氧化鈰奈米粒子與薑黃素用於肌少症預防之研究

Abstract

肌少症為肌力以及肌肉量或質低於標準以下、且可能伴隨身體功能表現不良的現象。肌力的下降造成患者出現容易跌倒、走路速度緩慢、從椅子上起身困難等生活上極大的不便，並且主觀上容易感到疲倦、力不從心。再者肌少症患者預後多半不佳，有容易跌倒、骨折與失能風險增加的情形，且常見共病症（comorbidity）而導致更高死亡風險，以上無論對病患或照顧者皆造成長期生活、心理及經濟上的負擔。然而目前針對肌少症的治療方式仍有效果不足、存在副作用或需每天給藥的缺點，因此迫切需要一個有效、安全性高且能維持長期療效的治療方式。 許多因素已經被指出與肌少症的形成有關，但相關機轉仍未完全明瞭；而氧化壓力對於老化的貢獻於近幾十年來受到相當的重視，更被指出在骨骼肌的老化與肌少症的形成中扮演了重要角色，其能夠同時影響骨骼肌纖維中蛋白質合成、分解、apoptosis等pathway，並且會與發炎反應相互影響造成更嚴重的結果。因此本研究結合氧化鈰奈米粒子（cerium oxide nanoparticle, CONP）的長效抗氧化能力與薑黃素（curcumin）的抗氧化、抗發炎能力，利用長效配合短效 agent 的共同作用，並直接經由肌肉注射於患部，期望長效緩解老化肌肉細胞之氧化壓力與發炎狀態，達到預防肌少症的效果。 本研究於材料部分合成出粒徑約為20 nm之CONP，於水溶液中傾向團聚，平均粒徑上升至約140 nm。晶體為立方螢石型結構，表面包含三價與四價鈰離子並且比表面積落於正常範圍內，顯示其具有一定的催化能力與抗氧化能力。 In vitro的部分，CONP與CCONP之材料生物相容性均符合ISO 10993-5的標準，並且能夠預防小鼠myoblasts受到氧化傷害導致細胞死亡、有效清除ROS及降低IL-6、TNF-α、Atrogin-1及Caspase-3基因表現，具有增加肌肉細胞存活並減少蛋白質流失的潛力。 In vivo的部分，CCONP組有較顯著的效果，抓力測試結果顯示能夠增強老化小鼠上肢肌力，並且MRI結果顯示能夠提升腿部肌肉之質與量，但於滾輪跑步機測試及肌肉拉伸試驗雖可見平均測試結果之提升然而無統計上差異。

Sarcopenia is characterized by progress loss of muscle strength and mass during aging, and is an important predictor of poor quality of life, disability, and mortality. Although many factors have been involved, the pathophysiology of sarcopenia is still not completely understood. In recent decades, while the contribution of oxidative stress to aging has received significant attention, oxidative stress is also been suggested as playing an important role in skeletal muscle aging and the progression of sarcopenia. It simultaneously influence protein synthesis, protein degradation, and apoptosis pathways, and can interact with inflammation state to exacerbate muscle atrophy. Therefore, in this study we utilize the combination of the long-term antioxidant effect of cerium oxide nanoparticles (CONP) and the antioxidant and anti-inflammatory effect of curcumin to treat sarcopenic muscle via intramuscular injection. The material analysis showed that the particle size of CONP synthesized in this study is around 20 nm, and CONPs tend to agglomerate to reach an average size of around 140 nm. It also demonstrated that CONP crystallizes in the fluorite structure. Furthermore, the results of XRD and gas adsorption method respectively showed that the surface of CONP contains Ce3+ and Ce4+, and the specific surface area of CONP is in normal range. These two results mean that the CONP we synthesized has catalytic and antioxidative ability. In vitro analysis showed that the biocompatibility of CONP and CCONP both meets the requirement of ISO 10993-5, and the materials can effectively reduce ROS level and have the potential to increase muscle cell viability and reduce protein degradation. The effect of CCONP group is more evident for in vivo analysis. It showed that the muscle strength of forelimbs was improved in grip strength test, and the leg muscle quality and quantity were increased in MRI analysis. However, the results of rotarod test and tensile test showed no significant difference between the control group and experimental groups.