Synthesis and in vitro evaluation of polyethylene glycol paclitaxel conjugates for lung cancer therapy
(2016) Pharmaceutical Research — Vol. 33, n° 7, p. 1671-1681 (2016)
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- Abstract
- Pulmonary delivery of chemotherapeutic agents is considered an attractive route of administration, with the advantages of high drug concentrations locally and low side effects systemically. However, the lung has the fast clearance mechanisms which result in short residence time of chemotherapeutics in the lungs. Thus, achieving sustained release of small molecule drugs in the lung is very challenging. In this study, we synthesized two different polyethylene glycol-paclitaxel (PEG-PTX) ester conjugates with molecular weights of 6 kDa and 20 kDa to achieve sustained release of paclitaxel in the lung. One structure PEG-N3-PTX was synthesized by “click” chemistry and the other structure PEG-suc-PTX was with a succinic spacer. These conjugates were characterized physicochemically. PEG-N3-PTX at both molecular weights showed good stability in PBS pH 6.9 (t1/2 around 72 h) and in brochoalveolar larvage (t1/2 6-9 h), but hydrolyzed quickly in mouse serum (t1/2 2 h) . The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than Taxol, which is the commercial paclitaxel formulated with Cremophor EL. The conjugates will be further investigated in vivo on Lewis lung cancer mouse model to test the sustained drug release as well as the anti-tumor efficacy.
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Luo, T., Magnusson, J., Préat, V., Frédérick, R., Alexander, C., Bosquillon, C., & 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 (Original work published 2016)