Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China, Qingdao 266003, China.
School of Chemical Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Int J Pharm. 2022 Jan 5;611:121317. doi: 10.1016/j.ijpharm.2021.121317. Epub 2021 Nov 25.
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 Fe 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/Fe) 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/Fe 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.
基于高分子的微球是目前较受青睐的肽类药物控释载体，但存在粒径大、粒径分布宽、载药量低、胶体稳定性差和突释效应明显等缺点，限制了其临床转化。本研究构建了基于小分子植酸（PA）、艾塞那肽（Lix）和 Fe3+的强多价相互作用（静电和配位络合）的纳米级 Lix 三元持续释放系统。利用闪式纳米复合法（FNC）促进三种成分的快速高效混合，并通过动力学控制组装过程，实现两种竞争化学反应的动态平衡（PA/Lix 的缓慢化学反应和 PA/Fe 的快速化学反应），生成结构均一的三元纳米颗粒，避免形成异质复合物。通过调节混合条件（如流速、质量比、浓度、pH 值等），可以以高均一性和可扩展性的方式重现性地制备三元 PA/Lix/Fe 纳米颗粒，获得小粒径（∼50nm）、均一组成（PDI：∼0.12）、良好的胶体稳定性、高包封效率（∼100%）和可调节的药物释放动力学。优化后的配方在第一天的 Lix 释放量较小（<20%），并延长了肽类药物的释放周期至 8 天以上。出乎意料的是，单次注射给药后，所制备的配方（600μg/kg）在最初 6 小时内迅速将高血糖（∼30mmol/L）恢复到正常范围（<10mmol/L），并在 T2D 小鼠模型中实现 180 小时的血糖控制。此外，该持续肽类药物递送系统表现出可重复的降血糖效果，并在多次注射后显著抑制主要器官的病理损伤。该具有水相、简便、可重现的制备工艺的持续肽类药物递送系统具有良好的生物相容性、可调节的释放动力学和延长的降血糖效果，预示着其在慢性病治疗方面具有巨大的转化潜力。
