Ma Shanshan, Liu Chang, Li Bo, Zhang Tingting, Jiang Li, Wang Rensheng
Department of Radiotherapy, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.
Onco Targets Ther. 2020 Jan 29;13:889-902. doi: 10.2147/OTT.S238126. eCollection 2020.
Transdermal drug delivery system has been researched for a long time because of its advantage in decreasing side effects such as nausea, vomiting, and gastrointestinal disturbance. Sonophoresis has been shown to be very effective in promoting the transdermal delivery of drugs. This study is on purpose to research the feasibility of sonophoresis promoting cisplatin in the treatment of cervical cancer and the optimum drug delivery mode.
Thirty-two female nude-mice model of cervical cancer were randomly divided into 4 groups (n=8 in each group): control group without any intervention, low, medium and high concentration groups were treated with the corresponding cisplatin concentrations of 0.2mg/mL, 0.4mg/mL and 0.8mg/mL, respectively, with concurrent sonophoresis applied on the skin of local tumor, 1 mL at a time, once a day for a total of 5 days. Therapeutic pulsed ultrasound (TPU) was 1.0 MHz, 2.0 W/cm and 60-min duration. Weight of mice and tumor diameters were measured every day during the intervention. The concentration of cisplatin in tumors was detected by HPLC. Meanwhile, tumor, skin, liver and kidney gross structures and ultrastructure were observed in order to evaluate the effectiveness and safety of experimental conditions. In addition, apoptosis and proliferation-related factors (MPO, Caspase-3, PCNA) were detected by immunohistochemistry, immunofluorescence and TUNEL assay.
The weight of nude mice in each group showed an increasing trend, except for a decrease of weight in the 0.8 mg/mL group. No obvious tumor inhibition effect was observed. Cisplatin was detected in the 0.4 mg/mL group and 0.8 mg/mL group, with relative concentrations of 0.081±0.033 mg/mL and 0.111±0.021 mg/mL, respectively. Both skin and kidney inflammation were observed in the 0.8 mg/mL group. The expression of MPO, caspase-3 and TUNEL was concentration dependent, with the highest expression in the 0.8 mg/mL group, followed by the 0.4 mg/mL group, with no significant differences between the control and the 0.2 mg/mL group. PCNA was highly expressed in both the control and 0.2 mg/mL groups but decreased in the 0.4 mg/mL and 0.8 mg/mL groups.
Sonophoresis enhanced transdermal delivery of cisplatin in a xenograft tumor model of cervical cancer. Considering the occurrence of skin inflammation and renal injury caused by cisplatin, the recommended concentration to be administered is 0.4mg/mL.
由于透皮给药系统在减少恶心、呕吐和胃肠道紊乱等副作用方面具有优势，因此已被研究了很长时间。超声透入法已被证明在促进药物透皮递送方面非常有效。本研究旨在探讨超声透入法促进顺铂治疗宫颈癌的可行性及最佳给药方式。
将32只雌性宫颈癌裸鼠模型随机分为4组（每组n = 8）：对照组不进行任何干预，低、中、高浓度组分别用0.2mg/mL、0.4mg/mL和0.8mg/mL的相应顺铂浓度进行治疗，同时在局部肿瘤皮肤处施加超声透入法，每次1 mL，每天1次，共5天。治疗性脉冲超声（TPU）为1.0 MHz、2.0 W/cm²，持续60分钟。在干预期间每天测量小鼠体重和肿瘤直径。通过高效液相色谱法检测肿瘤中顺铂的浓度。同时，观察肿瘤、皮肤、肝脏和肾脏的大体结构和超微结构，以评估实验条件的有效性和安全性。此外，通过免疫组织化学、免疫荧光和TUNEL检测法检测凋亡和增殖相关因子（MPO、Caspase-3、PCNA）。
除0.8mg/mL组体重下降外，各组裸鼠体重均呈增加趋势。未观察到明显的肿瘤抑制作用。在0.4mg/mL组和0.8mg/mL组中检测到顺铂，相对浓度分别为0.081±0.033mg/mL和0.111±0.021mg/mL。在0.8mg/mL组中观察到皮肤和肾脏炎症。MPO、caspase-3和TUNEL的表达呈浓度依赖性，在0.8mg/mL组中表达最高，其次是0.4mg/mL组，对照组和0.2mg/mL组之间无显著差异。PCNA在对照组和0.2mg/mL组中均高表达，但在0.4mg/mL组和0.8mg/mL组中降低。
在宫颈癌异种移植肿瘤模型中，超声透入法增强了顺铂的透皮递送。考虑到顺铂引起的皮肤炎症和肾损伤的发生，推荐给药浓度为0.
