期刊
CARBOHYDRATE POLYMERS
卷 127, 期 -, 页码 309-315出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.carbpol.2015.03.060
关键词
Chitosan; Isoniazid; Conjugate; Carbodiimide activation; Activated ester method; Drug delivery; Toxicity, Limax flavus
资金
- Russian Foundation for Basic Research [15-04-06664]
- St. Petersburg State University [12.38.220.2015]
- Russian President scholarship [SP-249.2012.4]
Novel water-soluble chitosan-isoniazid conjugates were synthesized by two methods: (I) the carbodiimide method using isoniazid (INH) and N-(2-carboxyethyl)chitosan (CEC), and (2) the reaction between INH and N-(3-chloro-2-hydroxypropyl)chitosan (CHPC). The solubility of the conjugates under physiological conditions was enhanced by phosphorylation. Method (1) is preferable in terms of obtaining conjugates with a high content of active substance; depending on reaction conditions, the degree of substitution in the INH-CEC conjugates varies from 0.08 to 0.39. Ultrasound treatment increased the reaction rate by a factor of 1.3-1.5, but caused partial degradation of the polymer. Consecutive modification led to a considerable decrease in polymer biodegradability in the following order: chitosan >CEC or CHPC> conjugate. In vitro screening of the antimicrobial activity against Mycobacterium tuberculosis H37Rv demonstrated a comparable or slightly higher minimum inhibitory concentration for conjugates than for INH itself (0.20, 0.25, and 1.05 mu g INH/mL for INH, CEC-INH, and CHPC-INH, respectively). A slug mucosal irritation test employing Limax flavus revealed a lower toxicity for the conjugates than for INH by a factor of 3-4; the most noticeable toxicity decrease was observed for the conjugates obtained by method (1). Studies of acute toxicity in mice revealed a 3-4-fold increase in median lethal dose for the conjugates compared with INH (LD50 210, 850, and 650 mg INH/kg for INH, CEC-INH, and CHPC-INH, respectively). (C) 2015 Elsevier Ltd. All rights reserved.
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