title: An interferon-γ-delivery system based on chitosan/poly(γ-glutamic acid) polyelectrolyte complexes modulates macrophage-derived stimulation of cancer cell invasion in vitro.
abstract: Macrophages represent a large component of the tumour microenvironment and are described to establish interactions with cancer cells, playing crucial roles in several stages of cancer progression. The functional plasticity of macrophages upon stimulation from the environment makes them susceptible to the influence of cancer cells and also renders them as promising therapeutic targets. In this work, we describe a drug delivery system to modulate the phenotype of macrophages, converting them from the pro-tumour M2 phenotype to the anti-tumour M1 phenotype, based on the incorporation of a pro-inflammatory cytokine (interferon-γ) in chitosan (Ch)/poly(γ-glutamic acid) (γ-PGA) complexes. Ch is a biocompatible cationic polysaccharide extensively studied and γ-PGA is a biodegradable, hydrophilic and negatively charged poly-amino acid. These components interact electrostatically, due to opposite charges, resulting in self-assembled structures that can be designed to deliver active molecules such as drugs and proteins. Ch and γ-PGA were self-assembled into polyelectrolyte multilayer films (PEMs) of 371nm thickness, using the layer-by-layer method. Interferon-γ (IFN-γ) was incorporated within the Ch layers at 100 and 500ng/mL. Ch/γ-PGA PEMs with IFN-γ were able to modulate the phenotype of IL-10-treated macrophages at the cell cytoskeleton and cytokine profile levels, inducing an increase of IL-6 and a decrease of IL-10 production. More interestingly, the pro-invasive role of IL-10-treated macrophages was hindered, as their stimulation of gastric cancer cell invasion in vitro decreased from 4 to 2-fold, upon modulation by Ch/γ-PGA PEMs with IFN-γ. This is the first report proposing Ch/γ-PGA PEMs as a suitable strategy to incorporate and release bioactive IFN-γ with the aim of modulating macrophage phenotype, counteracting their stimulating role on gastric cancer cell invasion.
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; FEUP-Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Cardoso
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Gonçalves
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Joana C
authors.initials: JC
authors.lastname: Antunes
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Marta L
authors.initials: ML
authors.lastname: Pinto
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; FEUP-Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Pinto
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Flávia
authors.initials: F
authors.lastname: Castro
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Monteiro
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Mário A
authors.initials: MA
authors.lastname: Barbosa
authors.affiliation: I(3)S-Instituto de Investigação e Inovação em Saúde, Universidade doPorto, Porto, Portugal; INEB-Institute of Biomedical Engineering, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Oliveira
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D048271:Chitosan / Q000737:chemistry*; D016207:Cytokines / Q000276:immunology; D004573:Electrolytes; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D016207:Cytokines; D004573:Electrolytes; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D007371:Interferon-gamma; D048271:Chitosan
keywords: Cancer; Drug delivery; Immunomodulation; Macrophage; Polyelectrolyte multilayers