School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
AAPS PharmSciTech. 2018 Aug;19(6):2610-2619. doi: 10.1208/s12249-018-1092-2. Epub 2018 Jun 18.
The complex design of multifunctional nanomedicine is beneficial to overcome the multiple biological barriers of drug delivery, but it also presents additional hurdles to clinical translation (e.g., scaling-up and quality control). To address this dilemma, we employed a simple imidazole-bearing polymer micelle for enhanced cellular uptake, facilitated endosomal escape, and on-demand release of a model drug, SN-38. The micelles were crosslinked by the reversible imidazole/Zn coordination with a drug loading of ca. 4% (w/w) and a diameter less than 200 nm. Under mimicked tumor microenvironment (pH 6.8), the surface charge of micelles reversed from negative to positive, leading to enhanced micelles uptake by model 4T1 cells. Such effect was verified by fluorescent labelling of micelles. Compared to imidazole-free nanocarriers, the charge-reversal micelles delivered significantly more SN-38 to 4T1 cells. Due to the proton sponge effect, imidazole-bearing micelles could rapidly escape from endosomes compared to the control micelles, as evidenced by the kinetic analysis of micelle/endosome co-localization. The coordination crosslinking also enabled the acid-triggered drug release. This work provides a "three birds with one stone" approach to achieve the multifunctionality of nanocarriers without complicated particle design, and opens new avenues of advancing nanomedicine translation via simple tailored nanocarriers.
多功能纳米医学的复杂设计有利于克服药物递送的多种生物屏障，但它也给临床转化带来了额外的障碍（例如，扩大规模和质量控制）。为了解决这个困境，我们采用了一种简单的含咪唑聚合物胶束来增强细胞摄取、促进内涵体逃逸和按需释放模型药物 SN-38。胶束通过可逆的咪唑/Zn 配位交联，药物载量约为 4%（w/w），直径小于 200nm。在模拟的肿瘤微环境（pH 6.8）下，胶束的表面电荷从负变为正，导致模型 4T1 细胞对胶束的摄取增强。这种效果通过胶束的荧光标记得到了验证。与不含咪唑的纳米载体相比，带电荷反转的胶束将更多的 SN-38 递送到 4T1 细胞中。由于质子海绵效应，含咪唑的胶束能够比对照胶束更快地从内涵体中逃逸，这可以通过胶束/内涵体共定位的动力学分析得到证明。配位交联还实现了酸触发的药物释放。这项工作提供了一种“一石三鸟”的方法，无需复杂的粒子设计即可实现纳米载体的多功能性，并通过简单的定制纳米载体为推进纳米医学转化开辟了新途径。
