Pegylated zinc protoporphyrin: A water-soluble heme oxygenase inhibitor with tumor-targeting capacity
Pegylated zinc protoporphyrin: A water-soluble heme oxygenase inhibitor with tumor-targeting capacity
复制标题
DOI：
10.1021/bc020010k
复制
发表时间：
2002-09-01
影响因子：
4.7
通讯作者：
Maeda, H
中科院分区：
文献类型：
--
作者：
Sahoo, SK;Sawa, T;Maeda, H
血红素加氧酶（HO）是血红素代谢的关键酶；它将血红素氧化降解为胆绿素，并伴有游离铁和一氧化碳的形成。胆绿素随后被胞质胆绿素还原酶还原成胆红素，一种有效的抗氧化剂。我们最近发现肿瘤细胞利用HO通过产生抗氧化胆红素来保护自己免受氧化应激。这一结果提示了一个重要的潜在治疗策略：使用HO抑制剂抑制胆红素的产生；因此，癌细胞容易受到抗癌药物或宿主白细胞诱导的氧化应激的影响。这一概念通过在非生理溶液中使用HO抑制剂原卟啉锌动脉内给药得到了验证。本研究将原卟啉锌（ZnPP）与分子量为5000的聚乙二醇（PEG）偶联，制备了水溶性化合物（PEG-ZnPP），提高了其肿瘤靶向效率。通过在原卟啉的C6和C7上加入乙二胺残基，将PEG偶联到ZnPP上。将二价锌阳离子螯合到原卟啉环上，得到PEG-ZnPP。PEG-ZnPP确实具有高度水溶性，并且在水介质中与大于70 kDa的分子形成多分子缔合。PEG-ZnPP在血红素存在下以竞争方式抑制脾微粒体HO活性，表观抑制常数为0.12 muM。最重要的是，在小鼠实体瘤模型中，静脉注射PEG-ZnPP可显著抑制肿瘤内HO活性，这表明使用PEG-ZnPP可实现肿瘤靶向抑制HO。
Heme oxygenase (HO) is a key enzyme in heme metabolism; it oxidatively degrades heme to biliverdin, accompanied by formation of free iron and carbon monoxide. Biliverdin is subsequently reduced by cytosolic biliverdin reductase to form bilirubin, a potent antioxidant. We recently found that tumor cells utilize HO to protect themselves from oxidative stress by producing the antioxidant bilirubin. This result suggested an important potential therapeutic strategy: suppression of bilirubin production with the use of HO inhibitors; hence, cancer cells become vulnerable to oxidative stress induced by anticancer drugs or leukocytes of the host. This concept was validated by using the intraarterial administration of an HO inhibitor, zinc protoporphyrin, in nonphysiological solution. In the present study, zinc protoporphyrin (ZnPP) was conjugated with poly(ethylene glycol) (PEG) with molecular weight of 5000, to make ZnPP, a water-soluble compound (PEG-ZnPP), and to improve its tumor-targeting efficiency. PEG was conjugated to ZnPP through newly introduced amino groups, where ethylenediamine residues were added at C6 and C7 of protoporphyrin. The divalent zinc cation was chelated into the protoporphyrin ring to obtain PEG-ZnPP. PEG-ZnPP did become highly water-soluble, and it formed multimolecular associations with molecules larger than 70 kDa in aqueous media. PEG-ZnPP inhibited splenic microsomal HO activity in vitro in a competitive manner in the presence of hemin, with an apparent inhibitory constant of 0.12 muM. Most important, PEG-ZnPP injected intravenously significantly suppressed intratumor HO activity in a murine solid tumor model, which suggests that tumor-targeted inhibition of HO is possible with the use of PEG-ZnPP.