title: Oil-filled lipid nanoparticles containing 2'-(2-bromohexadecanoyl)-docetaxel for the treatment of breast cancer.
abstract: A docetaxel (DX) lipid conjugate 2'-(2-bromohexadecanoyl)-docetaxel (2-Br-C16-DX) is synthesized to enhance the drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The conjugate is successfully entrapped in the previously optimized NPs with an entrapment efficiency of 56.8%. In-vitro release studies in 100% mouse plasma show an initial 45% burst release with no additional release within 8 h. The conjugate is able to be hydrolyzed to release DX by esterases in-vitro. The conjugate is less potent than unmodified DX in DU-145 and 4T1 cells. However, NPs containing the conjugate show significantly higher cytotoxicity compared to its free form especially in 4T1 cells. In-vivo, the AUC0-∞ value of NP-formulated 2-Br-C16-DX is about 100-fold higher than DX formulated in Taxotere. Furthermore, 2-Br-C16-DX NPs improve DX AUC 4.3-fold compared to Taxotere. The high concentration and prolonged exposure of both 2-Br-C16-DX and DX from 2-Br-C16-DX NPs in circulation result in a 10-fold and 1.5-fold higher accumulation of 2-Br-C16-DX and DX, respectively, in tumors compared to Taxotere. In mice bearing syngeneic 4T1 tumors, 2-Br-C16-DX NPs show markedly greater anticancer efficacy, as well as survival benefit over all controls. The results of these studies support that the oil-filled NPs containing hydrolyzable lipophilic DX prodrug 2-Br-C16-DX improve the therapeutic index of DX and are more efficacious in the treatment of breast cancer.
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Feng
authors.forename: Soumya R
authors.initials: SR
authors.lastname: Benhabbour
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Mumper
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009821:Oils / Q000737:chemistry*; D043823:Taxoids / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: C000592763:2'-(2-bromohexadecanoyl)docetaxel; D000970:Antineoplastic Agents; D009821:Oils; D043823:Taxoids; D000077143:Docetaxel
keywords: docetaxel; drug delivery; ester prodrug; nanoparticle; oil-filled