Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration.
Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration.
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阿霉素诱导的慢性心脏毒性及其脂质体给药的保护。
DOI：
10.5555/uri:pii:0093775484900460
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发表时间：
1982
期刊：
影响因子：
11.2
通讯作者：
P. Schein
中科院分区：
文献类型：
--
作者：
A. Rahman;N. More;P. Schein
在小鼠中以4 mg/kg的剂量静脉注射给药7次，从形态学上评价了游离药物或包埋在阳性和阴性脂质体中的多柔比星的慢性心脏毒性。脂质体由磷脂酰胆碱、胆固醇和硬脂胺（带正电荷）或磷脂酰丝氨酸（带负电荷）组成。游离阿霉素给药引起一种心脏损伤模式，其特征为肌纤维成分丢失、线粒体损伤、核异常、肌浆网肿胀和扩张导致空泡化，以及髓样体蓄积增加。用包埋在带负电荷的脂质体中的多柔比星处理的小鼠的心脏组织表现出明显的细丝损失、线粒体增大、嵴破坏性损失和核膜扩张。然而，用阳性脂质体处理的小鼠的心肌的电子显微镜检查证明了对药物诱导的毒性的显著保护，在有限的焦点区域中仅轻微损失平行原纤维排列和肌丝。与对照组相比，大部分组织显示出正常的血管系统和肌细胞嵌入。游离阿霉素和包埋在阴性脂质体中的毒性病变的平均定性和定量评分分别为2.7和2.23。然而，用阳性脂质体处理的小鼠组的平均评分仅为1.12，显示对心脏病变的程度和严重性的评分保护优于2倍。
The chronic cardiotoxicity of doxorubicin as a free drug or entrapped in positive and negative liposomes was morphologically evaluated in mice treated seven times i.v. at a dose of 4 mg/kg. Liposomes were composed of phosphatidylcholine, cholesterol, and stearylamine (positive charge) or phosphatidylserine (negative charge). Administration of free doxorubicin caused a pattern of cardiac damage characterized by loss of myofiber elements, mitochondrial damage, nuclear abnormalities, swollen and distended sarcoplasmic reticulum leading to vacuolization, and increasing myeloid body accumulation. Cardiac tissues of mice treated with doxorubicin entrapped in negatively charged liposomes demonstrated pronounced loss of filaments, enlarged mitochondria, disruptive loss of crests, and expanded nuclear membrane. However, electron microscopic examination of the cardiac muscles of mice treated with positive liposomes demonstrated a significant protection from drug-induced toxicity, with only minor loss of parallel fibrillar arrangement and myofilaments in limited focal areas. The majority of the tissue demonstrated normal vasculature and intercalation of myocytes as compared to control groups. The mean qualitative and quantitative scores of toxic lesions for free doxorubicin and entrapped in negative liposomes are 2.7 and 2.23, respectively. However, the mean score for the group of mice treated with positive liposomes is only 1.12, showing a better than 2-fold scoring protection of both the extent and severity of cardiac lesions.