Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México.
Centro de Investigación y de Estudios Avanzados del IPN, Unidad-Monterrey, Apodaca NL, México.
Ultrasound Med Biol. 2021 Jun;47(6):1559-1572. doi: 10.1016/j.ultrasmedbio.2021.02.003. Epub 2021 Mar 15.
In the endothelium, nitric oxide synthase (eNOS) is the enzyme that generates nitric oxide, a key molecule involved in a variety of biological functions and cancer-related events. Therefore, selective inhibition of eNOS represents an attractive therapeutic approach for NO-related diseases and anticancer therapy. Ultrasound-mediated microbubble destruction (UMMD) conjugated with cell-permeable peptides has been investigated as a drug delivery system for effective delivery of anticancer molecules. We investigated the feasibility of loading antennapedia-caveolin-1 peptide (AP-Cav), a specific eNOS inhibitor, onto microbubbles to be delivered by UMMD in rat aortic endothelium. AP-Cav-loaded microbubbles (AP-Cav-MBs) and US parameters were characterized. Aortas were treated with UMMD for 30 s with 1.3 × 10 MBs/mL AP-Cav (8 μM)-MBs at 100-Hz pulse repetition frequency, 0.5-MPa acoustic pressure, 0.5 mechanical index and 10% duty cycle. NO-dependent vascular responses were assessed using an isolated organ system, 21 h post-treatment. Maximal relaxation response was inhibited 61.8% ± 1.6% in aortas treated with UMMD-AP-Cav-MBs, while in aortas treated with previously disrupted AP-Cav-MBs and then US, the inhibition was 31.6% ± 1.6%. The vascular contractile response was not affected. The impact of UMMD was evaluated in aortas treated with free AP-Cav; 30 μM of free AP-Cav was necessary to reach an inhibition response similar to that obtained with UMMD-AP-Cav-MBs. In conclusion, UMMD enhances the delivery and potentiates the effect of AP-Cav in the endothelial layer of rat aorta segments.
在内皮细胞中，一氧化氮合酶（eNOS）是生成一氧化氮的酶，一氧化氮是参与多种生物功能和与癌症相关事件的关键分子。因此，选择性抑制 eNOS 代表了一种有吸引力的治疗方法，可用于与 NO 相关的疾病和抗癌治疗。超声介导的微泡破坏（UMMD）与细胞穿透肽结合已被研究作为一种药物输送系统，用于有效输送抗癌分子。我们研究了将一种特定的 eNOS 抑制剂，即触角足囊泡-1 肽（AP-Cav）加载到微泡中，通过 UMMD 在大鼠主动脉内皮细胞中递送的可行性。对载有 AP-Cav 的微泡（AP-Cav-MBs）和 US 参数进行了表征。用 1.3×10 MBs/mL AP-Cav（8 μM）-MBs 通过 UMMD 处理主动脉 30 s，脉冲重复频率为 100-Hz，声压为 0.5-MPa，机械指数为 0.5，占空比为 10%。在治疗后 21 h 使用离体器官系统评估 NO 依赖性血管反应。用 UMMD-AP-Cav-MBs 处理的主动脉的最大松弛反应抑制率为 61.8%±1.6%，而在用先前破坏的 AP-Cav-MBs 处理然后再用 US 处理的主动脉中，抑制率为 31.6%±1.6%。血管收缩反应不受影响。用游离 AP-Cav 处理的主动脉评估了 UMMD 的影响；需要 30 μM 的游离 AP-Cav 才能达到与 UMMD-AP-Cav-MBs 相同的抑制反应。总之，UMMD 增强了 AP-Cav 在大鼠主动脉段内皮层中的递释并增强了其作用。
