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Published on: December 15, 2010
A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and
Shigeki Kato1, Shiro Mori2, Tetsuya Kodama1
11. Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi 980-8575, Japan.
Abstract:
Chemotherapy based on hematogenous administration of drugs to lymph nodes (LNs) located outside the surgically resected area shows limited tissue selectivity and inadequate response rates, resulting in poor prognosis. Here, we demonstrate proof of concept for a lymphatic drug delivery system using nano/microbubbles (NMBs) and ultrasound (US) to achieve sonoporation in LNs located outside the dissection area. First, we demonstrated the in vitro effectiveness of doxorubicin (Dox) delivered into three different tumor cell lines by sonoporation. Sonoporation increased the Dox autofluorescence signal and resulted in a subsequent decrease in cell viability. Next, we verified the antitumor effects of Dox in vivo using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs reaching 10 mm in diameter. We defined the subiliac LN (SiLN) as the upstream LN within the dissection area, and the proper axillary LN (PALN) as the downstream LN outside the dissection area. Dox and NMBs were injected into the SiLN and delivered to the PALN via lymphatic vessels; the PALN was then exposed to US when it had filled with solution. We found that sonoporation enhanced the intracellular uptake of Dox leading to high cytotoxicity. We also found that sonoporation induced extravasation of Dox from lymphatic endothelia and penetration of Dox into tumor tissues within the PALN. Furthermore, our method inhibited tumor growth and diminished blood vessels in the PALN while avoiding systemic toxic effects of Dox. Our findings indicate that a lymphatic drug delivery system with sonoporation represents a promising method for treating metastatic LNs located outside the dissection area.
Insights
This study introduces a novel lymphatic drug delivery system using nano/microbubbles and ultrasound to enhance chemotherapy effectiveness in lymph nodes outside the surgical area. This sonoporation technique improves drug uptake and tumor treatment while minimizing systemic toxicity.
Area of Science:
- Oncology
- Nanotechnology
- Medical Imaging & Diagnostics
Background:
- Conventional chemotherapy struggles with poor tissue selectivity and inadequate response rates for lymph nodes outside the resection area.
- Metastatic lymph nodes often lead to poor patient prognosis due to limited treatment options.
Purpose of the Study:
- To demonstrate a proof-of-concept for a lymphatic drug delivery system utilizing nano/microbubbles (NMBs) and ultrasound (US) for targeted sonoporation in lymph nodes.
- To evaluate the efficacy of doxorubicin (Dox) delivered via this system for treating lymph node metastasis outside the dissection area.
Main Methods:
- In vitro sonoporation of doxorubicin (Dox) into three tumor cell lines to assess drug uptake and cytotoxicity.
- In vivo study using MXH10/Mo-lpr/lpr mice with lymphadenopathy, delivering Dox and NMBs into an upstream lymph node (SiLN) for transport to a downstream lymph node (PALN).
- Application of ultrasound to the PALN to induce sonoporation and evaluate drug delivery, tumor inhibition, and vascular effects.
Main Results:
- Sonoporation significantly enhanced intracellular Dox uptake and cytotoxicity in vitro.
- In vivo, sonoporation increased Dox extravasation from lymphatic vessels and penetration into tumor tissues within the PALN.
- The lymphatic drug delivery system effectively inhibited tumor growth and reduced blood vessels in the PALN, without causing systemic Dox toxicity.
Conclusions:
- Lymphatic drug delivery combined with sonoporation is a promising strategy for treating metastatic lymph nodes beyond the surgical resection margins.
- This approach offers improved drug delivery, enhanced therapeutic effects, and reduced systemic side effects compared to conventional chemotherapy.
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