Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Southern Renmin Road, No. 17, Section 3, Chengdu 610041, PR China.
Int J Pharm. 2013 Nov 1;456(1):223-34. doi: 10.1016/j.ijpharm.2013.07.064. Epub 2013 Aug 21.
Mycophenolic acid has played an important role in treating immunosuppression and autoimmune diseases. Nevertheless, the agent needs a high dosage in treatment, following some side effects. To tackle this problem, in this study, mycophenolic acid-glucosamine conjugate (MGC), modified by 2-glucosamine, was synthesized to achieve kidney targeting and improved drug efficacy with a lower dosage. (1)H NMR, (13)C NMR and HRMS spectroscopy were used to verify the conjugate whose stability was good in vitro. The transport of MGC by human proximal renal tubular epithelial HK-2 cells was temperature-, time-, concentration-dependent and saturable, suggesting the involvement of carrier-mediated uptake. In addition, the cellular uptake of MGC dropped substantially with the inhibition of megalin receptor. The specific tissue distribution indicated the commendable renal-targeting capability of MGC. The concentration of MGC was improved in the kidney except for other tissues, about 6.76 times higher than that of MPA. Further, the bioavailability of MGC in plasma decreased as compared with mycophenolic acid. Moreover, therapeutic effect of MGC was enhanced significantly compared with MPA in the acute kidney injury model. All the findings suggested the potential of mycophenolic acid-glucosamine conjugate in kidney targeted drug delivery.
麦考酚酸在治疗免疫抑制和自身免疫性疾病方面发挥了重要作用。然而，该药物在治疗中需要高剂量，随之会产生一些副作用。为了解决这个问题，在本研究中，通过 2-氨基葡萄糖对麦考酚酸进行了修饰，合成了麦考酚酸-氨基葡萄糖缀合物（MGC），以实现肾脏靶向，并以较低剂量提高药物疗效。（1）H NMR、（13）C NMR 和高分辨率质谱（HRMS）光谱用于验证该缀合物，其体外稳定性良好。MGC 可被人近端肾管状上皮细胞（HK-2）以温度、时间和浓度依赖的方式摄取，且呈饱和状态，表明其涉及载体介导的摄取。此外，MGC 的细胞摄取量随着巨球蛋白受体的抑制而显著下降。特定的组织分布表明 MGC 具有良好的肾脏靶向能力。除其他组织外，MGC 在肾脏中的浓度显著提高，约为 MPA 的 6.76 倍。此外，与麦考酚酸相比，MGC 在血浆中的生物利用度降低。此外，与 MPA 相比，MGC 在急性肾损伤模型中的治疗效果显著增强。所有这些发现都表明麦考酚酸-氨基葡萄糖缀合物在肾脏靶向药物递送方面具有潜力。
