Efficacy of intranasal delivery of VEGFR inhibitors to cervical lymph nodes for inhibiting tongue cancer metastasis in mice

Oral cancers frequently metastasise to adjacent cervical lymph nodes (CLNs), leading to systemic dissemination and poor prognosis. Intranasal (i.n.) drug delivery provides direct access to cervical lymphatics, enabling high local drug concentrations while minimising systemic exposure. This study evaluated the pharmacokinetics (PK) and anti-metastatic efficacy of two vascular endothelial growth factor receptor (VEGFR)-3 inhibitors - cediranib maleate (CDNB) and pazopanib hydrochloride (PPNB) - administered i.n. in a mouse model of tongue cancer. Pharmacokinetic analysis showed that i.n. delivery yielded significantly higher CLN concentrations of both drugs than intravenous administration, despite lower plasma levels. In tumour-bearing mice, i.n. CDNB markedly reduced the incidence of CLN metastasis (0.167) versus controls (0.875, <i>p</i> < .01) and was more effective than intraperitoneal CDNB (0.571) or i.n. PPNB (0.500). Although less potent, PPNB significantly reduced the number of metastatic CLNs (0.438, <i>p</i> < .05). CDNB exhibited superior and more consistent efficacy. The reduced effect of PPNB may reflect its lower dose - limited by solubility - and possible differences in target specificity. These findings highlight the potential of i.n. administration to deliver VEGFR-3 inhibitors to CLNs, suppress lymphangiogenesis and lymphatic metastasis, and reduce systemic toxicity. This approach may offer a non-invasive alternative to neck dissection in oral cancer.