Intravesical treatment of liposomal doxorubicin nanoparticles in mouse orthotopic bladder cancer model

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Intravesicle instillation of doxorubicin (Dox) is one of the established modalities in the prophylaxis of superficial bladder cancer recurrence or progression. BCG instillation has been widely applied in high risk or recurrent superficial bladder cancer, however, BCG sometimes shows difficulty of completion of treatment due to its toxicity. In this study, we have investigated the efficacy of 3 types of liposomal Dox aiming high tumor concentrations by effective transportability and less toxicity in vivo. To examine the therapeutic effect of liposomal Dox nanoparticles, we used a human bladder cancer cell line KU-7/GFP, a stable transfectant with GFP, growing as superficial bladder tumors in nude mice. KU-7/GFP tumor cells were implanted transurethrally in female nude mice on day 0. Mice were then assigned into 6 groups and intravesically received a single instillation of liposome/Dox (Group 4), PEG-CHO liposome/Dox modified with polyethyleneglycol-cholesterol (Group 5), and mixed PEG liposome/Dox modified with polyethyleneglycol-distearoylglycerol and polyethyleneglycol -cholesterol (Group 6) at the Dox concentration of 100µg/100µl, which is clinically relevant concentration per body weight, compared to PBS (Group 1), empty liposome (Group 2), and Dox solution (Group 3) on day 10 after cell inoculation. Two weeks after treatment, the mice were then sacrificed and processed for histopathological examination. Tumor burden in the bladder was determined utilizing KU-7/GFP cancer cells containing GFP. Marked tumor regression was observed following liposomal Dox instillations in Group 4, 5, and 6 compared to the treatment with PBS or liposome, and no toxicity was observed. Tumor incidence (mean tumor area) by GFP observation is represented 6/6 (10.6mm²), 6/6 (11.7mm²), 5/6 (1.1mm²), 2/7 (0.58mm²), 5/6 (12.3mm²), and 4/7 (2.1mm²) in Groups 1, 2, 3, 4, 5, and 6, respectively. Treatments with liposomal Dox have a more significant therapeutic efficacy comparing to Dox itself, even in a single administration. These findings demonstrate that liposomal Dox nanoparticles can overcome a disadvantage of conventional Dox and can be a promising application for the treatment of superficial bladder cancer.