School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China; National-regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen University, Shenzhen, Guangdong 518055, China.
School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China; National-regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen University, Shenzhen, Guangdong 518055, China.
Int J Pharm. 2023 Oct 15;645:123359. doi: 10.1016/j.ijpharm.2023.123359. Epub 2023 Aug 29.
This study employed superficial ultrasound exposure of good ocular safety and a drug-loaded hydrogel of long residence time to enable transscleral delivery. First, we designed an acoustic adaptor to limit the ultrasound exposure depth to 1.59 mm to protect the posterior eye segments. Then, we optimized the alginate/polyacrylamide ratio (3:7) of a dual-crosslinked hydrogel to enable ultrasound-triggered release of model drug (70-kDa fluorescein isothiocyanate-conjugated dextran). Using fluorescence imaging to quantify the drug release, we showed that the developed method resulted in enhanced transscleral delivery in both ex vivo porcine scleras (2.6-fold) and in vivo rabbit scleras (2.2-fold). We also demonstrated that the method increased the drug penetration depth to the whole thickness of the sclera. In particular, the drug release efficiency increased with increasing ultrasound exposure time (1 and 3 min) and intensity (8, 19, 36, and 61 mW/cm). Using scanning electron microscopy, we revealed that ultrasound exposure resulted in rougher surfaces and microscale rupture of the hydrogel. Moreover, Masson staining of scleral slices showed that the integrity of the top scleral fibers was disturbed by ultrasound exposure, and this disturbance recovered 3 days later. Our work demonstrates that the developed method holds great potential for mediating ocular drug delivery.
本研究采用具有良好眼部安全性的表面超声照射和具有长驻留时间的载药水凝胶来实现经巩膜递药。首先，我们设计了一个声适配体将超声照射深度限制在 1.59mm 以保护后眼部。然后，我们优化了藻酸盐/聚丙烯酰胺（3:7）双交联水凝胶的比例，以实现模型药物（70kDa 荧光素异硫氰酸酯标记的葡聚糖）的超声触发释放。使用荧光成像定量药物释放，我们表明所开发的方法在离体猪巩膜（2.6 倍）和体内兔巩膜（2.2 倍）中均实现了增强的经巩膜递药。我们还表明该方法增加了药物渗透到巩膜全厚度的深度。特别是，药物释放效率随超声照射时间（1 和 3 分钟）和强度（8、19、36 和 61mW/cm）的增加而增加。使用扫描电子显微镜，我们揭示了超声照射导致水凝胶表面更粗糙和微尺度破裂。此外，巩膜切片的 Masson 染色显示，超声照射会干扰顶部巩膜纤维的完整性，这种干扰在 3 天后恢复。我们的工作表明，所开发的方法在介导眼部药物递送方面具有很大的潜力。
