Journal
ADVANCED FUNCTIONAL MATERIALS
Volume 27, Issue 42, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201703303
Keywords
acetalated dextran nanoparticles; chemo-immunotherapy; dendritic Cells; Nutlin-3a; T-cell activation
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia [SFRH/BD/110859/2015]
- FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal
- FCT - Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Inovacao [POCI-01-0145-FEDER-007274]
- Jane and Aatos Erkko Foundation [4704010]
- Academy of Finland [297580, 252215, 281300]
- University of Helsinki
- Biocentrum Helsinki
- Sigrid Juselius Foundation [4704580]
- Helsinki Institute of Life Science
- European Research Council under European Union's Seventh Framework Programme [310892]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/110859/2015] Funding Source: FCT
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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.
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