Synthesis and in vitro evaluation of polyethylene glycol-paclitaxel conjugates for lung cancer therapy

Alexander, Cameron; Luo, Tian; Magnusson, Johannes; Bosquillon, Cynthia; Pr�at, V�ronique; Fr�d�rick, Raphael; Vanbever, Rita

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.

Citation

Alexander, C., Luo, T., Magnusson, J., Bosquillon, C., Préat, V., Frédérick, R., & Vanbever, R. (2016). Synthesis and in vitro evaluation of polyethylene glycol-paclitaxel conjugates for lung cancer therapy. Pharmaceutical Research, 33(7), 1671-1681. https://doi.org/10.1007/s11095-016-1908-2

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2016
• Online Publication Date: Mar 18, 2016
• Publication Date: Jul 1, 2016
• Deposit Date: May 31, 2018
• Print ISSN: 0724-8741
• Electronic ISSN: 1573-904X
• Publisher: American Association of Pharmaceutical Scientists
• Peer Reviewed: Peer Reviewed
• Volume: 33
• Issue: 7
• Pages: 1671-1681
• DOI: https://doi.org/10.1007/s11095-016-1908-2
• Public URL: https://nottingham-repository.worktribe.com/output/1117175
• Publisher URL: https://link.springer.com/article/10.1007%2Fs11095-016-1908-2
• PMID: 26984129