National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Int J Mol Sci. 2020 Mar 11;21(6):1922. doi: 10.3390/ijms21061922.
Methylprednisolone (MP) is often used in the treatment of various kidney diseases, but overcoming the systemic side effects caused by its nonspecific distribution in the body is a challenge. This article reports the design, synthesis, and renal targeting of methylprednisolone-lysozyme (MPS-LZM). This conjugate was obtained by covalently linking MP with the renal targeting carrier LZM through a linker containing an ester bond, which could utilize the renal targeting of LZM to deliver MP to renal proximal tubular epithelial cells and effectively release MP. The reaction conditions for the preparation of the conjugate were mild, and the quality was controllable. The number of drug payloads per LZM was 1.1. Cell-level studies have demonstrated the safety and endocytosis of the conjugate. Further pharmacokinetic experiments confirmed that, compared with that of free MP, the conjugate increased the renal exposure (AUC) of active MP from 17.59 to 242.18 h*ng/mL, and the targeting efficiency improved by approximately 14 times. Tissue and organ imaging further revealed that the conjugate could reach the kidneys quickly, and fluorescence could be detected in the kidneys for up to 12 h. This study preliminarily validates the feasibility of a renal targeting design strategy for MPS-LZM, which is expected to provide a new option for improving kidney-specific distribution of glucocorticoids.
甲泼尼龙（MP）常用于治疗各种肾脏疾病，但克服其在体内非特异性分布引起的全身副作用是一个挑战。本文报道了甲泼尼龙-溶菌酶（MPS-LZM）的设计、合成和肾脏靶向。该缀合物通过将 MP 与肾脏靶向载体 LZM 通过含有酯键的连接子连接而获得，该连接子可以利用 LZM 的肾脏靶向作用将 MP 递送至肾近端管状上皮细胞并有效释放 MP。缀合物的制备反应条件温和，质量可控。每个 LZM 的药物有效载药量为 1.1。细胞水平研究表明该缀合物的安全性和内吞作用。进一步的药代动力学实验证实，与游离 MP 相比，该缀合物将活性 MP 的肾脏暴露（AUC）从 17.59 增加到 242.18 h*ng/mL，靶向效率提高了约 14 倍。组织和器官成像进一步表明，该缀合物可以快速到达肾脏，并且在肾脏中可以检测到长达 12 小时的荧光。这项研究初步验证了 MPS-LZM 的肾脏靶向设计策略的可行性，有望为改善糖皮质激素的肾脏特异性分布提供新的选择。
