Guangdong Provincial Key Laboratory of Advanced Drug Delivery & Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System & Class III Laboratory of Modern Chinese Medicine Preparation & Key Laboratory of Modern Chinese Medicine of Education Department of Guangdong Province, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Guangdong Sunho Pharmaceutical Co. Ltd, Zhongshan 528437, China.
Eur J Pharm Sci. 2023 Aug 1;187:106490. doi: 10.1016/j.ejps.2023.106490. Epub 2023 Jun 7.
Hearing loss is mainly due to outer hair cell (OHC) damage in three cochlear turns. Local administration via the round window membrane (RWM) has considerable otological clinical potential in bypassing the blood-labyrinth barrier. However, insufficient drug distribution in the apical and middle cochlear turns results in unsatisfactory efficacy. We functionalized poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) with targeting peptide A665, which specifically bound to prestin, a protein uniquely expressed in OHCs. The modification facilitated the cellular uptake and RWM permeability of NPs. Notably, the guide of A665 towards OHCs enabled more NPs perfusion in the apical and middle cochlear turns without decreasing accumulation in the basal cochlear turn. Subsequently, curcumin (CUR), an appealing anti-ototoxic drug, was encapsulated in NPs. In aminoglycoside-treated guinea pigs with the worst hearing level, CUR/A665-PLGA NPs, with superior performance to CUR/PLGA NPs, almost completely preserved the OHCs in three cochlear turns. The lack of increased low-frequencies hearing thresholds further confirmed that the delivery system with prestin affinity mediated cochlear distribution rearrangement. Good inner ear biocompatibility and little or no embryonic zebrafish toxicity were observed throughout the treatment. Overall, A665-PLGA NPs act as desirable tools with sufficient inner ear delivery for improved efficacy against severe hearing loss.
听力损失主要归因于三个耳蜗转中的外毛细胞（OHC）损伤。通过圆窗膜（RWM）进行局部给药具有绕过血迷路屏障的相当大的耳科学临床潜力。然而，由于药物在耳蜗顶部和中部的分布不足，导致疗效不理想。我们用靶向肽 A665 对聚（乳酸-共-乙醇酸）纳米颗粒（PLGA NPs）进行了功能化，该肽特异性结合于 prestin，这是一种仅在外毛细胞中表达的蛋白质。这种修饰促进了 NPs 的细胞摄取和 RWM 通透性。值得注意的是，A665 引导 NPs 向 OHCs 的方向移动，使更多的 NPs 在耳蜗顶部和中部转中灌注，而不会减少在耳蜗底部转中的积累。随后，将有吸引力的抗耳毒性药物姜黄素（CUR）封装在 NPs 中。在氨基糖苷类药物处理的听力水平最差的豚鼠中，CUR/A665-PLGA NPs 的表现优于 CUR/PLGA NPs，几乎完全保留了三个耳蜗转中的 OHCs。没有增加低频听力阈值进一步证实了该递药系统通过与 prestin 亲和力介导的耳蜗分布重排来发挥作用。在整个治疗过程中，观察到良好的内耳生物相容性和很少或没有胚胎斑马鱼毒性。总的来说，A665-PLGA NPs 是一种有前途的工具，具有足够的内耳传递能力，可提高对严重听力损失的疗效。
