Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy

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• 作者：Ré ; mi Rosiè ; re^a ; ^{rrosiere@ulb.ac.be" class="auth_mail" title="E-mail the corresponding author} ; Matthias Van Woensel^a ; ^b ; Vé ; ronique Mathieu^c ; Ingrid Langer^d ; Thomas Mathivet^e ; Marjorie Vermeersch^f ; Karim Amighi^a ; Nathalie Wauthoz^a
• 关键词：3 ; 3&prime ; -Dioctadecyloxacarbocyanine perchlorate (PubChem CID ; 2762625) ; Dextran (PubChem CID ; 71315856) ; Ethylene glycol (PubChem CID ; 174) ; Folic acid (PubChem CID ; 6037) ; Leucine (PubChem CID ; 6106) ; Mannitol (PubChem CID ; 6251) ; Paclitaxel (PubChem CID ; 36314) ; Stearic acid (PubChem CID ; 5281)
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：30 March 2016
• 年：2016
• 卷：501
• 期：1-2
• 页码：148-159
• 全文大小：1587 K

文摘

Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of ∼50 nm and a zeta potential of ∼−4 mV were prepared with an encapsulation efficiency of ∼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1β, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.