Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics
Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics
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DOI：
10.7150/thno.41309
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Janjic, Jelena M.
中科院分区：
文献类型：
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作者：
Liu, Lu;Karagoz, Huseyin;Janjic, Jelena M.
单核细胞衍生的巨噬细胞 (MDM) 浸润感染或损伤部位，并上调环氧合酶 2 (COX-2)，这是一种刺激前列腺素 E2 (PgE2) 的酶。纳米治疗学将治疗剂和诊断剂结合到一个纳米系统中。在之前的研究中，我们证明了基于载有 COX-2 抑制剂（塞来昔布，CXB）并配备近红外荧光（NIRF）报告基因的治疗诊断纳米乳剂（NE）的纳米治疗策略可以专门针对循环单核细胞和 MDM。这种细胞特异性 COX-2 抑制的抗炎和抗伤害作用在雄性小鼠的完全弗氏佐剂 (CFA) 或神经损伤后持续数天。本研究的总体目标是调查 MDM 靶向 COX-2 抑制的长期（长达 40 天）影响以及治疗反应中基于性别的差异；两者均未知。我们的研究还评估了临床前纳米治疗策略的可行性和有效性，该策略用于研究性别差异对临床结果影响的机制。方法：将 CFA 注射到雄性和雌性小鼠的右后爪中。所有小鼠在注射 CFA 前 12 小时接受单次静脉注射 NIRF 标记的 CXB 负载 NE。依次进行体内全身 NIRF 成像和机械超敏反应测定，并在 40 天终点进行离体 NIRF 成像和足垫组织的免疫组织病理学分析。 结果：靶向 COX-2 抑制雄性和雌性小鼠的 MDM，成功改善了 CFA 损伤后的机械超敏反应。然而，我们观察到伤害性反应的强度或持续时间存在明显的性别差异。在男性中，与无药物 NE (DF-NE)（未治疗）对照组相比，通过尾静脉注射单剂量 CXB-NE 可显着改善 32 天的机械超敏反应。在女性中，CXB-NE 产生了类似的效果，但效果不太明显且持续时间较短，可持续长达 11 天。 NIRF 成像证实，在注射 CFA 的男女足垫组织中，长达 40 天的时间里都可以检测到 CXB-NE。男性和女性之间存在明显的信号分布趋势，表明性别之间巨噬细胞浸润动力学存在差异。这也可能与性别之间巨噬细胞周转率的差异有关，这种可能性需要在该模型中进一步研究。 结论：这项研究首次提供了对 MDM 动力学以及临床可转化纳米治疗剂对 MDM 介导的炎症的早期和长期靶向作用和功效的独特见解。我们的数据支持纳米治疗学在阐明对炎症触发因素的适应性或先天免疫反应的动力学、动力学和性别差异方面的潜力。总而言之，我们的研究结果使我们更接近于针对多种炎症性疾病的真正的个性化、性别特异性疼痛纳米药物。
Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes.Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days.Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model.Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.