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Published on: December 15, 2010
Evaluation of antitumor effects following tumor necrosis factor-α gene delivery using nanobubbles and ultrasound
Sachiko Horie1, Yukiko Watanabe, Masao Ono
1Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
Abstract:
The antitumor effects of tumor necrosis factor (TNF-α) were evaluated following transfection of TNF-α plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 × 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-α (5 μg/μL) or TNF-α mock plasmid DNA (5 μg/μL) with/without NBs (15 μL) and saline was injected intratumorally in a total volume of 30 μL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-α, caspase-3, and p53 were quantified using real-time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-α gene delivery using NBs and US can lead to the local production of TNF-α. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-α gene delivery into tumor cells.
Insights
Tumor necrosis factor-alpha (TNF-α) gene delivery using nanobubbles and ultrasound effectively reduced tumor size by activating apoptosis and decreasing tumor vessels. This novel gene therapy shows promise for cancer treatment.
Area of Science:
- Oncology
- Gene Therapy
- Biomedical Engineering
Background:
- Solid tumors pose a significant challenge in cancer therapy.
- Effective gene delivery systems are crucial for targeted cancer treatments.
- Tumor necrosis factor-alpha (TNF-α) has known antitumor properties.
Purpose of the Study:
- To evaluate the antitumor effects of TNF-α gene delivery.
- To assess the efficacy of nanobubbles (NBs) and ultrasound (US) as a gene delivery system for TNF-α.
- To investigate the mechanisms underlying TNF-α mediated tumor suppression.
Main Methods:
- TNF-α plasmid DNA was delivered into murine breast carcinoma tumors using NBs and US.
- Tumor growth was monitored using bioluminescent imaging and calipers.
- Tumor vascularization was assessed via contrast-enhanced US and immunohistochemistry (CD31).
- Gene and protein expression (TNF-α, caspase-3, p53) were analyzed using RT-PCR and immunohistochemistry.
Main Results:
- Repeated TNF-α gene delivery via NBs and US successfully induced local TNF-α production.
- Significant reduction in tumor size was observed.
- Activation of p53-dependent apoptosis and decreased tumor vessel density were confirmed.
- NBs and US demonstrated effectiveness for intratumoral gene delivery.
Conclusions:
- Nanobubble and ultrasound-mediated TNF-α gene delivery is an effective strategy for cancer treatment.
- This approach leads to apoptosis and anti-angiogenic effects, suppressing tumor growth.
- The study highlights the potential of NBs and US as a non-invasive gene therapy tool.
