Polyethylene Glycol Camouflaged Earthworm Hemoglobin
Polyethylene Glycol Camouflaged Earthworm Hemoglobin
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DOI：
10.1371/journal.pone.0170041
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发表时间：
2017-01-18
期刊：
影响因子：
3.7
通讯作者：
Cabrales, Pedro
中科院分区：
文献类型：
--
作者：
Jani, Vivek P.;Jelvani, Alborz;Cabrales, Pedro
在美国，每年有近2100万份血液和全血成分被输血，而平均只有1360万单位的血液被捐献。随着人口老龄化对红细胞（rbc）的需求不断增加，这一赤字将更加显著。尽管数十年的研究开发血红蛋白（Hb）为基础的氧（O-2）载体（HBOCs）作为红细胞替代品，没有产品被批准用于临床应用。地蚓红蛋白（LtEc）是在地蚓中发现的携带O-2的大型脱细胞蛋白复合物。LtEc是一种非常稳定的蛋白质复合物，具有抗自氧化性，并且在输入哺乳动物体内时能够将O-2转运到组织中。这些特点使LtEc成为开发下一代hboc的一个有希望的候选者。LtEc在循环中的半衰期很短，这限制了它作为桥梁的应用，直到有血液可用。与聚乙二醇（PEG-LtEc）偶联可延长LtEc循环时间。本研究探讨PEG-LtEc的药代动力学和药效学。为了研究PEG-LtEc的药代动力学，采用背窗室对仓鼠进行10 g/dL PEG-LtEc或LtEc 40%换血，随访48小时。为研究PEG-LtEc的血管反应，采用背窗室装置，仓鼠多次注射10 g/dL PEG-LtEc或LtEc溶液，将血浆LtEc浓度分别提高到0.5、1.0和1.5 g/dL，同时监测动物的全身和微循环参数。结果证实，聚乙二醇化的LtEc增加了其循环时间，将半衰期延长至70小时，比未聚乙二醇化的LtEc长4倍。然而，聚乙二醇化增加了体内LtEc的氧化速率。血管分析证实PEG-LtEc显示没有微血管收缩或全身性高血压。与LtEc相比，PEG-LtEc的分子大小没有改变胶体渗透压或血容量扩张能力，这是由于LtEc的分子大小已经很大。综上所述，这些结果进一步促进了PEG-LtEc作为O-2载体治疗药物的发展。
Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O-2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O-2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O-2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O-2 carrying therapeutic.