质，包括mRNAs和microRNAs(MiRNAs)。我们 发现CEC-exos联合奥沙利铂治疗荷瘤小鼠可诱导出一系列 坐骨神经中的miRNAs/mRNAs在坐骨神经和DRG神经元中发挥神经保护作用，但触发 肿瘤中一个独特的miRNAs/mRNAs网络促进癌细胞死亡。因此，我们假设CEC- EXOS减轻铂类药物外周神经毒性及CEC-EXOS增强抗肿瘤作用 铂类药物对肿瘤细胞的致癌作用。提出了三个具体目标来全面检验这一点 假设。目的1探讨CEC-exos对铂类药物诱导的改善作用。 外周神经毒性和提高肿瘤治疗水平。目标2是研究分子机制 CEC-exos对铂类药物所致周围神经病的治疗作用 CEC外体miRNAs与其靶蛋白在轴突和背根节神经元中的相互作用。目标3是 探讨CEC-exos增敏肿瘤铂类药物的分子机制 重点研究CEC外体miRNAs与其在肿瘤细胞中的靶蛋白之间的相互作用。 实现这些目标可能会导致开发一种新的基于CEC-exo的CIPN治疗方法， 从而提高生活质量，并有可能治愈癌症。

Abstract: Platinum-based drugs are commonly used to treat cancers. Platinum drugs are the first line therapy for ovarian and colorectal cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common complications. More than 70% of the patients receiving oxaliplatin are affected by neuropathy. Oxaliplatin induces two symptoms of peripheral sensory neuropathy; an acute and transient cold-aggravated, and a chronic form that has onset after multiple exposures to the drug and does not disappear with drug cessation. The neurotoxicity often leads to platinum drug dose reductions, compromising efficiency of platinum drugs to suppress tumor progression. On an average of 6 years after chemotherapy, 47% of women still reported symptoms of CIPN. Studies to develop a neuroprotective agent have, to date, been unsuccessful to reduce CIPN. There is an imperative need to develop new therapies to CIPN. Challenges to develop such therapies include that a therapy needs not to impede antitumor efficacy, but to effectively inhibit CIPN. Our preliminary data demonstrated cerebral endothelial cell derived exosomes (CEC-exos) abolish oxaliplatin- induced peripheral neuropathy in tumor bearing mice and sensitize oxaliplatin on cancer cell killing. Exosomes are nanovesicles and mediate intercellular communication by transferring cargo proteins, lipids, and genomic materials including mRNAs and microRNAs (miRNAs) between source and target cells. We found that treatment of the tumor bearing mice with CEC-exos along with oxaliplatin induces a network of miRNAs/mRNAs in sciatic nerves that exerts neuroprotection in sciatic nerves and DRG neurons, but triggers a distinct miRNAs/mRNAs network in tumor to promote cancer cell death. We, thus, hypothesized that CEC- exos mitigate peripheral neurotoxicity induced by platinum drugs and that CEC-exos enhance the anti- cancer efficacy of platinum drugs on tumor cells. Three specific aims are proposed to test this overall hypothesis. Aim 1 is to investigate the efficacy of the CEC-exos on ameliorating platinum drug-induced peripheral neurotoxicity and on improving the treatment of tumor. Aim 2 is to investigate molecular mechanisms underlying the therapeutic effect of CEC-exos on platinum drug-induced peripheral neuropathy with a focus on the interaction between CEC exosomal miRNAs and their target proteins in axons and DRG neurons. Aim 3 is to investigate molecular mechanisms underlying the effect of CEC-exos on sensitizing tumors to platinum drugs with a focus on the interaction between CEC exosomal miRNAs and their target proteins in tumor cells. Accomplishing these aims will potentially lead to development of a new CEC-exo based therapy for CIPN, leading to improvement in the quality of life and possibly cure of cancers.