Liao Ai-Ho, Wang Chih-Hung, Wang Bo-Han, Lin Yi-Chun, Chuang Ho-Chiao, Liu Hao-Li, Shih Cheng-Ping
Graduate Institute of Biomedical Engineering National Taiwan University of Science and Technology Taipei Taiwan.
Department of Biomedical Engineering National Defense Medical Center Taipei Taiwan.
Bioeng Transl Med. 2022 Nov 16;8(5):e10450. doi: 10.1002/btm2.10450. eCollection 2023 Sep.
We have previously applied ultrasound (US) with microbubbles (MBs) to enhance inner ear drug delivery, with most experiments conducted using single-frequency, high-power density US, and multiple treatments. In the present study, the treatment efficacy was enhanced and safety concerns were addressed using a combination of low-power-density, single-transducer, dual-frequency US ( = 213 mW/cm) and MBs of different sizes coated with insulin-like growth factor 1 (IGF-1). This study is the first to investigate the drug-coating capacity of human serum albumin (HSA) MBs of different particle sizes and their drug delivery efficiency. The concentration of HSA was adjusted to produce different MB sizes. The drug-coating efficiency was significantly higher for large-sized MBs than for smaller MBs. In vitro Franz diffusion experiments showed that the combination of dual-frequency US and large MB size delivered the most IGF-1 (24.3 ± 0.47 ng/cm) to the receptor side at the second hour of treatment. In an in vivo guinea pig experiment, the efficiency of IGF-1 delivery into the inner ear was 15.9 times greater in animals treated with the combination of dual-frequency US and large MBs (D-USMB) than in control animals treated with round window soaking (RWS). The IGF-1 delivery efficiency was 10.15 times greater with the combination of single-frequency US and large size MBs (S-USMB) than with RWS. Confocal microscopy of the cochlea showed a stronger distribution of IGF-1 in the basal turn in the D-USMB and S-USMB groups than in the RWS group. In the second and third turns, the D-USMB group showed the greatest IGF-1 distribution. Hearing assessments revealed no significant differences among the D-USMB, S-USMB, and RWS groups. In conclusion, the combination of single-transducer dual-frequency US and suitably sized MBs can significantly reduce US power density while enhancing the delivery of large molecular weight drugs, such as IGF-1, to the inner ear.
我们之前已将超声（US）与微泡（MBs）联用，以增强内耳药物递送，大多数实验采用单频、高功率密度超声并进行多次治疗。在本研究中，通过低功率密度、单换能器、双频超声（= 213 mW/cm²）与涂有胰岛素样生长因子1（IGF-1）的不同大小微泡相结合的方法，提高了治疗效果并解决了安全问题。本研究首次探究了不同粒径人血清白蛋白（HSA）微泡的药物包载能力及其药物递送效率。通过调整HSA浓度以产生不同大小的微泡。大尺寸微泡的药物包载效率显著高于小尺寸微泡。体外弗兰兹扩散实验表明，在治疗的第二小时，双频超声与大尺寸微泡相结合向受体侧递送的IGF-1最多（24.3 ± 0.47 ng/cm²）。在体内豚鼠实验中，双频超声与大微泡（D-USMB）联合治疗的动物内耳中IGF-1的递送效率比圆窗灌注（RWS）治疗的对照动物高15.9倍。单频超声与大尺寸微泡（S-USMB）联合使用时IGF-1的递送效率比RWS高10.15倍。耳蜗共聚焦显微镜检查显示，D-USMB组和S-USMB组基底转中IGF-1的分布比RWS组更强。在第二和第三转中，D-USMB组的IGF-1分布最广。听力评估显示，D-USMB组、S-USMB组和RWS组之间无显著差异。总之，单换能器双频超声与合适大小的微泡相结合可显著降低超声功率密度，同时增强大分子量药物（如IGF-1）向内耳的递送。
