title: Synthesis and In Vitro Evaluation of Polyethylene Glycol-Paclitaxel Conjugates for Lung Cancer Therapy.
abstract: Pulmonary drug delivery is considered an attractive route of drug administration for lung cancer chemotherapy. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lung. Therefore, achieving a sustained presence of chemotherapeutics in the lung is very challenging. In this study, we synthesized two different polyethylene glycol-paclitaxel ester conjugates with molecular weights of 6 and 20 kDa in order to achieve sustained release of paclitaxel in the lung.
  
  
  
  One structure was synthesized with azide linker using "click" chemistry and the other structure was synthesized with a succinic spacer. The physicochemical and biological properties of the conjugates were characterized in vitro.
  
  
  
  Conjugation to polyethylene glycol improved the solubility of paclitaxel by up to four orders of magnitude. The conjugates showed good stability in phosphate buffer saline pH 6.9 (half-life ≥72 h) and in bronchoalveolar lavage (half-life of 3 to 9 h) at both molecular weights, but hydrolyzed quickly in mouse serum (half-life of 1 to 3 h). The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than free paclitaxel or Taxol, the commercial paclitaxel formulation.
  
  
  
  These properties imply that the conjugates have the potential to retain paclitaxel in the lung for a prolonged duration and to sustain its release locally for a better efficacy.
authors.affiliation: Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium.|School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Tian
authors.initials: T
authors.lastname: Luo
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Magnusson
authors.affiliation: Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
authors.affiliation: Medicinal Chemistry, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Raphael
authors.initials: R
authors.lastname: Frédérick
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Cameron
authors.initials: C
authors.lastname: Alexander
authors.affiliation: School of Pharmacy, University of Nottingham, Nottingham, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bosquillon
authors.affiliation: Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium. rita.vanbever@uclouvain.be.
authors.forename: Rita
authors.initials: R
authors.lastname: Vanbever
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage / Q000379:methods; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006207:Half-Life; D008175:Lung Neoplasms / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008970:Molecular Weight; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: drug conjugate; lung cancer; paclitaxel; polyethylene glycol; pulmonary drug delivery