Zhou Yinjian, Dong Ying, Huang Gang, Wang Yiguang, Huang Xiaonan, Zhang Fayun, Boothman David A, Gao Jinming, Liang Wei
Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390.
J Mater Chem B. 2016 Dec 14;4(46):7429-7440. doi: 10.1039/C6TB02049F. Epub 2016 Oct 21.
β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage. The conversion to β-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. β-lap aryl imine prodrug conjugated ultra pH-sensitive (UPS) polymer reached high β-lap loading density (8.3%) and exhibited dual-stages responsiveness to pH variation. In pHs under pH, at stage I, micelle immediately dissociation and subsequently entering stage II, micelles start quickly release β-lap. release study showed that the micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pH in 72 h, whereas boosted release of β-lap (79.4 ± 1.2%) at pH 5.0. Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently β-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to free drug in both efficacy and mechanism of cell death. The lysosome-oriented dual-stage ultra pH responsive β-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+ cancer therapies.
β-拉帕醌（β-lap）是一种新型抗癌剂，可被烟酰胺腺嘌呤二核苷酸磷酸（还原型）：醌氧化还原酶1（NQO1）生物激活，该酶在包括肺癌、胰腺癌、乳腺癌和前列腺癌在内的多种肿瘤中过表达。临床制剂（β-拉帕醌-羟丙基-β-环糊精复合物）的快速肾脏清除率以及高铁血红蛋白血症/溶血副作用阻碍了其临床应用。在此，我们研究了一种用于递送β-拉帕醌的双模式pH响应聚合物。三种pH敏感键，包括用于合成β-拉帕醌前药的酰腙键、缩酮键和亚胺键，结果表明芳基亚胺键是最理想的键。在pH 7.4、6.5和5.0条件下，8小时内转化为β-拉帕醌的比例分别为2.8%、4.5%和100%。β-拉帕醌芳基亚胺前药与超pH敏感（UPS）聚合物共轭，达到了高β-拉帕醌负载密度（8.3%），并对pH变化表现出双阶段响应。在pH值低于某一值时，在第一阶段，胶束立即解离，随后进入第二阶段，胶束开始快速释放β-拉帕醌。释放研究表明，在pH值高于某一值时，胶束在72小时内持续释放β-拉帕醌（14.9±0.1%），而在pH 5.0时β-拉帕醌的释放量增加（79.4±1.2%）。胶束在细胞内主要分布于溶酶体细胞器，确保了它们的pH响应解离以及随后β-拉帕醌的控释。M-P胶束在A549肺癌细胞中保留了NQO1依赖性细胞毒性，在疗效和细胞死亡机制方面与游离药物相似。面向溶酶体的双阶段超pH响应β-拉帕醌前药胶束可能为肺癌以及其他NQO1阳性癌症的治疗提供一种替代性的纳米治疗策略。
