title: Biotin-targeted Pluronic(®) P123/F127 mixed micelles delivering niclosamide: A repositioning strategy to treat drug-resistant lung cancer cells.
abstract: 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.
authors.affiliation: Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Annapina
authors.initials: A
authors.lastname: Russo
authors.affiliation: Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy; Research Nucleus of Photodynamic Therapy, Chemistry Department State University of Maringá, Av. Colombo 5.790, 87020-900, Maringá, Paraná, Brazil.
authors.forename: Diogo Silva
authors.initials: DS
authors.lastname: Pellosi
authors.affiliation: Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pagliara
authors.affiliation: Experimental Pharmacology Unit, Department of Research, Istituto Nazionale Tumori- IRCCS G. Pascale Via M. Semmola, 80131 Napoli, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Milone
authors.affiliation: Experimental Pharmacology Unit, Department of Research, Istituto Nazionale Tumori- IRCCS G. Pascale Via M. Semmola, 80131 Napoli, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Pucci
authors.affiliation: Research Nucleus of Photodynamic Therapy, Chemistry Department State University of Maringá, Av. Colombo 5.790, 87020-900, Maringá, Paraná, Brazil.
authors.forename: Wilker
authors.initials: W
authors.lastname: Caetano
authors.affiliation: Research Nucleus of Photodynamic Therapy, Chemistry Department State University of Maringá, Av. Colombo 5.790, 87020-900, Maringá, Paraná, Brazil.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hioka
authors.affiliation: Experimental Pharmacology Unit, Department of Research, Istituto Nazionale Tumori- IRCCS G. Pascale Via M. Semmola, 80131 Napoli, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
authors.affiliation: Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: ungaro@unina.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ungaro
authors.affiliation: Laboratory of Biochemistry, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: giulia.russo@unina.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
authors.affiliation: Laboratory of Drug Delivery, Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quaglia
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D001710:Biotin / Q000008:administration & dosage* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008823:Micelles; D041681:NIH 3T3 Cells; D009534:Niclosamide / Q000008:administration & dosage* / Q000378:metabolism; D011060:Poloxalene / Q000008:administration & dosage* / Q000378:metabolism; D020442:Poloxamer / Q000008:administration & dosage* / Q000378:metabolism; D000090822:Ribosomal Protein L3
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; C000716548:Rpl3 protein, mouse; D020442:Poloxamer; C464484:pluronic block copolymer P123; D001710:Biotin; D009534:Niclosamide; D011060:Poloxalene
keywords: Lung cancer cells; Micelle; Multidrug resistance; Niclosamide; Pluronic(®)