Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8573, Japan.
Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.
Acta Biomater. 2023 Sep 15;168:515-528. doi: 10.1016/j.actbio.2023.07.005. Epub 2023 Jul 9.
l-Ornithine (Orn) is a core amino acid responsible for ammonia detoxification in the body via the hepatic urea cycle. Clinical studies in Orn therapy have focused on interventions for hyperammonemia-associated diseases, such as hepatic encephalopathy (HE), a life-threatening neurological symptom affecting more than 80% of patients with liver cirrhosis. However, its low molecular weight (LMW) causes Orn to diffuse nonspecifically and be rapidly eliminated from the body after oral administration, resulting in unfavorable therapeutic efficacy. Hence, Orn is constantly supplied by intravenous infusion in many clinical settings; however, this treatment inevitably decreases patient compliance and limits its application in long-term management. To improve the performance of Orn, we designed self-assembling polyOrn-based nanoparticles for oral administration through ring-opening polymerization of Orn-N-carboxy anhydride initiated with amino-ended poly(ethylene glycol), followed by acylation of free amino groups in the main chain of the polyOrn segment. The obtained amphiphilic block copolymers, poly(ethylene glycol)-block-polyOrn(acyl) (PEG-block-POrn(acyl)), enabled the formation of stable nanoparticles (Nano) in aqueous media. We employed the isobutyryl (iBu) group for acyl derivatization in this study (Nano). In the healthy mice, daily oral administration of Nano for one week did not induce any abnormalities. In the mice exhibiting acetaminophen (APAP)-induced acute liver injury, oral pretreatment with Nano effectively reduced systemic ammonia and transaminases levels compared to the LMW Orn and untreated groups. The results suggest that the application of Nano is of significant clinical value with the feasibility of oral delivery and improvement in APAP-induced hepatic pathogenesis. STATEMENT OF SIGNIFICANCE: Liver injury is often accompanied by hyperammonemia, a life-threatening condition characterized by elevated blood ammonia levels. Current clinical treatments for reducing ammonia typically entail the invasive approach of intravenous infusion, involving the administration of l-ornithine (Orn) or a combination of Orn and -aspartate. This method is employed due to the poor pharmacokinetics associated with these compounds. In our pursuit of enhancing therapy, we have developed an orally administrable nanomedicine based on Orn-based self-assembling nanoparticle (Nano), which provides sustained Orn supply to the injured liver. Oral administration of Nano to healthy mice did not cause any toxic effects. In a mouse model of acetaminophen-induced acute liver injury, oral administration of Nano surpassed Orn in reducing systemic ammonia levels and liver damage, thereby establishing Nano as a safe and effective therapeutic option.
l-鸟氨酸（Orn）是一种核心氨基酸，通过肝脏尿素循环负责体内氨的解毒。Orn 治疗的临床研究集中在干预与高氨血症相关的疾病，如肝性脑病（HE），这是一种危及生命的神经系统症状，影响超过 80%的肝硬化患者。然而，其低分子量（LMW）导致 Orn 非特异性扩散，并在口服后迅速从体内消除，导致治疗效果不理想。因此，在许多临床情况下，Orn 通过静脉输注不断供应；然而，这种治疗不可避免地降低了患者的依从性，并限制了其在长期管理中的应用。为了改善 Orn 的性能，我们通过 Orn-N-羧酸酐的开环聚合设计了自组装的聚 Orn 基纳米粒子，该聚合由氨基封端的聚（乙二醇）引发，然后酰化聚 Orn 段主链上的游离氨基。所得两亲嵌段共聚物，聚（乙二醇）-嵌段-聚 Orn（酰基）（PEG-嵌段-POrn（酰基）），可在水介质中形成稳定的纳米粒子（Nano）。在这项研究中，我们采用异丁酰基（iBu）基团进行酰基衍生化（Nano）。在健康小鼠中，每周口服给予 Nano 一周不会引起任何异常。在乙酰氨基酚（APAP）诱导的急性肝损伤小鼠中，与低分子量 Orn 和未处理组相比，口服预处理 Nano 可有效降低系统氨和转氨酶水平。结果表明，Nano 的应用具有显著的临床价值，具有口服递送的可行性，并改善了 APAP 诱导的肝发病机制。意义声明：肝损伤常伴有高氨血症，这是一种危及生命的病症，其特征是血液氨水平升高。目前降低氨的临床治疗方法通常需要采用静脉输注的侵入性方法，涉及 l-鸟氨酸（Orn）或 Orn 和 -天冬氨酸的组合的给药。由于这些化合物的药代动力学不佳，因此采用了这种方法。在我们追求增强治疗的过程中，我们开发了一种基于 Orn 自组装纳米粒子的可口服纳米药物（Nano），它为受损的肝脏提供持续的 Orn 供应。口服给予 Nano 健康小鼠不会引起任何毒性作用。在乙酰氨基酚诱导的急性肝损伤小鼠模型中，口服给予 Nano 可降低系统氨水平和肝损伤，优于 Orn，从而确立了 Nano 作为一种安全有效的治疗选择。
