PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma
Pulmonary delivery offers an attractive route of administration for chemotherapeutic agents, with the advantages of high drug concentrations locally and low side effects systemically. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lungs. Moreover, th...
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Elsevier
2016
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| Online Access: | https://eprints.nottingham.ac.uk/37380/ |
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| author | Luo, Tian Loira-Pastoriza, Cristina Patil, Harshad P. Ucakar, Bernard Muccioli, Giulio G. Bosquillon, Cynthia Vanbever, Rita |
| author_facet | Luo, Tian Loira-Pastoriza, Cristina Patil, Harshad P. Ucakar, Bernard Muccioli, Giulio G. Bosquillon, Cynthia Vanbever, Rita |
| author_sort | Luo, Tian |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Pulmonary delivery offers an attractive route of administration for chemotherapeutic agents, with the advantages of high drug concentrations locally and low side effects systemically. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lungs. Moreover, the local toxicity induced by antineoplastic drugs is considered a major obstacle for the clinical application of inhaled chemotherapy. In this study, we explored the utility of 6 kDa and 20 kDa polyethylene glycol-paclitaxel (PEG-PTX) conjugates to retain paclitaxel within the lungs, achieve its sustained release locally, and thereby, improve its efficacy and reduce its pulmonary toxicity. The conjugates increased the maximum tolerated dose of paclitaxel by up to 100-fold following intratracheal instillation in healthy mice. PEG-PTX conjugates induced lung inflammation. However, the inflammation was lower than that induced by an equivalent dose of the free drug and it was reversible. Conjugation of paclitaxel to both PEG sizes significantly enhanced its anti-tumor efficacy following intratracheal instillation of a single dose in a Lewis lung carcinoma model in mice. PEG-PTX 20k showed equivalent efficacy as PEG-PTX 6k delivered at a 2.5-fold higher dose, suggesting that the molecular weight of the conjugate plays a role in anti-cancer activity. PEG-PTX 20k conjugate presented a prolonged residency and a sustained paclitaxel release within the lungs. This study showed that PEGylation of paclitaxel offers a potential delivery system for inhalation with improved anti-cancer efficacy, prolonged exposure of lung-resident tumors to the antineoplastic drug and reduced local toxicity. |
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| format | Article |
| id | nottingham-37380 |
| institution | University of Nottingham Malaysia Campus |
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| last_indexed | 2025-11-14T19:32:14Z |
| publishDate | 2016 |
| publisher | Elsevier |
| recordtype | eprints |
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| spelling | nottingham-373802020-05-04T18:07:31Z https://eprints.nottingham.ac.uk/37380/ PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma Luo, Tian Loira-Pastoriza, Cristina Patil, Harshad P. Ucakar, Bernard Muccioli, Giulio G. Bosquillon, Cynthia Vanbever, Rita Pulmonary delivery offers an attractive route of administration for chemotherapeutic agents, with the advantages of high drug concentrations locally and low side effects systemically. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lungs. Moreover, the local toxicity induced by antineoplastic drugs is considered a major obstacle for the clinical application of inhaled chemotherapy. In this study, we explored the utility of 6 kDa and 20 kDa polyethylene glycol-paclitaxel (PEG-PTX) conjugates to retain paclitaxel within the lungs, achieve its sustained release locally, and thereby, improve its efficacy and reduce its pulmonary toxicity. The conjugates increased the maximum tolerated dose of paclitaxel by up to 100-fold following intratracheal instillation in healthy mice. PEG-PTX conjugates induced lung inflammation. However, the inflammation was lower than that induced by an equivalent dose of the free drug and it was reversible. Conjugation of paclitaxel to both PEG sizes significantly enhanced its anti-tumor efficacy following intratracheal instillation of a single dose in a Lewis lung carcinoma model in mice. PEG-PTX 20k showed equivalent efficacy as PEG-PTX 6k delivered at a 2.5-fold higher dose, suggesting that the molecular weight of the conjugate plays a role in anti-cancer activity. PEG-PTX 20k conjugate presented a prolonged residency and a sustained paclitaxel release within the lungs. This study showed that PEGylation of paclitaxel offers a potential delivery system for inhalation with improved anti-cancer efficacy, prolonged exposure of lung-resident tumors to the antineoplastic drug and reduced local toxicity. Elsevier 2016-08-08 Article PeerReviewed Luo, Tian, Loira-Pastoriza, Cristina, Patil, Harshad P., Ucakar, Bernard, Muccioli, Giulio G., Bosquillon, Cynthia and Vanbever, Rita (2016) PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma. Journal of Controlled Release, 239 . pp. 62-71. ISSN 1873-4995 Polymer-drug conjugates; Inhaled chemotherapy; Lung cancer; Pulmonary delivery; Paclitaxel; Prodrug http://www.sciencedirect.com/science/article/pii/S0168365916305107 doi:10.1016/j.jconrel.2016.08.008 doi:10.1016/j.jconrel.2016.08.008 |
| spellingShingle | Polymer-drug conjugates; Inhaled chemotherapy; Lung cancer; Pulmonary delivery; Paclitaxel; Prodrug Luo, Tian Loira-Pastoriza, Cristina Patil, Harshad P. Ucakar, Bernard Muccioli, Giulio G. Bosquillon, Cynthia Vanbever, Rita PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title | PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title_full | PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title_fullStr | PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title_full_unstemmed | PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title_short | PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| title_sort | pegylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma |
| topic | Polymer-drug conjugates; Inhaled chemotherapy; Lung cancer; Pulmonary delivery; Paclitaxel; Prodrug |
| url | https://eprints.nottingham.ac.uk/37380/ https://eprints.nottingham.ac.uk/37380/ https://eprints.nottingham.ac.uk/37380/ |