Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.
Bioconjug Chem. 2009 Aug 19;20(8):1419-40. doi: 10.1021/bc800431d. Epub 2009 Feb 10.
Hemoglobin (Hb, Mw: 64 500) and albumin (Mw: 66 500) are major protein components in our circulatory system. On the basis of bioconjugate chemistry of these proteins, we have synthesized artificial O(2) carriers of two types, which will be useful as transfusion alternatives in clinical situations. Along with sufficient O(2) transporting capability, they show no pathogen, no blood type antigen, biocompatibility, stability, capability for long-term storage, and prompt degradation in vivo. Herein, we present the latest results from our research on these artificial O(2) carriers, Hb-vesicles (HbV) and albumin-hemes. (i) HbV is a cellular type Hb-based O(2) carrier. Phospholipid vesicles (liposomes, 250 nm diameter) encapsulate highly purified and concentrated human Hb (35 g/dL) to mimic the red blood cell (RBC) structure and eliminate side effects of molecular Hb such as vasoconstriction. The particle surface is modified with PEG-conjugated phospholipids, thereby improving blood compatibility and dispersion stability. Manipulation of physicochemical parameters of HbV, such as O(2) binding affinity and suspension rheology, supports the use of HbV for versatile medical applications. (ii) Human serum albumin (HSA) incorporates synthetic Fe(2+)porphyrin (FeP) to yield unique albumin-based O(2) carriers. Changing the chemical structure of incorporated FeP controls O(2) binding parameters. In fact, PEG-modified HSA-FeP showed good blood compatibility and O(2) transport in vivo. Furthermore, the genetically engineered heme pocket in HSA can confer O(2) binding ability to the incorporated natural Fe(2+)protoporphyrin IX (heme). The O(2) binding affinity of the recombinant HSA (rHSA)-heme is adjusted to a similar value to that of RBC through optimization of the amino acid residues around the coordinated O(2).
血红蛋白（Hb，Mw：64500）和白蛋白（Mw：66500）是我们循环系统中的主要蛋白质成分。基于这些蛋白质的生物缀合化学，我们合成了两种类型的人工 O2 载体，它们将作为临床情况下输血的替代品非常有用。它们具有足够的 O2 运输能力，没有病原体、没有血型抗原、生物相容性、稳定性、长期储存能力以及在体内迅速降解的能力。在此，我们介绍了我们在这些人工 O2 载体（Hb-囊泡（HbV）和白蛋白血红素）研究方面的最新成果。（i）HbV 是一种基于细胞的 Hb 型 O2 载体。磷脂囊泡（脂质体，直径 250nm）包裹高度纯化和浓缩的人 Hb（35g/dL），以模拟红细胞（RBC）结构并消除分子 Hb 的副作用，如血管收缩。颗粒表面用 PEG 修饰的磷脂进行修饰，从而提高血液相容性和分散稳定性。HbV 的物理化学参数的操纵，如 O2 结合亲和力和悬浮流变学，支持 HbV 用于多种医疗应用。（ii）人血清白蛋白（HSA）结合合成的 Fe2+卟啉（FeP），从而产生独特的基于白蛋白的 O2 载体。改变结合的 FeP 的化学结构可以控制 O2 结合参数。事实上，PEG 修饰的 HSA-FeP 在体内表现出良好的血液相容性和 O2 转运。此外，HSA 中的基因工程血红素口袋可以赋予结合的天然 Fe2+原卟啉 IX（血红素）O2 结合能力。通过优化配位 O2 周围的氨基酸残基，重组 HSA（rHSA）-血红素的 O2 结合亲和力被调整到与 RBC 相似的值。
