title: 2'-(2-bromohexadecanoyl)-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model.
abstract: A nanoparticle (NP) formulation with 2'-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC). The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg) than Taxol (19 mg/kg) and provided significantly longer median survival (88 days versus 70 days, P<0.05) in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC)₀₋₉₆ h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group.
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Peng
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Allison N
authors.initials: AN
authors.lastname: Schorzman
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Madden
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA ; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, North Carolina, NC, USA ; UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Soumya Rahima
authors.initials: SR
authors.lastname: Benhabbour
authors.affiliation: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, NC, USA ; UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Mumper
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002470:Cell Survival; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D017239:Paclitaxel
keywords: A549 cell tumor model; bioluminescence imaging; efficacy; maximum tolerated dose; pharmacokinetic; pleural fluid; tubulin polymerization
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