Nutlin‐3a and Cytokine Co‐loaded Spermine‐Modified Acetalated Dextran Nanoparticles for Cancer Chemo‐Immunotherapy |
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| Authors: | Tomás Bauleth‐Ramos Mohammad‐Ali Shahbazi Dongfei Liu Flavia Fontana Alexandra Correia Patrícia Figueiredo Hongbo Zhang João Pedro Martins Jouni T Hirvonen Pedro Granja Bruno Sarmento Hélder A Santos |
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| Affiliation: | 1. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland;2. Instituto de Investiga??o e Inova??o em Saúde (I3S), University of Porto, Porto, Portugal;3. Instituto de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal;4. Instituto Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal;5. Department of Micro‐ and Nanotechnology, Technical University of Denmark, Kgs. Lyngby, Denmark;6. Department of Pharmaceutical Science, ?bo Akademi University, Turku, Finland;7. CESPU, Instituto de Investiga??o e Forma??o Avan?ada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal;8. Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland |
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| Abstract: | The combination of chemo‐ and immunotherapy represents one promising strategy to overcome the existent challenges in the present‐day anticancer therapy. Here, spermine‐modified acetalated dextran nanoparticles (Sp‐AcDEX NPs), co‐loaded with the non‐genotoxic molecule Nutlin‐3a (Nut3a), and the cytokine granulocyte–macrophage colony‐stimulating factor (GM‐CSF), are developed to induce cancer cell death and create a specific antitumor immune response. These polymeric NPs release Nut3a in a pH dependent fashion and induce endosomal escape. Due to Nut3a, the loaded NPs exert specific toxicity toward wild‐type p53 cancer cells while avoiding toxicity in immune cells. Furthermore, the NPs show intrinsic immune adjuvancy on monocyte derived‐dendritic cells, upregulating the expression of cell surface CD83 and CD86 costimulatory markers. Finally, it is examined that by inducing MCF‐7 breast cancer cell death and acting as immune adjuvants, the NPs can downregulate the expression of IL‐10 and upregulate IL‐1β, leading to proliferation of CD3+ and cytotoxic CD8+ T cells. Overall, the study suggests that Sp‐AcDEX NPs loaded with Nut3a and GM‐CSF is a promising system for chemo‐immunotherapy, capable of inducing tumor cell death and stimulating immune response. |
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| Keywords: | acetalated dextran nanoparticles chemo‐immunotherapy dendritic Cells Nutlin‐3a T‐cell activation |
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