Optimal range of injection rates for a lymphatic drug delivery system

Fujii, Hatsumi; Horie, Seichi; Takeda, Kazuhisa; Mori, Shiro; Kodama, Tetsuya

doi:10.1002/jbio.201700401

Cited by 13 publications

(12 citation statements)

References 19 publications

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“…CDDP (or control solution) was administered with the LDDS on day 7 after tumor cell inoculation (defined as day 0 T ). Solution III, IV, or V with or without CDDP (Table 1) was injected into the right SiLN at a constant rate of 10 µL/min (total volume, 200 µL) using a syringe pump (Legato100; KD Scientific), previously described by Fujii et al (2018) 26 …”

Section: Methodsmentioning

confidence: 99%

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system

et al. 2021

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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 properties of the solvent used to carry the drug have not been determined. Here, we show that the osmotic pressure and viscosity of the solvent influenced the antitumor effect of cisplatin (CDDP) in a mouse model of LN metastasis. Tumor cells were inoculated into the proper axillary LN (PALN), and the LDDS was used to inject CDDP solution into the subiliac LN (SiLN) to treat the tumor cells in the downstream PALN. CDDP dissolved in saline had no therapeutic effects in the PALN after it was injected into the SiLN using the LDDS or into the tail vein (as a control). However, CDDP solution with an osmotic pressure of ~ 1,900 kPa and a viscosity of ~ 12 mPa⋅s suppressed tumor growth in the PALN after it was injected into the SiLN using the LDDS. The high osmotic pressure dilated the lymphatic vessels and sinuses to enhance drug flow in the PALN, and the high viscosity increased the retention of CDDP in the PALN. Our results demonstrate that optimizing the osmotic pressure and viscosity of the solvent can enhance the effects of CDDP, and possibly other anticancer drugs, after administration using the LDDS.

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Section: Methodsmentioning

confidence: 99%

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system

et al. 2021

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“…Development of a minimally invasive treatment to prevent lymph nodemediated hematogenous metastasis is desirable, and we have previously reported (using the same animal model) that anticancer drugs can be injected into an upstream lymph node to treat micrometastasis in a downstream lymph node. [31][32][33] A lymphatic anticancer drug delivery system can remove the origin of lymph node-mediated hematogenous metastasis by targeting micrometastases in lymph nodes, avoiding surgical intervention and preventing the risk of activation of distant metastatic lesions by lymph node resection. Therefore, this novel cancer chemotherapy approach may be a promising technique that should be further investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Lymph node resection induces the activation of tumor cells in the lungs

et al. 2019

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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 activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non‐tumor‐bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor‐bearing and non‐tumor‐bearing LN affects distant metastases in MXH10/Mo‐lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity was detected in the lungs of mice that did not undergo LN resection (excluding the intravenous inoculation group). Our results indicate that resection of an LN can activate distant metastases regardless of whether the LN contains tumor cells. Hence, lung metastatic lesions are suppressed while metastatic LN are present but activated after LN resection. If this phenomenon occurs in patients with cancer, it is likely that lung metastatic lesions may be activated by elective LN dissection in clinical N0 cases. The development of minimally invasive cancer therapy without surgery would help to minimize the risk of activation of distant metastatic lesions by LN resection.

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“…1B–D), it remains likely that a small proportion of the drug had leaked outside the SiLN. High lymphatic pressure due to intranodal injection may contribute to lymphatic leakage 8 . In the present study, lymphorrhea was not detected during the 10-day experimental period, although it may take longer for this adverse effect to develop.…”

Section: Discussionmentioning

confidence: 99%

“…1B). Thus, after injection into the subiliac LN (SiLN), the drug could reach the proper axillary LN (PALN) via the LVs 8 . US-mediated drug delivery using ALs and sonoporation generates mechanical pressures and induces cell membrane permeability, which permits foreign molecules to enter live cells without the occurrence of tissue damage or immune responses 9–15 .…”

Section: Introductionmentioning

confidence: 99%

Use of a Lymphatic Drug Delivery System and Sonoporation to Target Malignant Metastatic Breast Cancer Cells Proliferating in the Marginal Sinuses

Kato

Shirai

Sakamoto

et al. 2019

Sci Rep

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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, we investigated whether lymphatic administration of a drug combined with sonoporation could be used to treat a LN containing proliferating murine FM3A breast cancer cells, which are highly invasive, in its marginal sinus. First, we used contrast-enhanced high-frequency ultrasound and histopathology to analyze the structure of LVs in MXH10/Mo-lpr/lpr mice, which exhibit systemic lymphadenopathy. We found that contrast agent injected into the subiliac LN flowed into the marginal sinus of the proper axillary LN (PALN) and reached the cortex. Next, we examined the anti-tumor effects of our proposed technique. We found that a strong anti-tumor effect was achieved by lymphatic administration of doxorubicin and sonoporation. Furthermore, our proposed method prevented tumor cells in the marginal sinus from invading the parenchyma of the PALN and resulted in tumor necrosis. We conclude that lymphatic administration of a drug combined with sonoporation could exert a curative effect in LNs containing metastatic cells in their marginal sinuses.

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Optimal range of injection rates for a lymphatic drug delivery system

Cited by 13 publications

References 19 publications

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system

Lymph node resection induces the activation of tumor cells in the lungs

Use of a Lymphatic Drug Delivery System and Sonoporation to Target Malignant Metastatic Breast Cancer Cells Proliferating in the Marginal Sinuses

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