The tumor microenvironment is one of the key factors contributing to the efficiency of drug delivery to a
tumor. It has been reported that lymphangiogenesis is induced in certain
tumors. Because the lymphatic system functions as a drainage one, it is possible that
tumor lymphatic vessels alter not only the tumor microenvironment, but also the distribution of drug nanocarriers accumulated in the
tumor tissue. Herein, we aimed to elucidate the involvement of the
tumor lymphatic system in the translocation of intratumoral
liposomes to regional lymph nodes by using
vascular endothelial growth factor (
VEGF)-C-overexpressing B16F10
tumor-bearing mice (B16/
VEGF-C). When the amount of
polyethylene glycol (PEG)-modified
liposomes in lymph nodes (cervical, brachial, axillary, and inguinal lymph nodes) was measured after the radiolabeled
liposomes had been intratumorally injected into B16/
VEGF-C-bearing mice or wild-type B16-bearing mice, the accumulation of
liposomes in the axillary and inguinal lymph nodes was significantly higher on the
tumor-implanted side of B16/
VEGF-C-bearing mice than on that of the B16-bearing ones. On the other hand, the accumulation of
liposomes in these lymph nodes on the control side (no implantation) of either type of
tumor-bearing mice was very low; and no difference could be observed between the 2 sides. Furthermore, the intratumoral distribution of
liposomes was observed to be located near the lymphatic vessels. These results indicate that the
tumor lymphatic system contributed to the extrusion of a portion of PEG-modified
liposomes from the
tumor tissue, suggesting that
tumor lymphangiogenesis would be one of the key factors to determine the intratumoral distribution of
liposomes and their subsequent fate.