5 years ago

Nutlin-3a and Cytokine Co-loaded Spermine-Modified Acetalated Dextran Nanoparticles for Cancer Chemo-Immunotherapy

Nutlin-3a and Cytokine Co-loaded Spermine-Modified Acetalated Dextran Nanoparticles for Cancer Chemo-Immunotherapy
Flavia Fontana, Pedro Granja, Alexandra Correia, Hélder A. Santos, Jouni T. Hirvonen, João Pedro Martins, Hongbo Zhang, Tomás Bauleth-Ramos, Patrícia Figueiredo, Bruno Sarmento, Mohammad-Ali Shahbazi, Dongfei Liu
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. Nutlin-3a and granulocyte–macrophage colony-stimulator factor are co-loaded into spermine-modified acetalated dextran nanoparticles to produce a nanosystem for cancer chemo-immunotherapy. The nanosystem is biocompatible, exerts cancer cell death, has intrinsic immunoadjuvancy, induces upregulation of the costimulatory signals in dendritic cells, and changes the cytokine balance, leading to T-cell proliferation and development of CD8+ T-cell subset.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/adfm.201703303

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