title: Biodistribution, tumor uptake and efficacy of 5-FU-loaded liposomes: why size matters.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  This study suggests that particle size is critical to achieve higher selectivity and efficacy in experimental oncology, including in resistant tumors.
authors.affiliation: Pharmacokinetics Unit, UMR S_911, CRO2, Aix Marseille University, Marseille, France, raphaelle.fanciullino@univ-amu.fr.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Fanciullino
authors.forename: Severine
authors.initials: S
authors.lastname: Mollard
authors.forename: Florian
authors.initials: F
authors.lastname: Correard
authors.forename: Sarah
authors.initials: S
authors.lastname: Giacometti
authors.forename: Cindy
authors.initials: C
authors.lastname: Serdjebi
authors.forename: Athanassios
authors.initials: A
authors.lastname: Iliadis
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004339:Drug Compounding; D004355:Drug Stability; D004705:Endocytosis; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D010316:Particle Size; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D005472:Fluorouracil
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