Tian Luo1,2, Johannes Magnusson2, Véronique Préat1, Raphael Frédérick3, Cameron Alexander2, Cynthia Bosquillon2, Rita Vanbever4. 1. Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium. 2. School of Pharmacy, University of Nottingham, Nottingham, UK. 3. Medicinal Chemistry, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. 4. Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium. rita.vanbever@uclouvain.be.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Entities:
Keywords:
drug conjugate; lung cancer; paclitaxel; polyethylene glycol; pulmonary drug delivery
Authors: N Rocks; S Bekaert; I Coia; G Paulissen; M Gueders; B Evrard; J-C Van Heugen; P Chiap; J-M Foidart; A Noel; D Cataldo Journal: Br J Cancer Date: 2012-08-28 Impact factor: 7.640