抗氧化聚合物前药微球作为急性肝衰竭的治疗系统。
Antioxidant polymeric prodrug microparticles as a therapeutic system for acute liver failure.
机构信息
Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, South Korea.
Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, South Korea; Department of Polymer Nano Science and Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, South Korea.
出版信息
Biomaterials. 2014 Apr;35(12):3895-902. doi: 10.1016/j.biomaterials.2014.01.048. Epub 2014 Feb 5.
Acetaminophen (APAP) is the most widely used analgesic and its overdose, intentional or unintentional, is known to cause massive oxidative stress and liver tissue damages characterized by hepatocellular apoptosis and hemorrhagic necrosis, leading to acute liver failure (ALF). There has been great interest in the use of antioxidant and anti-inflammatory drugs for the effective treatment of ALF. Manganese porphyrin (MnP), a nonpeptidyl mimic of superoxide dismutase is a promising compound with antioxidant activity, but its application is curtailed by a short half-life in blood. We have recently developed a new family of biodegradable and antioxidant polymeric prodrug, poly(vanillyl alcohol-co-oxalate) (PVAX), which is able to scavenge H2O2 and release antioxidant and anti-inflammatory vanillyl alcohol. In this work, we developed MnP-loaded PVAX particles and evaluated their potential as antioxidant and anti-inflammatory therapeutic agents for APAP-induced ALF. PVAX particles and MnP showed synergistic antioxidant and anti-inflammatory activities in macrophages stimulated with LPS (lipopolysaccharide). Animal studies using a mouse model of APAP-induced ALF revealed that MnP-loaded PVAX particles significantly reduced the serum ALT level and protected liver damages. We anticipated that MnP-loaded PVAX particles have great potential as a therapeutic agent for oxidative stress-associated diseases such as APAP-induced ALF.
对乙酰氨基酚（APAP）是应用最广泛的镇痛药，其无论是故意还是无意的过量使用，都会导致大量的氧化应激和肝组织损伤，其特征是肝细胞凋亡和出血性坏死，从而导致急性肝衰竭（ALF）。人们对使用抗氧化剂和抗炎药物来有效治疗 ALF 非常感兴趣。锰卟啉（MnP）是一种超氧化物歧化酶的非肽模拟物，具有抗氧化活性，是一种很有前途的化合物，但由于其在血液中的半衰期短，其应用受到限制。我们最近开发了一种新型的可生物降解的抗氧化聚合物前药，聚（香草醇-草酸）（PVAX），它能够清除 H2O2 并释放抗氧化和抗炎性香草醇。在这项工作中，我们制备了负载 MnP 的 PVAX 颗粒，并评估了它们作为治疗 APAP 诱导的 ALF 的抗氧化和抗炎治疗剂的潜力。负载 MnP 的 PVAX 颗粒和 MnP 显示出与 LPS（脂多糖）刺激的巨噬细胞协同的抗氧化和抗炎活性。使用 APAP 诱导的 ALF 小鼠模型进行的动物研究表明，负载 MnP 的 PVAX 颗粒显著降低了血清 ALT 水平并保护了肝脏损伤。我们预计，负载 MnP 的 PVAX 颗粒具有很大的潜力成为治疗与氧化应激相关的疾病（如 APAP 诱导的 ALF）的治疗剂。
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