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

T Bauleth-Ramos, MA Shahbazi, DF Liu, F Fontana, A Correia, P Figueiredo, Hongbo Zhang, JP Martins, JT Hirvonen, P Granja, B Sarmento, HA Santos

Research output: Contribution to journalArticleScientificpeer-review

30 Citations (Scopus)

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-1 beta, 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.
Original languageUndefined/Unknown
Pages (from-to)
Number of pages14
JournalAdvanced Functional Materials
Volume27
Issue number42
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

Keywords

  • acetalated dextran nanoparticles
  • chemo-immunotherapy
  • Nutlin-3a
  • T-cell activation
  • DENDRITIC CELLS

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