title: Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis.
abstract: 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 (LN). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stages of LN metastasis. Luciferase-expressing tumor cells were injected into the subiliac LN of the MXH10/Mo-lpr/lpr mouse to induce metastasis to the proper axillary LN (PALN). In vivo biofluorescence imaging was used to confirm metastasis induction and to quantify the EPR effect, measured as PALN accumulation of intravenously injected indocyanine green (ICG) liposomes. PALN blood vessel volume changes were measured by contrast-enhanced high-frequency ultrasound imaging. The volume and density of blood vessels in the PALN increased until day 29 after inoculation, whereas the LN volume remained constant. ICG retention was first detected on day 29 post-inoculation. While CD31-positive cells increased up to day 29 post-inoculation, α-smooth muscle actin-positive cells were detected on day 29 post-inoculation for the first time. These results suggest that the EPR effect was not induced in the early stages of LN metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of LN metastasis. The development of an alternative drug delivery system, independent of the EPR effect, is required for the treatment of LN metastasis.
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Mikada
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Graduate School of Dentistry, Tohoku University, Aoba, Sendai, Japan.
authors.forename: Ariunbuyan
authors.initials: A
authors.lastname: Sukhbaatar
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Horie
authors.affiliation: Department of Oral Diagnosis, Tohoku University Hospital, Aoba, Sendai, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai, Japan.|Department of Oral and Maxillofacial Surgery, Tohoku University Hospital, Aoba, Sendai, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Mori
authors.affiliation: Laboratory of Biomedical Engineering for Cancer, Tohoku University, Aoba, Sendai, Japan.|Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Aoba, Sendai, Japan.
authors.forename: Tetsuya
authors.identifier: http://orcid.org/0000-0003-4727-9558
authors.initials: T
authors.lastname: Kodama
mesh_terms: D000818:Animals; D001365:Axilla / Q000473:pathology; D002478:Cells, Cultured; D008081:Liposomes / Q000008:administration & dosage; D008156:Luciferases / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000473:pathology*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000473:pathology*; D010539:Permeability
chemical_list: D008081:Liposomes; D008156:Luciferases
keywords: Drug delivery system; MXH10/Mo-lpr/lpr mouse; enhanced permeability and retention effect; indocyanine green; lymph node metastasis