Degradability of chitosan micro/nanoparticles for pulmonary drug delivery

Abstract

Chitosan, a natural carbohydrate polymer, has long been investigated for drug delivery and medical applications due to its biodegradability, biocompatibility and low toxicity. The micro/nanoparticulate forms of chitosan are reported to enhance the efficiency of drug delivery with better physicochemical properties including improved solubility and bioavailability. This polymer is known to be biodegradable and biocompatible; however, crosslinked chitosan particles may not be biodegradable. Crosslinkers (e.g., tripolyphosphate and glutaraldehyde) are needed for efficient micro/nanoparticle formation, but it is not clear whether the resultant particles are biodegradable or able to release the encapsulated drug fully. To date, no studies have conclusively demonstrated the complete biodegradation or elimination of chitosan nanoparticles in vivo. Herein we review the synthesis and degradation mechanisms of chitosan micro/nanoparticles frequently used in drug delivery especially in pulmonary drug delivery to understand whether these nanoparticles are biodegradable.

Keywords: Analytical chemistry; Bioengineering; Biogeoscience; Biomedical engineering; Cancer research; Infectious disease; Materials chemistry; Nanotechnology; Pharmaceutical chemistry; Physical chemistry.

Fig. 1

Chemical structure of Chitosan showing residual N-acetyl groups from the parent chitin.

Fig. 2

Chitosan ionically crosslinked with TPP.

Fig. 3

Chitosan chemically crosslinked with glutaraldehyde.

Fig. 4

Structure of crosslink formed by Schiff base reaction of glutaraldehyde with amino groups of two chitosan or conjugate repeat units (R₁ and R₂). Note the two aldehyde end groups.

Fig. 5

Structure of crosslink formed by Michael-type reaction of glutaraldehyde with amino groups of two chitosan or conjugate repeat units (R₁ and R₂). Note the in-chain as well as the two end-chain aldehyde groups.

Fig. 6

Chitosan catalyses the polymerization of glutaraldehyde and produces inhomogeneous products, Reproduced from .

Fig. 7

Schematic diagram of chitosan nanoparticles formed by crosslinking agents.

Scheme 1

Simplified schematics of the original ionic cross-linking configurations (a) H-link and (b) T-link. Combinations of fundamental linking types lead to (c) secondary linking types. In configuration (c), the dotted monomer structures are off-plane and form T-links with the TPP units below them. Reproduced from .

Fig. 8

The enzymatic degradation profiles of the prepared chitosan microparticles in phosphate buffer (PBS, pH 7.4) in the presence of lysozyme (adapted from El-Sherbiny and Smyth 2010 [78]).