Targeted nanotherapy for the prevention of post-traumatic osteoarthritis

摘要 最新的人口普查表明，美国有5000多万成年人患有某种形式的关节炎，到2030年， 据估计，有6700万年龄在18岁的美国人被诊断为关节炎。骨性关节炎 (OA)是最常见的关节炎形式，是老龄人口发病的主要原因。 但对于这种疾病，治疗方法有限，也没有治疗疾病的药物。虽然有效的疾病- 修饰骨性关节炎药物(DMOAD)是迫切需要的，但还没有一种药物成功地出现在临床上。邮寄- 创伤性骨性关节炎(PTOA)是关节损伤后发生的骨性关节炎的一种形式，其性质和时间 创伤是众所周知的。大约12%的骨性关节炎总负担可以追溯到关节创伤。千真万确 考虑到受伤和PTOA之间的长时间延迟(10-15年)，PTOA的患病率可能更高。PTOA 影响了美国560万人。年患膝关节PTOA的预计终生风险 前十字韧带(ACL)断裂或半月板损伤的患者占50%-70%。PTOA 占所有关节置换的20%。退伍军人健康相关性：在服役人群中 成员们，PTOA的所有原因都会导致28%的士兵不同程度的永久性残疾 12%遭受关节创伤的平民。此外，退伍军人患关节炎的频率 美国正在进行的军事行动估计为11.8%。战斗相关性关节炎的诊断 损伤加速，往往伴随着不良的结局，需要在较小的年龄进行关节置换。 退伍军人人数与一般人相比。因此，任何改变曲线和 降低PTOA的发展风险将使普通人群和军队的患者受益 军人和退伍军人。 研究证明，关节损伤后立即会出现强烈的炎症反应(即 在第一周到2-3个月)，这种情况持续了几个月到几年，尽管水平较低。这 炎症反应可能导致软骨细胞死亡、软骨修复受损以及随后的 软骨退变是PTOA的特征。我们假设，对这种早期炎症限制的调节 急性软骨损伤，而输送促进软骨修复/内稳态的合成代谢因子将 进一步延缓或阻止最终的PTOA发展。我们使用了一种基于多肽的自组装 纳米复合体，提供广泛的核酸[小干扰(Si)RNA和信使(M)RNA]和 允许使用相同的细胞穿透肽同时靶向多个通路，而不需要 需要对主干或端件进行更改。我们表明，关节内(IA)递送我们的基于我们的肽 纳米颗粒下调NFKB的表达减轻早期建立的PTOA在不稳定的 内侧半月板(DMM)手术诱导PTOA模型。我们还证明了同时交付 NFkB siRNA和mRNA过度表达WNT16，这是一条对维持心脏功能至关重要的信号通路 软骨内稳，进一步减轻DMM模型中早期建立的PTOA。探索独一无二的 我们提出的决定长期结果的自组装肽-核纳米平台的潜力 联合抗炎和合成代谢纳米疗法在DMM模型中的应用。我们相信，这些努力很可能 为PTOA创造一种治疗疾病的纳米疗法。从这些研究中获得的洞察力可能是 一般适用于骨性关节炎的治疗。

ABSTRACT The latest census indicates that 50+ million adults in the US bear some form of arthritis and by 2030, an estimated 67 million Americans ages > 18 years are projected to have the diagnosis of arthritis. Osteoarthritis (OA) represents the most common form of arthritis and is a major cause of morbidity in the aging population but for which there are limited medical treatments and no disease modifying drugs. Although effective disease- modifying OA drugs (DMOADs) are critically needed, none has successfully emerged in the clinic. Post- traumatic OA (PTOA) is a form of OA that develops after a joint injury and in which the nature and time of trauma is generally known. Approximately 12% of the overall OA burden can be traced to joint trauma. True prevalence for PTOA may be higher, given the long delay between injury and PTOA (10-15 years). PTOA affects 5.6 million individuals in the US. The projected lifetime risk of developing PTOA of the knee in individuals who sustain anterior cruciate ligament (ACL) rupture or meniscal damage is 50-70%. PTOA accounts for 20% of all joint replacements. Veteran Health Relevance: Among the population of service members, all causes of PTOA result in some degree of permanent disability in 28% of soldiers compared to 12% of civilians who sustain joint trauma. In addition, the frequency of arthritis among combat veterans from ongoing US military operations is estimated at 11.8%. The diagnosis of arthritis resulting from combat-related injury is accelerated and often accompanied by poor outcomes, requiring joint replacement at a younger age in the veteran population compared to the general population. Thus, any intervention that shifts the curve and decreases the risk of PTOA development will benefit the patients in the general population as well as military service members and veterans. Studies have documented a robust inflammatory response in the immediate aftermath of joint injury (i.e. during the first week up to 2-3 months) that persists for months to years, albeit at a lower level. This inflammatory response likely contributes to chondrocyte death, impaired cartilage repair and the subsequent cartilage degeneration that characterizes PTOA. We posit that modulation of this early inflammation limits acute cartilage damage while delivery of an anabolic factor that promotes cartilage repair/homeostasis will further delay or prevent eventual PTOA development. We employed a peptide-based self-assembling nanocomplex, delivering a wide range of nucleic acids [small interfering (si)RNA and messenger (m)RNA] and allowing for the simultaneous targeting of multiple pathways using the same cell-penetrating peptide, with no need for backbone or end-piece alterations. We show that intra-articular (IA) delivery of our peptide-based nanoparticle to knock down expression of NFKB mitigates early established PTOA in the Destabilization of the Medial Meniscus (DMM) model of surgery-induced PTOA. We also demonstrate that simultaneous delivery of NFKB siRNA and mRNA that overexpresses WNT16, a signaling pathway important for the maintenance of cartilage homeostasis, further mitigates early established PTOA in the DMM model. To explore the unique potential of our self-assembling peptide-nucleic nanoplatform we propose to determine the long-term outcomes of combined anti-inflammatory and anabolic nanotherapy in the DMM model. We believe these efforts will likely produce a disease-modifying nanotherapeutic approach for PTOA. Insight gained from these studies may be applicable to OA treatment in general.