基于动态层层组装膜的延时释放载体研究

Unlike ordinary drug carriers, delayed release drug carriers do not release drug immediately, but start to release drug after a predetermined lag time. Erodible polymers were commonly used as barrier layers for the design of delayed release drug carriers, in which the lag time is determined by the erosion of the barrier layer. However, the erosion of the two types of erodible polymers presently used in delayed release drug carriers is quite complicated, making the lag time is difficult to control. Here we propose that dynamic layer-by-layer assembled films may be a new type of erodible material for the delayed release of drugs, especially macromolecular drugs, such as proteins. Dynamic layer-by-layer assembled films are fabricated using dynamic bonds as driving forces. Because of the reversibility of dynamic bonds, these films gradually disintegrate when soaked in water. Particularly when both components in the film have a narrow molecular weight distribution, the film disintegrates at a constant rate. The time for the film to complete disintegration is proportional to the film thickness, therefore these films will be ideal erodible material for delayed release drug carriers. Under this project dynamic films will be fabricated using hydrogen bonds and phenylboronate ester bonds as driving forces. They will then be used as barrier layer to achieve delayed release of protein drugs. By using films with different thickness as barrier layers, multiple pulse release of the same drug and programmed release of several different drugs will be further achieved.

与常见的控释载体不同，延时释放载体在给药后并不立即释放药物，而是在经过一段预先设定的延迟时间（lag time）后才释放药物。使用可溶蚀（Erodible）聚合物构筑隔离层、利用其在水相中缓慢溶蚀的特性可实现药物的延时释放。现有的两类可溶蚀聚合物溶蚀机理复杂，因此难以调控载体的延迟时间。本项目提出动态层层组装膜作为一种新的可溶蚀材料，可望用于延时释放体系的设计，特别是蛋白质等大分子药物的延时释放。动态层层组装膜是以动态键为驱动力组装的层层组装膜，由于动态键的可逆性，动态组装膜可在水中缓慢解离。特别地，当膜中两个组分均具有窄的分子量分布时，动态膜以恒定的速率解离，其解离时间与膜厚成正比，因此是理想的可溶蚀材料。拟以氢键和苯硼酸酯键为动态键构筑动态层层组装膜，实现药物的延时释放，并进一步实现同一药物的多次脉冲释放和不同药物的程序释放。

延时释放属非常规释药动力学，虽经长期研究仍难以实现。现有可溶蚀聚合物溶蚀机理及行为非常复杂，难以调控延迟释放时间。本项目首次提出以溶蚀机理明确、溶蚀速度恒定的动态层层组装膜为新的可溶蚀材料，实现对延迟时间的精确控制，并进一步实现同一药物的多次脉冲释放和不同药物的程序释放。首先以氢键动态层层组装膜TA/PEG为溶蚀层成功实现了延迟释放，通过控制TA/PEG膜的厚度实现了对延迟时间的精确控制。进一步以该延迟释放体系为基础提出了可实现任意次脉冲释放、并可精确控制每次释放时间点的高度可编程的程序释放体系，该体系是现有功能最强大的程序释放体系。进一步利用这一功能强大的程序释放体系，通过实现蛋白抗原的多次脉冲释放，模拟普通免疫程序抗原的释放动力学，一次注射即可达到普通疫苗多次注射的免疫效果，成功地实现了“一针免疫”，解决了四十多年“一针免疫”难以实现的问题。