Purpose: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox®) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer.
Material and methods: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD + HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX + HT) and (iii) IV LTLD without hyperthermia (LTLD - HT). Drug formulations were delivered via 30 min IV infusion coinciding with 1-h bladder irrigation (45 °C water for HT groups, 37 °C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD.
Results: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD + HT, IV DOX + HT and LTLD - HT, respectively, were 20.32-3.52 μg/g, 2.34-0.61 μg/g and 2.18-0.51 μg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7 ± 0.67 and 4.09 ± 0.81 μg/g for IV LTLD + HT, 1.2 ± 0.39 and 0.86 ± 0.24 μg/g for IV DOX + HT, and 1.15 ± 0.38 and 0.62 ± 0.15 μg/g for LTLD - HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD.
Conclusions: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.
Keywords: Bladder cancer; ThermoDox; bladder wall; doxorubicin; hyperthermia; nanomedicine; non-muscle invasive; targeted drug delivery; temperature-sensitive liposomes.