Tetsuya Kodama

• PhD(Eng) , PhD(Med)
• Professor (Full) at Tohoku University

Intravesical instillation of chemotherapy has been performed to reduce the risk of intravesical recurrence of bladder cancer. However, its antitumor effect is not necessarily sufficient, which may be partially due to inadequate delivery of intravesically administered chemotherapeutic agents to bladder tumors. Ultrasound irradiation to target tissue...

The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti‐CTLA‐4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic sy...

Gold nanorods (AuNRs) are powerful photothermal agents (PTAs) in cancer treatment due to their near-infrared laser light absorption ability. However, the cytotoxicity of AuNRs caused by the presence of cationic surfactants often used and their lack of specificity affect their application in photothermal therapy. Thus, we herein developed a bioconju...

A R T I C L E I N F O Keywords: Docetaxel Lymph node Lymphatic drug delivery system (LDDS) Longitudinal efficacy Double shot Single shot A B S T R A C T Recently, sentinel lymph nodes (LNs) have been recognized as a starting point of hematogenous metastasis; thus, an increase in the control rate of LN metastasis is expected to improve the survival...

We herein report, for the first time, the activity of copper indium selenide/zinc sulphide core-shell quantum dots (CISe/ZnS QDs) as an inhibitor against recombinant human furin, an enzyme that has been implicated in the aetiology of many diseases, including Covid-19. The cell viability of the as-synthesised CISe/ZnS QDs was tested against mouse co...

A R T I C L E I N F O Keywords: Lymph node metastasis Lymphatic drug delivery Epirubicin Nimustine Osmotic pressure Chemotherapy A B S T R A C T Lymph node metastasis (LNM) has a significant impact on cancer prognosis, emphasizing the need for effective treatment strategies. This study investigated the potential use of high osmotic pressure drug so...

The graphene-based materials have been used as a potential coating material for nanoparticles due to their excellent passivation. Herein, we report for the first time the colloidal stability, photothermal profile, thermal stability, cytotoxicity, and photo-cytotoxicity of graphene quantum dots (GQDs) coupled with the second infrared window (NIR-II)...

Background: Immune checkpoint blockade (ICB) elicits a strong and durable therapeutic response, but its application is limited by disparate responses and its associated immune-related adverse events (irAEs). Previously, in a murine model of lymph node (LN) metastasis, we showed that intranodal administration of chemotherapeutic agents using a lymp...

Near-infrared quantum dots (NIR QDs) with tunable fluorescence emission are promising materials for bioimaging applications. However, they face several challenges, including low photostability, reduced brightness, and poor fluorescence emission. Herein, we report the synthesis of NIR emitting colloidal Mn-doped CuInSe/ZnS QDs synthesised via the hy...

Background: Metastasis is the prime cause of cancer associated mortality. Lymph nodes (LNs) facilitate the systemic exposure of tumor cells, resulting in fatal systemic metastasis. Treatment of metastatic LNs is therefore imperative. However, successful treatment of metastatic LNs is challenging. Immune checkpoint inhibitor (ICI) therapy is an emer...

Chemotherapy using a lymphatic drug delivery system (LDDS) targeting lymph nodes (LNs) in the early stage of metastasis has a superior antitumor effect to systemic chemotherapy. LDDS produces a higher drug retention rate and tissue selectivity in LNs. To expand the therapeutic coverage of LDDS from local treatment of metastatic LNs to prevention of...

Treatment of metastatic lymph nodes (LNs) is challenging due to their unique architecture and biophysical traits. Systemic chemotherapy fails to impede tumor progression in LNs due to poor drug uptake and retention by LNs, resulting in fatal systemic metastasis. To effectively treat LN metastasis, achieving specific and prolonged retention of chemo...

Bioluminescence (BL) imaging is a powerful non-invasive imaging modality widely used in a broad range of biological disciplines for many types of measurements. The applications of BL imaging in biomedicine are diverse, including tracking bacterial progression, research on gene expression patterns, monitoring tumor cell growth/regression or treatmen...

A perfusion defect (PD) in non-enlarged lymph nodes (LNs) of oral squamous cell carcinoma (OSCC) is the most reliable radiological criterion for the diagnosis of metastasis. However, conventional contrast-enhanced (CE) T1 weighted images using turbo spin echo (TSE) sequence is limited in detecting PD in non-enlarged LNs due to flow artifacts from c...

Delivery of chemotherapeutic agents into metastatic lymph nodes (LNs) is challenging as they are unevenly distributed in the body. They are difficult to access via traditional systemic routes of drug administration, which produce significant adverse effects and low accumulation of drug into the cancerous LNs. To improve the survival rate of patient...

The cancer mortality rate has increased, and conventional cancer treatments are known for having many side effects. Therefore, it is imperative to find a new therapeutic agent or modify the existing therapeutic agents for better performance and efficiency. Herein, a synergetic phototherapeutic agent based on a combination of photothermal and photod...

A perfusion defect in a metastatic lymph node (LN) can be visualized as a localized area of low contrast on contrast-enhanced CT, MRI or ultrasound images. Hypotheses for perfusion defects include abnormal hemodynamics in neovascular vessels or a decrease in blood flow in pre-existing blood vessels in the parenchyma due to compression by LN tumor g...

Despite recent advances in diagnostic modalities and cancer treatment guidelines, systemic chemotherapy for the lymph node (LN) metastasis has poor treatment efficacy using conventional drugs. Therefore, a novel method, lymphatic drug delivery system (LDDS), has been proposed in a pre-clinical experiment that directly injects the anticancer drug in...

Metastasis is known to be the prime cause of cancer associated fatality. It is therefore imperative to treat and prevent metastasis in order to curb cancer-associated morbidity and mortality. Metastatic lymph nodes (MLNs) are known to be crucial diagnostic and prognostic indicators. Furthermore, as per the lymph node mediated hematogenous theory, d...

Metastatic lymph nodes (MLNs) are one of the most common causes of distant metastasis, and their presence signals a serious deterioration in the life prognosis of an affected patient. The treatment of MLNs at an early stage is necessary to inhibit metastases to distant LNs and organs. Radiation therapy is an effective therapeutic modality for local...

The link between the microbiome and cancer has led researchers to search for a potential probe for intracellular targeting of bacteria and cancer. Herein, we developed near infrared-emitting ternary AgInSe/ZnS quantum dots (QDs) for dual bacterial and cancer imaging. Briefly, water-soluble AgInSe/ZnS QDs were synthesized in a commercial kitchen pre...

The excellent photothermal properties of gold nanorods (Au-NRs) make them one of the most researched plasmonic photothermal nanomaterials. However, their biological applications have been hampered greatly due to surfactant-induced cytotoxicity. We herein report a simple synthesis of highly biocompatible gelatin stabilized Au-NRs (gelatin@Au-NRs) to...

Photothermal therapy has been established recently as a non-invasive treatment protocol for cancer metastatic lymph nodes. Although this treatment approach shows efficient tumour ablation towards lymph node metastasis, the monitoring and reporting of treatment progress using the lymphatic delivery channel still need to be explored. Herein, we inves...

Many studies of the autoimmune disease Sjögren's syndrome have been performed using spontaneous mouse models. In the present study, we describe the characteristics of McH/lpr-RA1 mice and propose their use as a novel murine model of autoimmune sialadenitis. The McH/lpr-RA1 mouse is a recombinant congenic strain derived from generation F54 or more o...

Lymph node (LN) metastasis is thought to account for 20–30% of deaths from head and neck cancer. The lymphatic drug delivery system (LDDS) is a new technology that enables the injection of drugs into a sentinel LN (SLN) during the early stage of tumor metastasis to treat the SLN and secondary metastatic LNs. However, the optimal physicochemical pro...

Conventional treatment for lymph node (LN) metastasis such as systemic chemotherapy have notable disadvantages that lead to the development of unwanted effects. Previously, we have reported the lymphatic administration of drugs into metastatic LNs using a lymphatic drug delivery system (LDDS). However, prior studies of the LDDS have not attempted t...

A perfusion defect in metastatic lymph nodes (LNs) can be visualized as a localized area of low contrast on contrast-enhanced CT, MRI or ultrasound images. Hypotheses for perfusion defect include abnormal hemodynamics in neovascular vessels and decrease in blood flow in pre-existing blood vessels in the parenchyma due to compression of tumor growth...

Cancer metastasis to lymph nodes (LNs) almost certainly contributes to distant metastasis. Elevation of LN internal pressure (intranodal pressure, INP) during tumor proliferation is associated with a poor prognosis for patients. We have previously reported that a lymphatic drug delivery system (LDDS) allows the direct delivery of anticancer drugs i...

Graphene oxide (GO) has been very useful in many applications however little is known about its toxicity in biological applications. Herein, we report the synthesis of GO and its cytotoxicity against four cancer (adherent and suspension) cell lines namely fibroblast histiocytoma (KM-Luc/GFP), breast (FM3A-Luc), ovarian (OV 2944-HM-1) and fibrosarco...

Therapies targeting tumor vasculature would improve the treatment of lung metastasis, although the early changes in vascular structure are incompletely understood. Here, we show that obstructive metastatic foci in lung arterioles decrease the pulmonary vascular network. To generate a mouse model of lung metastasis activation, luciferase-expressing...

Lymph node (LN) metastasis through the lymphatic network is a major route for cancer dissemination. Tumor cells reach the marginal sinuses of LNs via afferent lymphatic vessels (LVs) and form metastatic lesions that lead to distant metastasis. Thus, targeting of metastatic cells in the marginal sinuses could improve cancer treatment outcomes. Here,...

The lymphatic drug delivery system (LDDS) is a method that allows the injection of drugs into sentinel lymph nodes (SLNs) to facilitate their delivery to downstream lymph nodes (LNs) via the lymphatic network to treat or prevent cancer cell development in both LNs. A high concentration of drug is effectively maintained in both LNs. Here we show tha...

The lymphatic drug delivery system (LDDS) is a method that allows the injection of drugs into sentinel lymph nodes (SLNs) to facilitate their delivery to downstream lymph nodes (LNs) via the lymphatic network to treat or prevent cancer cell development in both LNs. A high concentration of drug is effectively maintained in both LNs. Here we show tha...

Background: McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of arthritis and enthesitis in McH...

Utilizing mice with swollen lymph nodes, we succeeded in irradiating individual metastatic lymph nodes through a hole in a lead shield. This system enabled us to increase the radiation dose to >8 Gy (the lethal dose for total-body irradiation) and evaluate both direct and abscopal antitumor effects.

Metastatic lymph nodes (LNs) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LNs at an early stage. False‐negative metastatic LNs, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape sim...

Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor‐bearing LN is involved in the activat...

Purpose Lymph node (LN) metastasis is detected prior to distant metastasis in many types of cancer. Detecting early stage LN metastasis can improve treatment outcomes. However, there are few clinical imaging modalities capable of diagnosing metastatic LNs of clinical N0 status (i.e., before their volume increases) with high precision. Here, we repo...

Aim: To investigate whether tumor cells in a lymph node (LN) can invade from the marginal sinus into extranodal veins via vessel branches that communicate with intranodal veins and whether this can be a starting point for hematogenous metastasis at the early stage of LN metastasis. Methods: Vascular and lymphatic networks of LNs in MXH10/Mo-lpr/lpr...

[Background] McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop arthritis in the ankle, leading finally to ankylosis. There is no published data that drug treatment has been trialed on these mice. [Objectives] This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of ankylosis in Mc...

Cancer metastasis is a major cause of death in cancer patients and metastatic lymph nodes (MLN) are associated with poor prognosis. In the field of breast cancer research, the role of MLN has been discussed for nearly a hundred years. Halsted formulated “Halsted theory”, whereby breast cancer spread through the lymphatic system first to nearby lymp...

Background: Surgical removal of primary tumors can promote the incidence of tumor metastasis. However, molecular mechanisms underlying this process remain unclear. Methods: We inoculated tumor cells expressing luciferase gene into subiliac lymph node (SiLN) of the MXH10/Mo-lpr/lpr mice. The tumor-bearing SiLNs were surgically removed at a certai...

Conventional treatment of lymph node metastasis involves dissection of the tumor and regional lymph nodes, but this may cause activation of latent metastatic tumor cells. However, there are few reports on animal models regarding the activation of latent metastatic tumor cells and effective methods of treating activated tumor cells. Here, we report...

The lymphatic drug delivery system (LDDS) is a new technique that permits the injection of drugs into a sentinel lymph node (SLN) at an early stage of tumor metastasis, thereby treating metastasis in the SLN and its secondary lymph nodes (LNs). The quantity of drug required for a LDDS is much smaller than that needed for systemic chemotherapy. Howe...

The acidic environment at bacterial infection sites is a potential external stimulus for targeted antibiotic delivery. This paper reports new biocompatible pH-sensitive lipids (PSLs) with three hydrocarbon tails, and a head group with a secondary amine and carboxylate function for site-specific nano delivery of vancomycin (VCM). PSLs formed stable...

Systemic administration of drugs into the blood circulation is a standard treatment for the prevention of metastasis. However, systemic delivery cannot maintain sufficiently high concentrations of anticancer drugs in lymphatic nodes (LNs). Here, we show that administering cisplatin (CDDP) using a lymphatic drug delivery system (LDDS) has the potent...

Systemic delivery of an anti-cancer agent often leads to only a small fraction of the administered dose accumulating in target sites. Delivering anti-cancer agents through the lymphatic network can achieve more efficient drug delivery for the treatment of lymph node metastasis. We show for the first time that polymeric gold nanorods (PAuNRs) can be...

Tumor metastasis to lymph nodes is an important contributory factor for cancer-related deaths despite recent developments in cancer therapy. In this study, we demonstrate that tumor in the proper axillary lymph node (PALN) of the mouse can be treated by the application of external laser light to trigger the unloading of doxorubicin (DOX) encapsulat...

Time-dependent alterations in the ultrasonography characteristics of lymph nodes during early-stage metastasis have not been compared with those of tumor-draining lymph nodes that do not develop tumor; this is partly due to the absence of an appropriate experimental model. In a previous study of lymph nodes with experimental early-stage metastasis,...

Cancer cells metastasize to lymph nodes, with distant metastasis resulting in poor prognosis. The role of lymph node metastasis (LNM) in the spread of cancer to distant organs remain incompletely characterized. The visualization of flow dynamics in the lymphatic and blood vessels of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of lymph no...

Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti-cancer drug enters the lymphatic system to reach metastatic lymph nodes (LNs). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stage...

We examined whether enhancement area ratios obtained by the new bubble detection method correlate with histologic microvessel density in invasive breast cancer. Forty consecutive patients with invasive breast cancer lesions underwent contrast-enhanced ultrasound. The ratio of enhanced area to manually segmented tumor area (enhancement area ratio) w...

The extended Bernoulli equation is formulated in an exact form for a microscopic and small Reynolds number Jeffery-Hamel flow in a two-dimensional convergent or divergent channel. The friction loss and the friction coefficient derived from the extended Bernoulli equation are also obtained for the purpose of engineering applications. The assumption...

We herein report a simple, economical and green synthesis of highly fluorescent, water soluble and stable arginine functionalised CdTe/CdSe/ZnSe multi core-shell nanoparticles (NPs) with enhanced cell viability for cellular imaging. The synthesis of the CdTe/CdSe/ZnSe NPs was carried out under ambient conditions in the absence of an inert environme...

Intravenous chemotherapy has poor access to metastatic lymph nodes (LNs) and is limited by short-lived drug concentrations. Here, we describe the administration of chemotherapy via the lymphatic network as a new concept for the prevention and treatment of metastatic LNs. A metastatic LN can be treated by the injection of drugs into an upstream LN,...

Vasohibin-1 (VASH1) was isolated as a negative-feedback regulator of angiogenesis expressed in endothelial cells (ECs). There are two transcripts of VASH1, that is, the full-length VASH1A consisting of seven exons and the splicing variant VASH1B consisting of four exons. Here, we compared the effects of VASH1A and VASH1B on tumor angiogenesis. When...

Table S1. Primer sequences used in this study.

Cancer is one of the major diseases that cause death all over the world. One of the first steps of metastasis is lymphatic metastasis. Systemic drug administration, which is major chemotherapeutic approach is of minor benefit for the metastatic lymph nodes and causes strong side effects. In our laboratory, we have studied on a novel drug delivery s...

Cancer is the leading cause of death in Japan, and most of the cancer patients die relation to the metastasis. However, there is still no reliable treatment for metastatic lymph nodes (LNs). In the present study, we propose a drug delivery method via lymph network for metastatic LNs using ultrasound and nano/micro bubbles. We used MXH10/Mo-lpr/lpr...

Cancer is one of the most common causes of death in modern society, and metastasis contributes its high mortality. Some types of cancer metastasize to the lymph node, and trigger to the distant metastasis, resulting in poor prognosis. Immigration of tumor cells to the distant organs via lymph node has not been poorly understood and metastasis route...

Since lymph node metastasis is a major prognostic factor of cancer, the development of early diagnosis system for lymph node metastasis is essential for improving the outcome of cancer treatment. It has been reported that metastatic cancer cells promote lymphngiogenesis. In this study, to test whether detection of lymphangiogenesis in the metastati...

Lymph node metastasis is regarded as the leading cause of cancer death, hence the development of early diagnosis system is essential for improving prognosis. In the previous research, it was reported that high lymph vessel density in lymph node may be a significant unfavorable prognostic factor. Furthermore, lymphatic metastasis has been show to ca...

CFD simulation is performed for the purpose of making one-dimensional model of flow with low velocity in a complicated-shape of microscopic lymphatic vessel. The vessel is supposed to be axially symmetric on the basis of visualized shape of the vessel. It is composed of eight-staged conical parts connected, in which there are seven tapered valves a...

Deep metastatic tumor drainage lymph nodes surgical resection leaves behind structural disruptions and associated risks (1,2). Hence, there is need for an alternative method with less disruption and risk. We herein report for the first time, the treatment of metastasis by incorporating lymphatic drug delivery system via the lymphatic network ⁽³⁾. P...

The friction loss and the friction or resistance coefficient derived from the extended Bernoulli equation are obtained for a microscopic and small Reynolds number Jeffery-Hamel flow in a two-dimensional convergent or divergent channel. The assumption of microscopic and low Reynolds number flow enables us to make the analysis simple. The cross-secti...

Regional lymph node status is an important prognostic indicator of tumor aggressiveness. However, early diagnosis of metastasis using intranodal pressure, at a stage when lymph node size has not changed significantly, has not been investigated in murine models. Here, we use an MXH10/Mo-lpr/lpr mouse model of lymph node metastasis to show that intra...

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 ach...

Supplementary Video SV1.

Supplementary Figure S1.

Photothermal therapy (PTT) using near-infrared (NIR) laser light and gold nanorods (GNRs) shows promise as a novel cancer treatment modality. However, the laser intensity required to destroy tumor cells located beneath the skin is greater than the threshold intensity that causes skin damage; thus, irradiation with laser light damages the skin as we...

An accurate method for detecting contrast agents using diagnostic ultrasound imaging systems is proposed. Contrast agents, such as microbubbles, passing through a blood vessel during ultrasound imaging are detected as blinking signals in the temporal axis, because their intensity value is constantly in motion. Ultrasound contrast agents are detecte...

The status of tumor-draining lymph nodes (LNs) is a prognostic factor for determining the cancer stage and thus treatment planning. As treatment of lymph node metastasis (LNM), chemotherapy or radiotherapy has been used. However, there have been no reports of evaluation methods of chemotherapy induced anti-tumor effect on metastatic lymph node (MLN...

Cancer is one of the major diseases that cause death all over the world, especially via metastasis. Systemic drug administration to treat metastatic lymph nodes are not so effective and cause side effects. In our laboratory, we have studied on a novel drug delivery system, combining nano/microbubbles with ultrasound (US), which shows considerable p...

Lymph node (LN) metastasis plays an important role in the development of distant metastasis to vital organs. For LN metastasis, administration of anti-cancer agents is a standard treatment, but it has been a problem about strong side effect and low treatment effect. In the present study, we propose a drug delivery method via lymph network for metas...

To evaluate whether visual assessment of T2-weighted imaging (T2WI) or an apparent diffusion coefficient (ADC) could predict lymphovascular invasion (LVI) status in cases with clinically node-negative invasive breast cancer. One hundred and thirty-six patients with 136 lesions underwent MRI. Visual assessment of T2WI, tumour-ADC, peritumoral maximu...