Optimization of lymphatic drug delivery system with carboplatin for metastatic lymph nodes

Systemic chemotherapy is a common method for treatment of metastatic lymph nodes (LNs), but it has low tissue selectivity and high toxicity. Lymphatic drug delivery system (LDDS) is a novel approach to treat and prevent LN metastases. In a previous study, it was found that the increase of osmotic pressure with varied viscosity of the drug reagent enhances drug retention in the LNs. Here, we optimized the administration conditions to achieve a long-term therapeutic response by varying the dosages and injection rate, using the optimized osmotic pressure and varied viscosity of drug reagent for LDDS. A metastatic LN mouse model was created with MXH10/Mo/lpr mice. Luciferase labelled FM3A mouse mammary carcinoma cells were inoculated in subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). 4 days post tumor cell inoculation, carboplatin (CBDCA) was injected into the tumor-bearing SiLN under different administration conditions. Superior drug retention was observed in the group that received two-doses of CBDCA solution adjusted to an osmotic pressure and viscosity of 1897 kPa and 12 mPa·s, at an injection rate of 10 µL/min. Furthermore, this effect persisted for 42 days. This effect was accompanied by an upregulated expression of CD8, IL-12a, and IFN-γ in the spleen. These results suggest that dual-dose administration at 10 µL/min with hyper-osmotic and high viscosity formulation is optimal and can improve the long-term therapeutic efficacy of LN metastasis.