Zhang Zhiling, Wang Zhicheng, Nong Jia, Nix Camilla A, Ji Hai-Feng, Zhong Yinghui
School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
Biofabrication. 2015 Jan 20;7(1):015006. doi: 10.1088/1758-5090/7/1/015006.
This study reports the development of novel drug delivery complexes self-assembled by divalent metal ion-assisted coacervation for controlled and sustained release of a hydrophilic small drug molecule minocycline hydrochloride (MH). MH is a multifaceted agent that has demonstrated therapeutic effects in infection, inflammation, tumor, as well as cardiovascular, renal, and neurological disorders due to its anti-microbial, anti-inflammatory, and cytoprotective properties. However, the inability to translate the high doses used in experimental animals to tolerable doses in human patients limits its clinical application. Localized delivery can potentially expose the diseased tissue to high concentrations of MH that systemic delivery cannot achieve, while minimizing the side effects from systemic exposure. The strong metal ion binding-assisted interaction enabled high drug entrapment and loading efficiency, and stable long term release for more than 71 d. Released MH demonstrated potent anti-biofilm, anti-inflammatory, and neuroprotective activities. Furthermore, MH release from the complexes is pH-sensitive as the chelation between minocycline and metal ions decreases with pH, allowing 'smart' drug release in response to the severity of pathology-induced tissue acidosis. This novel metal ion binding-mediated drug delivery mechanism can potentially be applied to other drugs that have high binding affinity for metal ions and may lead to the development of new delivery systems for a variety of drugs.
本研究报道了通过二价金属离子辅助凝聚自组装形成的新型药物递送复合物，用于亲水性小分子药物盐酸米诺环素（MH）的控释和缓释。MH是一种多效性药物，因其抗菌、抗炎和细胞保护特性，已在感染、炎症、肿瘤以及心血管、肾脏和神经系统疾病中显示出治疗效果。然而，无法将实验动物中使用的高剂量转化为人类患者可耐受的剂量限制了其临床应用。局部递送可能使患病组织暴露于全身递送无法达到的高浓度MH中，同时将全身暴露的副作用降至最低。强大的金属离子结合辅助相互作用实现了高药物包封率和载药效率，并能稳定长期释放超过71天。释放出的MH表现出强大的抗生物膜、抗炎和神经保护活性。此外，复合物中MH的释放对pH敏感，因为米诺环素与金属离子之间的螯合作用随pH降低，从而能够根据病理诱导的组织酸中毒的严重程度实现“智能”药物释放。这种新型的金属离子结合介导的药物递送机制可能适用于对金属离子具有高结合亲和力的其他药物，并可能导致开发多种药物的新型递送系统。
