Abstract
Nanoparticles (NPs) assumed an important role in the area of drug delivery. Despite the number of studies including NPs are growing over the last years, their side effects on the immune system are often ignored or omitted. One of the most studied polymers in the nano based drug delivery system field is chitosan (Chit). In the scientific literature, although the physicochemical properties [molecular weight (MW) or deacetylation degree (DDA)] of the chitosan, endotoxin contamination and appropriate testing controls are rarely reported, they can strongly influence immunotoxicity results. The present work aimed to study the immunotoxicity of NPs produced with different DDA and MW Chit polymers and to benchmark it against the polymer itself. Chit NPs were prepared based on the ionic gelation of Chit with sodium tripolyphosphate (TPP). This method allowed the production of two different NPs: Chit 80% NPs (80% DDA) and Chit 93% NPs (93% DDA). In general, we found greater reduction in cell viability induced by Chit NPs than the respective Chit polymers when tested in vitro using human peripheral blood monocytes (PBMCs) or RAW 264.7 cell line. In addition, Chit 80% NPs were more cytotoxic for PBMCs, increased reactive oxygen species (ROS) production (above 156 μg/mL) in the RAW 264.7 cell line and interfered with the intrinsic pathway of coagulation (at 1 mg/mL) when compared to Chit 93% NPs. On the other hand, only Chit 93% NPs induced platelet aggregation (at 2 mg/mL). Although Chit NPs and Chit polymers did not stimulate the nitric oxide (NO) production in RAW 264.7 cells, they induced a decrease in lipopolysaccharide (LPS)-induced NO production at all tested concentrations. None of Chit NPs and polymers caused hemolysis, nor induced PBMCs to secrete TNF-α and IL-6 cytokines. From the obtained results we concluded that the DDA of the Chit polymer and the size of Chit NPs influence the in vitro immunotoxicity results. As the NPs are more cytotoxic than the corresponding polymers, one should be careful in the extrapolation of trends from the polymer to the NPs, and in the comparisons among delivery systems prepared with different DDA chitosans.
Highlights
Studies have shown that nanoparticles (NPs) can interact with different components of the immune system, resulting in immunosuppression and in immunostimulation (Dobrovolskaia and McNeil, 2007)
Chit is known for its mucoadhesive properties and its ability to stimulate cells of the immune system, which supports the value of investigating Chit NPs as vaccine adjuvants (Dedloff et al, 2019)
In the early stages of the development of a nanotechnology-based medicine, when the drug is to be encapsulated into NPs, the first question to be considered is, whether it is supposed that the new nanomedicine, in addition to its main pharmacological action, acts on the immune system
Summary
Studies have shown that nanoparticles (NPs) can interact with different components of the immune system, resulting in immunosuppression and in immunostimulation (Dobrovolskaia and McNeil, 2007). Chit is known for its mucoadhesive properties and its ability to stimulate cells of the immune system, which supports the value of investigating Chit NPs as vaccine adjuvants (Dedloff et al, 2019) For this purpose, it has long been used by the group with various antigens, such as the hepatitis B surface antigen (HBsAg) (Borges et al, 2008; Lebre et al, 2016; Jesus et al, 2017, 2018; Soares et al, 2018a,b; Bento et al, 2019), the protective antigen (PA) from anthrax (Bento et al, 2015) or antigens from Schistosoma mansoni (Oliveira et al, 2012). In the context of Safe-by-Design (SbD) of new polymeric NPs for drug delivery, it is necessary to rely on assertive results of immunotoxicity and hemocompatibility, obtained with properly characterized polymeric NPs
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