title: Functionalized immunostimulating complexes with protein A via lipid vinyl sulfones to deliver cancer drugs to trastuzumab-resistant HER2-overexpressing breast cancer cells.
abstract: BACKGROUND
  Around 20%-30% of breast cancers overexpress the proto-oncogene human epidermal growth receptor 2 (HER2), and they are characterized by being very invasive. Therefore, many current studies are focused on testing new therapies against tumors that overexpress this receptor. In particular, there exists major interest in new strategies to fight breast cancer resistant to trastuzumab (Tmab), a humanized antibody that binds specifically to HER2 interfering with its mitogenic signaling. Our team has previously developed immunostimulating complexes (ISCOMs) as nanocapsules functionalized with lipid vinyl sulfones, which can incorporate protein A and bind to G immunoglobulins that makes them very flexible nanocarriers.
  
  
  RESULTS
  The aim of this in vitro study was to synthesize and evaluate a drug delivery system based on protein A-functionalized ISCOMs to target HER2-overexpressing cells. We describe the preparation of ISCOMs, the loading with the drugs doxorubicin and paclitaxel, the binding of ISCOMs to alkyl vinyl sulfone-protein A, the coupling of Tmab, and the evaluation in both HER2-overexpressing breast cancer cells (HCC1954) and non-overexpressing cells (MCF-7) by flow cytometry and fluorescence microscopy. Results show that the uptake is dependent on the level of overexpression of HER2, and the analysis of the cell viability reveals that targeted drugs are selective toward HCC1954, whereas MCF-7 cells remain unaffected.
  
  
  CONCLUSIONS
  Protein A-functionalized ISCOMs are versatile carriers that can be coupled to antibodies that act as targeting agents to deliver drugs. When coupling to Tmab and loading with paclitaxel or doxorubicin, they become efficient vehicles for the selective delivery of the drug to Tmab-resistant HER2-overexpressing breast cancer cells. These nanoparticles may pave the way for the development of novel therapies for poor prognosis resistant patients.
authors.affiliation: Institute of Biopathology and Regenerative Medicine.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Serrano
authors.affiliation: Institute of Biopathology and Regenerative Medicine.
authors.forename: Nuria
authors.initials: N
authors.lastname: Mut-Salud
authors.affiliation: Molecular Biochemistry and Parasitology Research Group, Department of Parasitology, Faculty of Sciences, Institute of Biotechnology, University of Granada.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cruz-Bustos
authors.affiliation: Molecular Biochemistry and Parasitology Research Group, Department of Parasitology, Faculty of Sciences, Institute of Biotechnology, University of Granada.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gomez-Samblas
authors.affiliation: Institute of Biopathology and Regenerative Medicine.
authors.forename: Esther
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: Department of Cardiovascular Surgery, Virgen de las Nieves Hospital.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garrido
authors.affiliation: Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology, University of Granada, Granada, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: López-Jaramillo
authors.affiliation: Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology, University of Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Santoyo-Gonzalez
authors.affiliation: Molecular Biochemistry and Parasitology Research Group, Department of Parasitology, Faculty of Sciences, Institute of Biotechnology, University of Granada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Osuna
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016882:ISCOMs / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010078:Oxazines / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013205:Staphylococcal Protein A / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry*; D000068878:Trastuzumab / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D016882:ISCOMs; D008055:Lipids; D010078:Oxazines; D017239:Paclitaxel; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D013205:Staphylococcal Protein A; D013450:Sulfones; D000068878:Trastuzumab; C000715470:MAS1 protein, human; C009873:divinyl sulfone; C044808:nile red
keywords: HER2; doxorubicin; nanoparticle; paclitaxel; protein A; targeted drug delivery; trastuzumab