Synthesis and in vitro evaluation of methotrexate conjugated O,N-carboxymethyl chitosan via peptidyl spacers

The use of methotrexate (MTX), an anticancer drug for the treatment of hematologic malignancies, has been limited in the clinical application due to its poor water solubility, high clearance rate, and lack of target specificity. To solve these problems, O,N-carboxymethyl chitosan–dipeptide-MTX conjugates have been synthesized and characterized by fourier transform infrared radiation spectroscopy and proton nuclear magnetic resonance (1H NMR). All polymeric conjugates showed satisfactory water solubility. The results of the study revealed that drug release and toxicity were affected by employing polymeric conjugation strategy and dipeptide spacers [glycylglycine (Gly–Gly), glycyl–l-phenylalanine (Gly–Phe), glycyl–l-tyrosine (Gly–Tyr)]. It has been found that drugs could be effectively loaded and released when polymeric prodrugs were combined with a dipeptide spacer. In conclusion, O,N-CMCS–dipeptide-MTX polymeric prodrugs could potentially be used as responsive drug delivery systems.