Saratov State University, 83 Astrakhanskaya str., Saratov 410012, Russia.
Saratov State University, 83 Astrakhanskaya str., Saratov 410012, Russia.
J Control Release. 2021 Jan 10;329:175-190. doi: 10.1016/j.jconrel.2020.11.051. Epub 2020 Dec 2.
Targeting drug delivery systems is crucial to reducing the side effects of therapy. However, many of them are lacking effectiveness for kidney targeting, due to systemic dispersion and accumulation in the lungs and liver after intravenous administration. Renal artery administration of carriers provides their effective local accumulation but may cause irreversible vessel blockage. Therefore, the combination of the correct administration procedure, suitable drug delivery system, selection of effective and safe dosage is the key to sparing local therapy. Here, we propose the 3-μm sized fluorescent capsules based on poly-L-arginine and dextran sulfate for targeting the kidney via a mice renal artery. Hemodynamic study of the target kidney in combination with the histological analysis reveals a safe dose of microcapsules (20 × 10), which has not lead to irreversible pathological changes in blood flow and kidney tissue, and provides retention of 20.5 ± 3% of the introduced capsules in the renal cortex glomeruli. Efficacy of fluorescent dye localization in the target kidney after intra-arterial administration is 9 times higher than in the opposite kidney and after intravenous injection. After 24 h microcapsules are not observed in the target kidney when the safe dose of carriers is being used but a high level of fluorescent signal persists for 48 h indicating that fluorescent cargo accumulation in tissues. Injection of non-safe microcapsule dose leads to carriers staying in glomeruli for at least 48 h which has consequences of blood flow not being restored and tissue damage being observed in histology.
靶向药物递送系统对于减少治疗的副作用至关重要。然而，由于许多药物在静脉给药后会系统性扩散并在肺部和肝脏中积聚，因此它们在肾脏靶向方面的效果并不理想。通过肾动脉给予载体可以实现其有效的局部积累，但可能导致不可逆转的血管阻塞。因此，正确的给药程序、合适的药物递送系统、有效和安全剂量的选择是实现局部治疗的关键。在这里，我们提出了基于聚 L-精氨酸和硫酸葡聚糖的 3μm 大小荧光胶囊，通过小鼠肾动脉靶向肾脏。目标肾脏的血液动力学研究结合组织学分析表明，微胶囊的安全剂量（20×10）不会导致血流和肾脏组织的不可逆病理变化，并提供了 20.5±3%的引入的胶囊在肾皮质肾小球中的保留。与静脉注射相比，经动脉内给药后荧光染料在目标肾脏中的定位效果高出 9 倍。当使用安全剂量的载体时，在 24 小时内不会在目标肾脏中观察到微胶囊，但荧光信号仍保持高水平达 48 小时，表明荧光货物在组织中的积累。注射非安全剂量的微胶囊会导致载体至少在 48 小时内留在肾小球中，从而导致血流无法恢复，并在组织学中观察到组织损伤。
