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A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound.

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.

SUBMITTER: Kato S

PROVIDER: S-EPMC4643085 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound.

Kato Shigeki S Mori Shiro S Kodama Tetsuya T

Journal of Cancer 20151020 12

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 th ...[more]

PMID: 26640589

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Project description:BackgroundLymph node metastasis constitutes a key event in tumor progression. The molecular control of this process is poorly understood. Heparan sulfate is a linear polysaccharide consisting of unique sulfate-modified disaccharide repeats that allow the glycan to bind a variety of proteins, including chemokines. While some chemokines may drive lymphatic trafficking of tumor cells, the functional and genetic importance of heparan sulfate as a possible mediator of chemokine actions in lymphatic metastasis has not been reported.ResultsWe applied a loss-of-function genetic approach employing lymphatic endothelial conditional mutations in heparan sulfate biosynthesis to study the effects on tumor-lymphatic trafficking and lymph node metastasis. Lymphatic endothelial deficiency in N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in sulfating nascent heparan sulfate chains, resulted in altered lymph node metastasis in tumor-bearing gene targeted mice. This occurred in mice harboring either a pan-endothelial Ndst1 mutation or an inducible lymphatic-endothelial specific mutation in Ndst1. In addition to a marked reduction in tumor metastases to the regional lymph nodes in mutant mice, specific immuno-localization of CCL21, a heparin-binding chemokine known to regulate leukocyte and possibly tumor-cell traffic, showed a marked reduction in its ability to associate with tumor cells in mutant lymph nodes. In vitro modified chemotaxis studies targeting heparan sulfate biosynthesis in lymphatic endothelial cells revealed that heparan sulfate secreted by lymphatic endothelium is required for CCL21-dependent directional migration of murine as well as human lung carcinoma cells toward the targeted lymphatic endothelium. Lymphatic heparan sulfate was also required for binding of CCL21 to its receptor CCR7 on tumor cells as well as the activation of migration signaling pathways in tumor cells exposed to lymphatic conditioned medium. Finally, lymphatic cell-surface heparan sulfate facilitated receptor-dependent binding and concentration of CCL21 on the lymphatic endothelium, thereby serving as a mechanism to generate lymphatic chemokine gradients.ConclusionsThis work demonstrates the genetic importance of host lymphatic heparan sulfate in mediating chemokine dependent tumor-cell traffic in the lymphatic microenvironment. The impact on chemokine dependent lymphatic metastasis may guide novel therapeutic strategies.

Project description:BACKGROUND:Papillary thyroid carcinoma is a type of indolent tumor with a dramatically increasing incidence rate and stably high survival rate. Reducing the overdiagnosis and overtreatment of papillary thyroid carcinoma is clinically emergent and important. A radiomics model is proposed in this article to predict lymph node metastasis, the most important risk factor of papillary thyroid carcinoma, based on noninvasive routine preoperative ultrasound images. METHODS:Four hundred fifty ultrasound manually segmented images of patients with papillary thyroid carcinoma with lymph node status obtained from pathology report were enrolled in our retrospective study. A radiomics evaluation of 614 high-throughput features were calculated, including size, shape, margin, boundary, orientation, position, echo pattern, posterior acoustic pattern, and calcification features. Then, combined feature selection strategy was used to select features with the greatest ability to discriminate lymph node status. A support vector machine classifier was employed to build and validate the prediction model. Another independent testing cohort was used to further evaluate the performance of the radiomics model. RESULTS:Among 614 radiomics features, 50 selected features most reflecting echo pattern, posterior acoustic pattern, and calcification showed the superior lymph node status distinguishable performance with area under the receiver operating characteristic curve of 0.753, 0.740, and 0.743 separately when using each type of features predicting the lymph node status. The results of model based on all 50 final features predicting the lymph node status shown an area under the receiver operating characteristic curve of 0.782, and accuracy of 0.712. In the independent testing cohort, the proposed approach showed similar results, with area under the receiver operating characteristic curve of 0.727 and accuracy of 0.710. CONCLUSION:Papillary thyroid carcinoma with lymph node metastasis usually shows a complex echo pattern, posterior region homogeneity, and macrocalcification or multiple calcification. The radiomics model proposed in this article is a promising method for assessing the risk of papillary thyroid carcinoma metastasis noninvasively.

Dataset Information

A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound.

Publications

A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound.

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