Polyketal microparticles: A new delivery vehicle for superoxide dismutase
Polyketal microparticles: A new delivery vehicle for superoxide dismutase
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DOI：
10.1021/bc060259s
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Murthy, Niren
中科院分区：
文献类型：
--
作者：
Lee, Sungmun;Yang, Stephen C.;Murthy, Niren
目前人们对开发能够增强蛋白质向巨噬细胞的递送的微粒非常感兴趣。在本次交流中，我们提出了一种用于药物输送的新型酸敏感聚合物，聚（环己烷-1,4-二基丙酮二亚甲基缩酮）（PCADK）。 PCADK 旨在被巨噬细胞吞噬后，在吞噬体的酸性环境中水解，并增强吞噬治疗药物的细胞内递送。 PCADK 用于药物输送的其他关键属性是其特征明确的降解产物和简单的合成。 PCADK 水解成 1,4-环己烷二甲醇（一种用于食品包装的化合物）和丙酮（FDA GRAS 清单上的一种化合物）。 PCADK是利用1,4-环己烷二甲醇和2,2-二甲氧基丙烷之间的缩醛交换反应合成的，并且可以一步获得数克规模的产物。 PCADK 中缩酮键的水解动力学通过 H-1 NMR 测量，并被确定为 pH 敏感的，在 pH 4.5 下半衰期为 24.1 天，在 pH 7.4 下半衰期超过 4 年。使用双乳化程序将治疗性酶超氧化物歧化酶 (SOD) 封装到基于 PCADK 的微粒中，该酶可清除活性氧。细胞培养实验表明，基于 PCADK 的微粒显着提高了 SOD 清除巨噬细胞产生的活性氧的能力。基于 PCADK 的酸敏感性、良好表征的降解产物和简单的合成，我们预计 PCADK 在药物输送中会有大量应用。
There is currently great interest in developing microparticles that can enhance the delivery of proteins to macrophages. In this communication, we present a new acid-sensitive polymer for drug delivery, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK). PCADK is designed to hydrolyze, after phagocytosis by macrophages, in the acidic environment of the phagosome and enhance the intracellular delivery of phagocytosed therapeutics. Other key attributes of PCADK for drug delivery are its well-characterized degradation products and straightforward synthesis. PCADK hydrolyzes into 1,4-cyclohexanedimethanol, a compound used in food packaging, and acetone, a compound on the FDA GRAS list. PCADK was synthesized using the acetal exchange reaction between 1,4-cyclohexanedimethanol and 2,2-dimethoxypropane, and could be obtained on a multigram scale in one step. The hydrolysis kinetics of the ketal linkages in PCADK were measured by H-1 NMR and were determined to be pH-sensitive, having a half-life of 24.1 days at pH 4.5 and over 4 years at pH 7.4. The therapeutic enzyme superoxide dismutase (SOD), which scavenges reactive oxygen species, was encapsulated into PCADK-based microparticles using a double emulsion procedure. Cell culture experiments demonstrated that PCADK-based microparticles dramatically improved the ability of SOD to scavenge reactive oxygen species produced by macrophages. We anticipate numerous applications of PCADK in drug delivery, based on its acid sensitivity, well-characterized degradation products, and straightforward synthesis.