Biodistribution, tumor uptake and efficacy of 5-FU-loaded liposomes: why size matters.

Purpose: We have investigated the impact of particle size on the biodistribution, tumor uptake and antiproliferative efficacy of 5-FU-loaded liposomes.

Methods: Three different batches of pegylated liposomes varying in size (i.e., 70, 120 and 250 nm respectively) were tested. The active compounds encapsulated were an equimolar mix of 5-FU, 2'-deoxyinosine and folinic acid. Liposomes were subsequently tested on the human breast cancer model MDA231 cells, a model previously found to be resistant to 5-FU. In vitro, antiproliferative efficacy and microscopy studies of liposomes uptake were carried out. In vivo, comparative biodistribution and efficacy studies were performed in tumor-bearing mice.

Results: Difference in size did not change in vitro antiproliferative activity. Fluorescence-Microscopy studies showed that liposomes were mainly uptaken by tumor cells through a direct internalization process, regardless of their size. Biodistribution profiles in tumor-bearing mice revealed higher accumulation of small liposomes in tumors throughout time as compared with normal and large liposomes (p < 0.05). Additionally, we observed that the bigger were the tumors, the more vascularised they were and the greater was the difference in accumulation between small and large liposomes. Consequently, in vivo efficacy studies showed at study conclusion that a 68% reduction in tumor size was achieved with small liposomes (p < 0.05), whereas larger liposomes failed to reduce significantly tumor growth. Similarly, at study conclusion a trend towards higher survival-rate in animals treated with smaller liposomes was observed.

Conclusion: This study suggests that particle size is critical to achieve higher selectivity and efficacy in experimental oncology, including in resistant tumors.