Yang Wende, Qiu Chen, Zhai Jiancheng, Zhang Wei, Huang Chengwu, Shao Jun, Zhang Jingke, Chen Shigao, Miao Xiaoyan, Chen Peng, Wei Bo, Ren Jie, Wei Hongbo
Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China.
Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China.
Bioeng Transl Med. 2023 Jul 2;8(5):e10568. doi: 10.1002/btm2.10568. eCollection 2023 Sep.
Erectile dysfunction (ED) caused by cavernous nerve injury (CNI) is refractory to heal mainly ascribed to the adverse remodeling of the penis induced by ineffectual microvascular perfusion, fibrosis, and neurotrophins scarcity in cavernosum. Phosphodiesterase type V inhibitors (PDE5i) have been regarded as an alternative candidate drug for avoiding penile neuropathy. However, the therapeutic efficacy is severely limited due to poor accumulation under systemic medication and endogenous nitric oxide (NO) deficiency in cavernosum. Herein, an innovative liposomal microbubble (MB) loaded with both Sildenafil (one of PDE5i) and NO was designed. Ultrasound-targeted MB destruction (UTMD)-mediated efficient release and integration erectogenic agents into corpus cavernosum with high biosafety. On a bilateral CNI rat model, the multifunctional MB-cooperated UTMD improved microvascular perfusion in penis, simultaneously, alleviated hypoxia and oxidative stress, indicating successful activation of NO-cyclic guanosine monophosphate pathway. Also, evaluation of the endothelial/muscular composition, intracavernosal pressure, and neural integrity in the penis proved that coordinated intervention reversed the abnormal structural remodeling and promoted the recovery of functional erection. Our work demonstrates that MB loading Sildenafil and NO combined with UTMD hold great promise to "awaken" the efficacy of PDE5i in neurogenic ED, which provided a superior option for ensuring penile rehabilitation.
海绵体神经损伤（CNI）所致勃起功能障碍（ED）难以治愈，主要归因于阴茎海绵体内无效的微血管灌注、纤维化及神经营养因子缺乏所引发的不良重塑。5型磷酸二酯酶抑制剂（PDE5i）被视为避免阴茎神经病变的候选替代药物。然而，由于全身用药时药物蓄积不佳以及阴茎海绵体内内源性一氧化氮（NO）缺乏，其治疗效果受到严重限制。在此，设计了一种负载西地那非（一种PDE5i）和NO的创新型脂质体微泡（MB）。超声靶向微泡破坏（UTMD）介导将勃起剂高效释放并整合到阴茎海绵体中，且具有高生物安全性。在双侧CNI大鼠模型上，多功能MB联合UTMD改善了阴茎的微血管灌注，同时减轻了缺氧和氧化应激，表明成功激活了NO-环磷酸鸟苷途径。此外，对阴茎内皮/肌肉组成、海绵体内压及神经完整性的评估证明，协同干预逆转了异常的结构重塑并促进了功能性勃起的恢复。我们的研究表明，负载西地那非和NO的MB联合UTMD有望“唤醒”PDE5i在神经源性ED中的疗效，为确保阴茎康复提供了一个更好的选择。
