title: Phospho-ibuprofen (MDC-917) incorporated in nanocarriers: anti-cancer activity in vitro and in vivo.
abstract: OBJECTIVE
  Phospho-ibuprofen (P-I; MDC-917) inhibits the growth of colon cancer in mice. Here, we investigated the use of nanocarriers to improve its pharmacokinetics (PKs) and anti tumour efficacy.
  
  
  METHODS
  The cellular uptake and cytotoxicity of P-I encapsulated into liposomes and micelles, and its in vitro metabolic stability, were determined in cultures of human colon adenocarcinoma cells. The performance of liposomal P-I was further evaluated in PK studies in mice, and in a model of colon cancer xenografts in nude mice.
  
  
  RESULTS
  Liposomal P-I and micellar P-I showed significantly enhanced cellular uptake in the colon cancer cells. Liposomal P-I also demonstrated increased cytotoxicity in vitro. Free P-I was metabolized rapidly to ibuprofen in the presence of purified esterases. In contrast, liposomal P-I, and to a lesser extent micellar P-I, was resistant to esterase-mediated hydrolysis. In mice, liposomal P-I partially protected P-I from hydrolysis in the circulation, and improved the biodistribution of intact P-I and its metabolites compared to free P-I. Liposomal P-I was more effective at inhibiting the growth of human colon cancer xenografts in mice, which may be explained on the basis of its improved PK profile compared to free P-I.
  
  
  CONCLUSIONS
  Liposome encapsulation of P-I partially protected P-I from esterase-mediated hydrolysis in mice, enhanced the cytotoxicity and bioavailability of P-I and increased its efficacy at inhibiting the growth of human colon cancer xenografts. These results indicate that liposomes are suitable nanocarriers for the delivery of P-I, and that the anti-tumour potential of liposomal P-I merits further evaluation.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8173, USA.
authors.forename: T
authors.initials: T
authors.lastname: Nie
authors.forename: C C
authors.initials: CC
authors.lastname: Wong
authors.forename: N
authors.initials: N
authors.lastname: Alston
authors.forename: P
authors.initials: P
authors.lastname: Aro
authors.forename: P P
authors.initials: PP
authors.lastname: Constantinides
authors.forename: B
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D010755:Organophosphates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010316:Particle Size; D013499:Surface Properties; D023041:Xenograft Model Antitumor Assays
chemical_list: C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D008823:Micelles; D010755:Organophosphates; D007052:Ibuprofen