School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangdong Research Center for Functional Biomaterials Engineering and Technology, Sun Yat-sen University, Guangzhou 510275, China; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
J Control Release. 2019 May 10;301:119-128. doi: 10.1016/j.jconrel.2019.03.014. Epub 2019 Mar 17.
Exendin-4 has been clinically adopted as an effective drug for treating type 2 diabetes (T2D), but its short circulation half-life in the blood requires two injections per day to maintain effective glycemic control. This significantly limits its clinical application. In this study, we developed a tannic acid/exendin-4/Fe ternary nanoparticle system to provide sustained release of exendin-4 in vivo. The formation of these nanoparticles relies on TA/exendin-4 complexation and stabilization through TA-Fe coordination, where the rapid reaction kinetics can benefit from efficient mixing of all three components. Adapting our recently developed flash nanocomplexation (FNC) method, we formulated nanoparticles with high encapsulation efficiency (~ 100%) of exendin-4, high payload capacity, and high degrees of uniformity and stability because the rapid turbulent mixing facilitated a homogeneous distribution of all three components in the complexation process. Intraperitoneal injection in mice showed that exendin-4 released from the nanoparticles had an AUC 7.2-fold higher than the free exendin-4 injection. Efficacy study in a T2D mouse model showed that the optimized formulation achieved a rapid reduction of the blood glucose level to the normal range within <12 h and maintained the same level for 72 h following a single intraperitoneal dose. The blood glucose level was maintained to below the therapeutic level (< 15 mmol/L) for 6 days, and the treatment led to reduced body weight with pathological and functional improvements in the kidney and liver. This tannic acid/exendin-4/Fe ternary nanoparticle system holds translational potential in treating T2D, due to its improved treatment outcomes in terms of extended release of exendin-4, prolonged control of blood glucose level, reduced dosing frequency, and improved pathological indicators.
Exendin-4 已被临床采用作为治疗 2 型糖尿病（T2D）的有效药物，但由于其在血液中的循环半衰期较短，每天需要注射两次才能维持有效的血糖控制。这极大地限制了其临床应用。在本研究中，我们开发了一种单宁酸/Exendin-4/Fe 三元纳米粒子系统，以提供体内 Exendin-4 的持续释放。这些纳米粒子的形成依赖于 TA/Exendin-4 络合和通过 TA-Fe 配位的稳定，其中快速的反应动力学可以受益于所有三种成分的高效混合。我们采用最近开发的闪络纳米复合（FNC）方法，将 Exendin-4 的包封效率（~100%）、高载药量以及高度均匀性和稳定性的纳米粒子进行配方设计，因为快速的湍流混合促进了络合过程中所有三种成分的均匀分布。在小鼠中的腹腔内注射表明，从纳米粒子中释放的 Exendin-4 的 AUC 比游离 Exendin-4 注射高 7.2 倍。在 T2D 小鼠模型中的功效研究表明，优化的配方在单次腹腔内给药后<12 h 内迅速将血糖水平降低到正常范围，并在 72 h 内维持相同水平。血糖水平维持在治疗水平（<15 mmol/L）以下 6 天，并且治疗导致体重减轻，同时改善了肾脏和肝脏的病理和功能。由于 Exendin-4 的延长释放、血糖水平的延长控制、减少给药频率以及改善的病理指标，这种单宁酸/Exendin-4/Fe 三元纳米粒子系统在治疗 T2D 方面具有转化潜力。
