Enhancing Aqueous Solubility and Anticancer Efficacy of Oligochitosan-Folate-Cisplatin Conjugates through Oleic Acid Grafting for Targeted Nanomedicine Development.

Oligochitosan is an anticancer water-soluble biomaterial. Conjugating cisplatin (anticancer drug) and folic acid (targeting ligand) with oligochitosan reduces its aqueous solubility, thus requiring excessive drug dose to be biologically active and organic instead of aqueous processing into nanomedicine. Covalent grafting of oleic acid onto oligochitosan-folate-cisplatin conjugate is envisaged to promote aqueous solubility via reducing interchain interaction, but it is challenging where multiple functional moieties are covalently attached onto a short oligomer (<5 kDa). This study produced oligochitosan-oleate-folate-cisplatin conjugate dissolvable in aqueous media pH 3-7, which represents common processing pH in drug vehicle development and tumor microenvironmental pHs. Oligochitosan-oleate conjugation was effected through -acylation to provide amino groups of oligochitosan for folate and cisplatin grafting. Oligochitosan-folate-cisplatin conjugate was poorly soluble in aqueous and organic media. A degree of oleic acid substitution (DS) < 10% conferred aqueous solubility beyond which became less soluble due to hydrophobicity rise. Oligochitosan-oleate-folate-cisplatin conjugate with 4.51 ± 0.32% DS, 8.50 ± 0.57% folate content, and 0.94 ± 0.80% cisplatin content was dissolvable in aqueous media pH 3.3-7, conferring processing safety with improved cancer cytotoxicity in the nanoparticulate form at the acidic tumor microenvironment.