Abstract：
The preferable choice of sustained peptide delivery systems is generally polymer-based microspheres in which their large particle size, wide size distribution, low drug encapsulation efficacy, poor colloidal stability, and undesirable burst release eventually hinder their clinical translation. In this study, a nanoscale ternary Lixisenatide (Lix) sustained delivery system based on strong multivalent interactions (electrostatic and coordination complexation) among small molecular phytic acid (PA), Lix and Fe3+ was developed. Flash nanocomplexation (FNC) was utilized to facilitate the rapid and efficient mixing of the three components and kinetically control the assembly process that enabled dynamic balance of two competitive chemical reactions with different kinetic rates (slow chemical reaction of PA/Lix and fast chemical reaction of PA/Fe3+) to generate structural uniform ternary nanoparticles and avoid heterogeneous complexes. By tuning the mixing conditions (i.e., flow rate, mass ratio, concentration, pH value, etc.), the ternary PA/Lix/Fe3+ nanoparticles were assembled with reproducible production in a manner of high uniformity and scalability, achieving small size (∼50 nm), uniform composition (PDI: ∼0.12), favourable colloidal stability, high encapsulation efficiency (∼100%), and tunable drug release kinetics. The optimized formulation exhibited a minor Lix release (<20%) in the first day and extended peptide release period over 8 days. Unexpectedly, upon a single injection administration, the as-prepared formulation (600 μg/kg) rapidly brought the high BGL (∼30 mmol/L) back to normal range (<10 mmol/L) within the initial 6 h and achieved a 180 h glycemic control in T2D mouse model. Moreover, this sustained peptide delivery system demonstrated a repeatable hypoglycemic effects and significantly suppressed the pathological damage of major organs following multiple injection. This sustained peptide delivery system with aqueous, facile and reproducible preparation process possesses good biocompatibility, tunable release kinetics, and prolonged hypoglycemic effects, portending its great translational potential in the chronic disease treatment.
摘要：
持续肽递送系统的优选选择通常是基于聚合物的微球，其中它们的大粒径，宽尺寸分布，药物包封功效低，胶体稳定性差，和不良的爆发释放最终阻碍了他们的临床翻译。在这项研究中,基于小分子植酸（PA）之间的强多价相互作用（静电和配位络合）的纳米级三元Lixisenatie（Lix）持续递送系统，发展了Lix和Fe3+。利用Flash纳米络合（FNC）来促进三种组分的快速有效混合，并动力学控制组装过程，从而实现具有不同动力学速率的两个竞争性化学反应（PA/Lix的缓慢化学反应和PA/Fe3的快速化学反应）的动态平衡，以生成结构均匀的三元纳米颗粒并避免异质复合物。通过调整混合条件(即，流量,质量比,浓度,pH值,等。),三元PA/Lix/Fe3+纳米粒子以高度均匀性和可扩展性的方式进行组装，实现小尺寸(~50纳米)，均匀成分(PDI：~0.12)，良好的胶体稳定性，高封装效率(100%)，和可调的药物释放动力学。优化的制剂在第一天表现出少量的Lix释放(<20%),并且在8天内表现出延长的肽释放期。出乎意料的是,在单次注射后，在T2D小鼠模型中,所制备的制剂(600μg/kg)在最初6小时内迅速将高BGL(~30mmol/L)恢复到正常范围(<10mmol/L),并实现180小时血糖控制。此外，这种持续的肽递送系统表现出可重复的降血糖作用,并显著抑制多次注射后主要器官的病理损伤.这种持续的肽递送系统具有水性，制备工艺具有良好的生物相容性,可调释放动力学，和长期的降血糖作用，预示了其在慢性病治疗中巨大的转化潜力。
