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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.

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