Solvent osmolarity and viscosity regulate lymph node pharmacokinetics and perinodal dynamics in lymphatic drug delivery

The lymphatic drug delivery system (LDDS) offers a promising strategy for treating lymph node (LN) metastases through direct administration of therapeutic agents into the sentinel LN, enabling subsequent delivery to downstream nodes via lymphatic vessels (LVs). While previous studies have shown that formulation properties such as osmolarity and viscosity can influence pharmacokinetics and therapeutic efficacy, the impact of these parameters on lymphatic and vascular flow dynamics - particularly during and after LDDS injection, when fluid behavior differs substantially - remains incompletely understood. Here, we systematically investigated how variations in osmotic pressure and viscosity modulate fluid dynamics and LN targeting efficiency using the MXH10/Mo/lpr mouse model, which possesses macroscopically enlarged LNs and intact lymphatic drainage pathways. By integrating intranodal pharmacokinetic profiling, injection pressure monitoring and high-resolution morphometric analyses of lymphatic vessels (LVs) and veins, we revealed that both sentinel and downstream LNs, along with their associated vessels, respond differentially depending on the physicochemical properties of the injected formulation. Elevated osmotic pressure induced lymphatic sinus dilation and increased vascular inflow, whereas high-viscosity formulations altered downstream LN delivery profiles and prolonged intranodal retention. These results demonstrate that osmotic pressure and viscosity critically govern solution distribution and retention within the lymphatic network, directly impacting drug delivery performance. The findings have established these parameters as essential formulation design factors for optimizing LDDS-based therapies targeting metastatic LNs.