Structure-Toxicity Relationship of Chemically Modified Chitosan as an Oral Protein Drug Delivery Carrier

Abstract

chitosan has been extensively used as an absorption enhancer for macromolecules and as a mucosal vaccine carrier. Both of these properties are molecular weight (MW ) and degree of quaternization (DQ) dependent. The aim of the present study was to evaluate the impact of some synthesized trimethylated chitosan with various MW and DQ on biological systems in terms of biocompatibility and providing guidelines for the rational design of chitosan derivatives for effective and safe drug delivery. For this purpose, cytotoxicity in HT29 cell line was monitored using the MTT assay and the release of the cytosolic enzyme lactate dehydrogenase (LDH). Microscopic observation was carried out as indicators for blood cell compatibility. Furthermore, haemolysis was quantified spectrophotometrically for evaluation of haematotoxicity. Two polymer doses were used for sub acute toxicity study in BALBc mice. After oral administration, animals were monitored over 28 days and necropised. Signs of toxicity were evaluated via mortality and histopathology of liver, kidney and spleen. The magnitude of the cytotoxic effects all chitosan derivatives were found to be concentration dependent. Higher concentration of trimethylated chitosan with 22% DQ and native chitosan did not cause significant abnormalities among experimental group of mice, whereas, trimethylated chitosan with higher DQ as 50% and 61% may lead to concentration dependent cytotoxicity, hematotoxicity and increased renal and hepatotoxicity. All assays yielded comparable results and concluded cationic charge density of the chitosan derivatives seems as key parameters for the interaction with the cell membranes and consequently the cell damage. These results indicate that structure-toxicity relationship is necessary to optimize the degree of modification of chitosan for the development of biocompatible and biodegradable derivatives.

Nanomedicine for increasing the oral bioavailability of cancer treatments

“…6 a). This phenomenon is most prominent at low pH [ 81 ], when chitosan protonation occurs, destabilizing the junctions, but chemical modifications like methylation can extend these properties and increase chitosan solubility in a broader range of pH [ 82 ]. Chitosan is also partially soluble in water, generating hydrogel formulations that can accommodate different payloads, including biologics like proteins and siRNA [ 83 ].…”

“…Polysac Chitosan modified with acrylonitrile and arginine – Increased curcumin bioavailability [ 74 ] Cyclodextrin micelles Sarcoma Increased docetaxel BA and tumor reduction [ 76 ] Guar gum (GG) NPs – Increased mammary gland targeting, tamoxifen BA, and decreased liver toxicity [ 77 ] 4. Protein Pectin coated casein/zein NP – Enhanced curcumin bioavailability (BA) [ 82 ] Apotransferrin and lactoferrin NP Hepatocellular carcinoma Enhanced doxorubicin BA and decreased liver nodule number [ 83 ] Milk casein NP – Increased resveratrol BA than free administered drug [ 88 ] Polydopamine NPs – Increased gastric targeting and local xanthatin delivery [ 120 ] 5. Lipid nanoparticles Hybrid lipid- poly(ε-caprolactone) NP Subcutaneous model of hepatic cancer Increased cabazitaxel BA and tumor growth inhibition [ 92 ] Hybrid polymer-lipid NP – Increased berberine bioavailability [ 93 ] Chitosan coated solid lipid NP – Increased curcumin bioavailability [ 95 ] Amphiphilic and pegylated lipids and cholesterol ...…”