title: Secondary cytotoxicity mediated by alveolar macrophages: a contribution to the total efficacy of nanoparticles in lung cancer therapy?
abstract: Local treatment of lung cancer using inhalable nanoparticles (NPs) is an emerging and promising treatment option. The aim of this study was to investigate the activation of alveolar macrophages by poly (isobutyl cyanoacrylate) (BIPCA) NPs and the consequences of this activation on H460 lung cancer cells. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to determine the primary cytotoxicity, that is, the immediate and direct cytotoxicity of doxorubicin (DOX)-loaded NPs on both cell lines. Macrophages were then treated using EC(50) concentrations of different treatments and co-cultured in a two-compartment system with H460 lung cancer cells. These treatments included DOX solution, blank NPs, and DOX-loaded NPs. The results showed that alveolar macrophages exposed to blank or DOX-loaded NPs showed cytotoxicity against cancer cells after 8 and 24h; this behavior was not expressed by naïve macrophages or macrophages treated with DOX solution. Sample analysis indicated that macrophages have the ability to release back fragments of NPs that were previously phagocytized. Further investigations showed that NPs can induce an increase in the excretion of Th1 cytokines namely, monocytes chemoattractant protein-1 (MCP-1), macrophages inflammatory protein (MIP-1), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). The Th1 cytokines released by the alveolar macrophages might explain the significant secondary cytotoxicity effect on H460 cancer cells. Secondary cytotoxicity mediated by macrophages might compliment the direct cytotoxic effect that NPs have on cancer cells.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Alberta, Canada.
authors.forename: Kamal M H D
authors.initials: KM
authors.lastname: Al-Hallak
authors.forename: Shirzad
authors.initials: S
authors.lastname: Azarmi
authors.forename: Anwar
authors.initials: A
authors.lastname: Anwar-Mohamed
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Roa
authors.forename: Raimar
authors.initials: R
authors.lastname: Löbenberg
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D003487:Cyanoacrylates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004659:Enbucrilate; D006801:Humans; D020128:Inhibitory Concentration 50; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D053758:Nanoparticles; D010587:Phagocytosis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D003487:Cyanoacrylates; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D007371:Interferon-gamma; D004659:Enbucrilate