Biological Safety and Biodistribution of Chitosan Nanoparticles.

Dmitry Sonin,Ilia Aleksandrov,Maria Istomina,Lyubov Vasina,Elena Naumysheva,Daria Mukhametdinova,Marina Vasyutina,Irina Zelinskaya,Dmitry Korolev,Natalia Rubanova,Evgeniia Pochkaeva,Viktor Postnov,Michael Galagudza,Daria Kostina,Pavel Somov,Yury Skorik,Anna Malashicheva,Sergei Zhuravskii

doi:10.3390/nano10040810

Abstract

The effect of unmodified chitosan nanoparticles with a size of ~100 nm and a weakly positive charge on blood coagulation, metabolic activity of cultured cardiomyocytes, general toxicity, biodistribution, and reactive changes in rat organs in response to their single intravenous administration at doses of 1, 2, and 4 mg/kg was studied. Chitosan nanoparticles (CNPs) have a small cytotoxic effect and have a weak antiplatelet and anticoagulant effect. Intravenous administration of CNPs does not cause significant hemodynamic changes, and 30 min after the CNPs administration, they mainly accumulate in the liver and lungs, without causing hemolysis and leukocytosis. The toxicity of chitosan nanoparticles was manifested in a dose-dependent short-term delay in weight gain with subsequent recovery, while in the 2-week observation period no signs of pain and distress were observed in rats. Granulomas found in the lungs and liver indicate slow biodegradation of chitosan nanoparticles. In general, the obtained results indicate a good tolerance of intravenous administration of an unmodified chitosan suspension in the studied dose range.

Highlights

Chitosan, the product of the complete or partial deacetylation of chitin, is a widely used excipient for topical or oral drug administration [1,2,3,4,5]
A tendency to a decrease was seen for the activated partial thromboplastin time (APTT), and an increase was noted for the thrombin time (TT) when a suspension of chitosan nanoparticles (CNPs) was mixed with human plasma (Table 1)
The IHC analysis with antibodies to CD68 revealed that the granulomas found in the lungs and liver at 14 days after intravenous CNP administration were formed by CD68+ macrophages (Figure 13)

Summary

Introduction

The product of the complete or partial deacetylation of chitin, is a widely used excipient for topical or oral drug administration [1,2,3,4,5] It is viewed as a useful material for the construction of drug and gene delivery systems for parenteral administration [1,6,7,8,9,10,11]. The prospect of using chitosan as a carrier matrix for drug delivery emphasizes the importance of knowing the biological safety of chitosan dispersal systems. This is especially the case when chitosan is supplied as a nanoscale formulation, as this raises issues about nanotoxicity. Particles larger than 300 nm can be eliminated from the human body by resident macrophages [13,15], but the activation of macrophages triggers aseptic inflammation, often with a granulomatous component (e.g., in the lungs and liver) [18,19,20]

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Discussion

Conclusion