Biotin-targeted Pluronic^® P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells

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• 作者：Annapina Russo^a ; ¹ ; Diogo Silva Pellosi^b ; ^c ; ¹ ; Valentina Pagliara^a ; Maria Rita Milone^d ; Biagio Pucci^d ; Wilker Caetano^c ; Noboru Hioka^c ; Alfredo Budillon^d ; Francesca Ungaro^b ; ^{ungaro@unina.it" class="auth_mail" title="E-mail the corresponding author} ; Giulia Russo^a ; ^{giulia.russo@unina.it" class="auth_mail" title="E-mail the corresponding author} ; Fabiana Quaglia^b
• 关键词：Micelle ; Pluronic® ; Niclosamide ; Lung cancer cells ; Multidrug resistance
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：10 September 2016
• 年：2016
• 卷：511
• 期：1
• 页码：127-139
• 全文大小：2652 K

文摘

With the aim to develop alternative therapeutic tools for the treatment of resistant cancers, here we propose targeted Pluronic^® P123/F127 mixed micelles (PMM) delivering niclosamide (NCL) as a repositioning strategy to treat multidrug resistant non-small lung cancer cell lines. To build multifunctional PMM for targeting and imaging, Pluronic^® F127 was conjugated with biotin, while Pluronic^® P123 was fluorescently tagged with rhodamine B, in both cases at one of the two hydroxyl end groups. This design intended to avoid any interference of rhodamine B on biotin exposition on PMM surface, which is a key fundamental for cell trafficking studies. Biotin-decorated PMM were internalized more efficiently than non-targeted PMM in A549 lung cancer cells, while very low internalization was found in NHI3T3 normal fibroblasts. Biotin-decorated PMM entrapped NCL with good efficiency, displayed sustained drug release in protein-rich media and improved cytotoxicity in A549 cells as compared to free NCL (P < 0.01). To go in depth into the actual therapeutic potential of NCL-loaded PMM, a cisplatin-resistant A549 lung cancer cell line (CPr-A549) was developed and its multidrug resistance tested against common chemotherapeutics. Free NCL was able to overcome chemoresistance showing cytotoxic effects in this cell line ascribable to nucleolar stress, which was associated to a significant increase of the ribosomal protein rpL3 and consequent up-regulation of p21. It is noteworthy that biotin-decorated PMM carrying NCL at low doses demonstrated a significantly higher cytotoxicity than free NCL in CPr-A549. These results point at NCL-based regimen with targeted PMM as a possible second-line chemotherapy for lung cancer showing cisplatin or multidrug resistance.