Abstract
Chitosan is a cationic polymer of natural origin and has been widely explored as a pharmaceutical excipient for a broad range of biomedical applications. While generally considered safe and biocompatible, chitosan has the ability to induce inflammatory reactions, which varies with the physical and chemical properties. We hypothesized that the previously reported zwitterionic chitosan (ZWC) derivative had relatively low pro-inflammatory potential because of the aqueous solubility and reduced amine content. To test this, we compared various chitosans with different aqueous solubilities or primary amine contents with respect to the intraperitoneal (IP) biocompatibility and the propensity to induce pro-inflammatory cytokine production from macrophages. ZWC was relatively well tolerated in ICR mice after IP administration and had no pro-inflammatory effect on naïve macrophages. Comparison with other chitosans indicates that these properties are mainly due to the aqueous solubility at neutral pH and relatively low molecular weight of ZWC. Interestingly, ZWC had a unique ability to suppress cytokine/chemokine production in macrophages challenged with lipopolysaccharide (LPS). This effect is likely due to the strong affinity of ZWC to LPS, which inactivates the pro-inflammatory function of LPS, and appears to be related to the reduced amine content. Our finding warrants further investigation of ZWC as a functional biomaterial.
Highlights
Chitosan is a linear copolymer of D-glucosamine (2-amino-2deoxy-D-glucose) and N-acetyl-D-glucosamine (2-acetamido-2deoxy-D-glucose), obtained by partial deacetylation of chitin, the main component of exoskeletons of insects and crustaceans [1]
We previously reported that a new chitosan derivative zwitterionic chitosan (ZWC) had excellent biocompatibility, comparing favorably with the precursor chitosan (LMCS) in hemocompatibility and with chitosan glutamate in the IP tissue responses [22]
Due to the ability to interact with serum proteins, chitosans activate macrophages and induce cytokine production [2]
Summary
Chitosan is a linear copolymer of D-glucosamine (2-amino-2deoxy-D-glucose) and N-acetyl-D-glucosamine (2-acetamido-2deoxy-D-glucose), obtained by partial (usually.80%) deacetylation of chitin, the main component of exoskeletons of insects and crustaceans [1]. With a pKa of ,6.5, chitosan is insoluble in water at neutral pH, where the majority of amines are deprotonated, but it is positively charged and water-soluble at acidic pH [11]. The limited solubility of chitosan in neutral pH provides a unique opportunity to form nanoparticulate drug/gene delivery platforms [11], but it is an obstacle if one intends to apply chitosan as a solution in the physiological condition [13]. To improve chitosan solubility in a broader range of pH, the amine groups of chitosan are partially quaternized [13] or conjugated with a sugar moiety [17]. A chitosan derivative with 2-hydroxyethylether groups in the 6-O position, is used when aqueous solubility of chitosan at neutral pH is desired [18,19,20,21]. The chitosan derivative, which we call zwitterionic chitosan (ZWC), is soluble in water at pH’s below and above the pI according to the change of its net charge
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