Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan.
Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan; Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan; Satellite Laboratory, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan.
Biomaterials. 2016 Apr;84:210-218. doi: 10.1016/j.biomaterials.2016.01.029. Epub 2016 Jan 19.
Although cancer immunotherapies are attracting much attention, it is difficult to develop bioactive proteins owing to the severe systemic toxicity. To overcome the issue, we designed new local protein delivery system by using a protein-loaded, redox-active, injectable gel (RIG), which is formed by a polyion complex (PIC) comprising three components, viz., cationic polyamine-poly(ethylene glycol)-polyamine triblock copolymer possessing ROS-scavenging moieties as side chains; anionic poly(acrylic acid); and a protein. The mixture formed the protein-loaded PIC flower micelles at room temperature, which immediately converted to a gel with high mechanical strength upon exposure to physiological conditions. Because the protein electrostatically interacts with the PIC gel network, RIG provided a sustained release of the protein without a significant initial burst, regardless of the types of proteins in vitro, and much longer retention of the protein at the local injection site in mice than that of the naked protein. Subcutaneous injections of IL-12@RIG in the vicinity of tumor tissue showed remarkable tumor growth inhibition in tumor-bearing mice, compared to that observed with injection of IL-12 alone, suppressing adverse events caused by IL-12-induced ROS. Our results indicate that RIG has potential as a platform technology for an injectable sustained-release carrier for proteins.
尽管癌症免疫疗法备受关注，但由于严重的全身毒性，很难开发生物活性蛋白。为了解决这个问题，我们设计了一种新的局部蛋白递药系统，使用载蛋白的氧化还原活性可注射凝胶（RIG），它由包含三个成分的聚离子复合物（PIC）组成，即具有 ROS 清除部分作为侧链的阳离子聚胺-聚（乙二醇）-聚胺三嵌段共聚物；阴离子聚丙烯酸；和一种蛋白质。该混合物在室温下形成载蛋白的 PIC 花状胶束，一旦暴露于生理条件下，立即转化为具有高机械强度的凝胶。由于蛋白质与 PIC 凝胶网络静电相互作用，RIG 提供了蛋白质的持续释放，而没有明显的初始突释，无论体外的蛋白质类型如何，并且在小鼠局部注射部位的蛋白质保留时间都明显长于裸蛋白。与单独注射 IL-12 相比，在肿瘤组织附近皮下注射 IL-12@RIG 可显著抑制荷瘤小鼠的肿瘤生长，抑制了由 IL-12 诱导的 ROS 引起的不良事件。我们的结果表明，RIG 作为蛋白质可注射持续释放载体的平台技术具有潜力。
