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. 2020 Jan 29:13:889-902.
doi: 10.2147/OTT.S238126. eCollection 2020.

Sonophoresis Enhanced Transdermal Delivery of Cisplatin in the Xenografted Tumor Model of Cervical Cancer

Shanshan Ma #  1 , Chang Liu #  1 , Bo Li  1 , Tingting Zhang  1 , Li Jiang  1 , Rensheng Wang  1
Affiliations

Sonophoresis Enhanced Transdermal Delivery of Cisplatin in the Xenografted Tumor Model of Cervical Cancer

Shanshan Ma et al. Onco Targets Ther. .

Abstract

Background: 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.

Methods: 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/cm2 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.

Results: 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.

Conclusion: 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.

Keywords: cervical cancer; cisplatin; sonophoresis; transdermal drug delivery.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Weight change curve of nude mice (g) during intervention (n=8). (B) Tumor volume change curve of nude mice (g) during intervention (n=8). (C) Tumor weight of mice in the different groups on day 5 (n=8). (D) Representative tumors from mice in the different groups on day 5. ***P<0.001 versus the control group.
Figure 2
Figure 2
(A) Chromatogram of cisplatin standards and representative chromatogram of each group. (B) Standard curve of DDTC-cisplatin. (C) Relative concentration of cisplatin in the different groups on day 5 (n=8). ***P<0.001 versus the control group.
Figure 3
Figure 3
Histological images from the major organs of mice in the different groups on day 5. Tissues were collected from the tumor, skin, kidney and liver. Images were taken at ×400 magnification with standard hematoxylin and eosin (HE) staining. The arrow indicated the areas of inflammatory cell infiltration.
Figure 4
Figure 4
Representative TEM×1700 images of tumor, skin, kidney and liver in each group.
Figure 5
Figure 5
(A) MPO expression in each group (n=8). (B) Caspase-3 expression in each group (n=8). (C) The results of TUNEL assay in each group (n=8). (D) PCNA expression in each group (n=8). *P<0.05, **P<0.01 and ***P<0.001versus the control group.
Figure 6
Figure 6
Representative immunohistochemical images of each factor in the different groups on day 5.
Figure 7
Figure 7
Representative immunofluorescence images of each factor in the different groups on day 5.
See this image and copyright information in PMC

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