Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Bor, Gizem; Mytych, Jennifer; Żebrowski, Jacek; Wnuk, Maciej; Şanlı‐Mohamed, Gülşah

doi:10.1016/j.ijpharm.2016.09.058

Cited by 18 publications

(9 citation statements)

References 46 publications

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“…Literature review showed several contradictory results regarding Chit NPs effect on cellular ROS production. One study suggested that Chit NPs had an inhibitory activity (Bor et al, 2016), two studies reported no Chit NPs effect (Omar Zaki et al, 2015;Arora et al, 2016) and three reported a stimulating effect (Hu et al, 2011;Sarangapani et al, 2018;Wang et al, 2018) on basal ROS cellular production. Concerning the polymer, same conflicting results were also found (Arora et al, 2016;Salehi et al, 2017;Sarangapani et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility

Jesus

Marques

Duarte

et al. 2020

Front. Bioeng. Biotechnol.

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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.

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Section: Discussionmentioning

confidence: 99%

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility

Jesus

Marques

Duarte

et al. 2020

Front. Bioeng. Biotechnol.

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“…In detail, Grabowski et al found a transient production of ROS with chitosan stabilized PLGA NPs in THP-1 cells (Grabowski et al, 2015), Sharma et al verified an increased oxidative effect of oleanolic acid when delivered by chitosan coated PLGA NPs in MDAMB-231 cells (Sharma et al, 2017), Sarangapani et al found an increase in ROS production in BCL2(AAA) Jurkat cells with chitosan NPs (Sarangapani et al, 2018) and Gao et al found an increase in ROS production in zebrafish embryos incubated with chitosan NPs (Hu et al, 2011). In contrast, Bor et al found a reduction in ROS production with plasmid loaded chitosan NPs and chitosan NPs in Hela, THP-1 and MDAMB-231 cells (Bor et al, 2016). These inconsistent results, obtained with different chitosan based nanomaterials, different cellular models and concentrations do not allow for a straightforward interpretation of the oxidative effect of nanoscale chitosan.…”

Section: Hazard Characterization Of Polymeric Nanomaterials—literaturmentioning

confidence: 96%

“…Also, it is important to note, that the tested concentrations (10–50 μg/mL), caused increasing cell death as verified by the MTT assay, and therefore, the oxidative stress was the mechanism identified as responsible for cellular toxicity. In contrast, Bor et al verified that chitosan NPs reduced ROS production in several cell lines (also tumor derived cells), but they used a concentration that did not cause cell death (Bor et al, 2016). Therefore, although at first sight the results are conflicting, they cannot be directly compared, but we can hypothesize that chitosan NPs might influence ROS production in a concentration dependent manner.…”

Section: Hazard Characterization Of Polymeric Nanomaterials—literaturmentioning

confidence: 99%

Hazard Assessment of Polymeric Nanobiomaterials for Drug Delivery: What Can We Learn From Literature So Far

Jesus

Schmutz

Som

et al. 2019

Front. Bioeng. Biotechnol.

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The physicochemical properties of nanobiomaterials, such as their small size and high surface area ratio, make them attractive, novel drug-carriers, with increased cellular interaction and increased permeation through several biological barriers. However, these same properties hinder any extrapolation of knowledge from the toxicity of their raw material. Though, as suggested by the Safe-by-Design (SbD) concept, the hazard assessment should be the starting point for the formulation development. This may enable us to select the most promising candidates of polymeric nanobiomaterials for safe drug-delivery in an early phase of innovation. Nowadays the majority of reports on polymeric nanomaterials are focused in optimizing the nanocarrier features, such as size, physical stability and drug loading efficacy, and in performing preliminary cytocompatibility testing and proving effectiveness of the drug loaded formulation, using the most diverse cell lines. Toxicological studies exploring the biological effects of the polymeric nanomaterials, particularly regarding immune system interaction are often disregarded. The objective of this review is to illustrate what is known about the biological effects of polymeric nanomaterials and to see if trends in toxicity and general links between physicochemical properties of nanobiomaterials and their effects may be derived. For that, data on chitosan, polylactic acid (PLA), polyhydroxyalkanoate (PHA), poly(lactic-co-glycolic acid) (PLGA) and policaprolactone (PCL) nanomaterials will be evaluated regarding acute and repeated dose toxicity, inflammation, oxidative stress, genotoxicity, toxicity on reproduction and hemocompatibility. We further intend to identify the analytical and biological tests described in the literature used to assess polymeric nanomaterials toxicity, to evaluate and interpret the available results and to expose the obstacles and challenges related to the nanomaterial testing. At the present time, considering all the information collected, the hazard assessment and thus also the SbD of polymeric nanomaterials is still dependent on a case-by-case evaluation. The identified obstacles prevent the identification of toxicity trends and the generation of an assertive toxicity database. In the future, in vitro and in vivo harmonized toxicity studies using unloaded polymeric nanomaterials, extensively characterized regarding their intrinsic and extrinsic properties should allow to generate such database. Such a database would enable us to apply the SbD approach more efficiently.

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“…Natural and synthetic polymers can be used for gene transfection (40,41). Some examples of natural polymers used in gene therapy are polysaccharides such as chitosan (41,42) and alginate (43), or proteins like albumin (44). Also, synthetic polymers can be employed, such as polycaprolactone (PLC) (45), polylactic acid (PLA) (46), polyethyleneimine (PEI) (47), poly (lactic-co-glycolic acid) (PLGA) (46,48) or polyethylene glycol (PEG) (49).…”

Section: Nanoparticles For Pdna Transfectionmentioning

confidence: 99%

Nanoparticles for death‑induced gene therapy in cancer (Review)

et al. 2017

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Due to the high toxicity and side effects of the use of traditional chemotherapy in cancer, scientists are working on the development of alternative therapeutic technologies. An example of this is the use of death‑induced gene therapy. This therapy consists of the killing of tumor cells via transfection with plasmid DNA (pDNA) that contains a gene which produces a protein that results in the apoptosis of cancerous cells. The cell death is caused by the direct activation of apoptosis (apoptosis‑induced gene therapy) or by the protein toxic effects (toxin‑induced gene therapy). The introduction of pDNA into the tumor cells has been a challenge for the development of this therapy. The most recent implementation of gene vectors is the use of polymeric or inorganic nanoparticles, which have biological and physicochemical properties (shape, size, surface charge, water interaction and biodegradation rate) that allow them to carry the pDNA into the tumor cell. Furthermore, nanoparticles may be functionalized with specific molecules for the recognition of molecular markers on the surface of tumor cells. The binding between the nanoparticle and the tumor cell induces specific endocytosis, avoiding toxicity in healthy cells. Currently, there are no clinical protocols approved for the use of nanoparticles in death‑induced gene therapy. There are still various challenges in the design of the perfect transfection vector, however nanoparticles have been demonstrated to be a suitable candidate. This review describes the role of nanoparticles used for pDNA transfection and key aspects for their use in death‑induced gene therapy.

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Cytotoxic and cytostatic side effects of chitosan nanoparticles as a non-viral gene carrier

Cited by 18 publications

References 46 publications

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility

Hazard Assessment of Polymeric Nanobiomaterials for Drug Delivery: What Can We Learn From Literature So Far

Nanoparticles for death‑induced gene therapy in cancer (Review)

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