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

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.

Preparation and Characterization of Dentin Phosphophoryn‐Derived Peptide‐Functionalized Lignin Nanoparticles for Enhanced Cellular Uptake

“…Moreover, the BZL@LNPs-DSS showed a superior efficacy than the BZL@LNPs-iRGD, as for MDA-MB-231 cell line. As expected, the antiproliferative effect of the BZL@LNPs was more pronounced toward the 2D cell model, Small 2019, 15,1901427…”

“…As for the size distribution (Figure 2a), the prepared LNPs and BZL@LNPs before and after functionalization exhibited PDI values lower than 0.20, suggesting a moderate dispersity of the LNPs. The size distribution and morphology of the LNPs was also verified by transmission electron microscopy (TEM, Figure 2b), where the particles showed an average size and moderate dispersity similar to the values found by Small 2019, 15,1901427 DLS. Furthermore, the LNPs showed symmetric and spherical shape, due to the suitable interaction between the lignin and water during the process of solvent exchange.…”

“…[53] Additionally, the peptide-decorated LNPs were generally taken-up more efficiently by the three cell lines than the bare LNPs in both cell culturing models. Furthermore, in some cases, the LNPs-DSS showed a superior cellular internalization Small 2019, 15,1901427 than the LNPs-iRGD. The DSS peptide derived from DPP is a repetitive DSS-rich domain that facilitates non-receptormediated endocytosis, acting as a cell penetrating peptide.…”

“…Small 2019, 15,1901427 Afterward, EDC/NHS coupling chemistry was carried out to conjugate the LNPs with equal molar amounts of both iRGD and DSS peptides, and consequently, the COOH groups on the LNPs were covalently bonded to the NH 2 group on the peptides. Then, the LNPs were characterized for their average particle size (Z-average), polydispersity index (PDI), and average zeta (ζ)-potential by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and ATR−FTIR (Figure 2a-c).…”

“…After 4 h, 10% FBS was added to increase the dissolution of the released drug, as the FBS is known to increase the solubility of some hydrophobic drugs, such as sorafenib. [44] Therefore, the release profiles of BZL from LNPs, LNPs-iRGD and LNPs-DSS at pH 5.5 were Small 2019, 15,1901427 significantly improved after 6 h, being ≈70%, 67%, and 65%, respectively. However, at pH 7.4, the release of BZL increased after addition of 10% FBS, but decreased after 6 h, which can be due to the precipitation or degradation of BZL.…”