title: Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents.
abstract: We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.
authors.affiliation: CSIRO Materials Science and Engineering, PO Box 184, North Ryde, NSW 1670, Australia.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Sagnella
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Gong
authors.forename: Minoo J
authors.initials: MJ
authors.lastname: Moghaddam
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Conn
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kimpton
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Waddington
authors.forename: Irena
authors.initials: I
authors.lastname: Krodkiewska
authors.forename: Calum J
authors.initials: CJ
authors.lastname: Drummond
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003460:Crystallization / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D050997:Nanomedicine / Q000379:methods; D011355:Prodrugs; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D008055:Lipids; D053769:Nanocapsules; D011355:Prodrugs; D005472:Fluorouracil