†Department of Chemical and Materials Engineering, University of Alberta, 116 Street and 85th Avenue, Edmonton T6G 2G6, Alberta, Canada.
Biomacromolecules. 2015 Jul 13;16(7):1978-86. doi: 10.1021/acs.biomac.5b00576. Epub 2015 Jun 3.
In this study, galactose-based nanogels were prepared by reversible addition-fragmentation chain transfer process to facilitate the targeted delivery of iodoazomycin arabinofuranoside (IAZA), a clinical drug for imaging solid hypoxic tumors, and evaluate its role in hypoxia-selective (radio)theranostic (therapy + diagnostic) management of therapy-resistant cancer cells. The nanogels have a cross-linked temperature-responsive core and a dense carbohydrate shell. Their thermoresponsive nature allowed the controlled encapsulation of IAZA drug for targeted delivery and release in hypoxic hepatocellular carcinoma via asialoglycoprotein receptor-mediated uptake. The synthesized nanogel-IAZA delivery systems demonstrated a stable, nonburst release of IAZA over 10 h with up to 0.6 mM loading capacity of IAZA within the nanogel. The cytotoxicity evaluations of the nanogels demonstrated that they are relatively nontoxic in multiple cell lines. The radiosensitization studies indicated that IAZA in encapsulated form offers a superior radiosensitization of hypoxic cells (sensitizer enhancement ratio for IAZA alone, 1.33; 1.62 for nanogel encapsulated IAZA). These studies suggest that galactose-based nanogels may serve as a versatile drug delivery system for IAZA (and other azomycin-based agents) and enable its hypoxia-selective multimodal theranostic applications to manage hypoxic solid (hepatocellular) tumors by facilitating position/single photon emission tomography-based imaging, external beam radiation therapy, and in situ molecular radiotherapy.
在这项研究中，通过可逆加成-断裂链转移过程制备了基于半乳糖的纳米凝胶，以促进碘代氮杂霉素阿拉伯呋喃糖苷（IAZA）的靶向递送，IAZA 是一种用于成像实体缺氧肿瘤的临床药物，并评估其在缺氧选择性（放射）治疗诊断（治疗+诊断）管理耐药癌细胞中的作用。纳米凝胶具有交联的温度响应性核和密集的碳水化合物外壳。它们的温度响应特性允许通过去唾液酸糖蛋白受体介导的摄取来控制 IAZA 药物的包封，以实现靶向递送至缺氧肝细胞癌中的释放。合成的纳米凝胶-IAZA 递药系统表现出稳定的、非爆发性的 IAZA 释放，在 10 小时内可达到高达 0.6mM 的纳米凝胶内 IAZA 的载药量。纳米凝胶的细胞毒性评估表明，它们在多种细胞系中相对无毒。放射增敏研究表明，包封形式的 IAZA 可提供缺氧细胞的优越放射增敏作用（单独使用 IAZA 的增敏比为 1.33；纳米凝胶包封的 IAZA 为 1.62）。这些研究表明，基于半乳糖的纳米凝胶可用作 IAZA（和其他氮杂霉素类药物）的多功能药物递送系统，并能够通过促进基于正电子发射断层扫描/单光子发射计算机断层扫描的成像、外部束放射治疗和原位分子放射治疗来实现其缺氧选择性的多模式治疗诊断应用，以治疗缺氧实体（肝细胞）肿瘤。
