Folic acid-decorated calix[4]resorcinol: Synthesis, dissolution in water and delivery of doxorubicin

Selective internalization in cancer cells has great potential to reduce the side effects of cancer therapy. One effective approach to increase targeting to cancer cells is modification of nanocarrier with folate groups, providing interaction with folic acid alpha receptors, which are overexpressed in some types of tumors. In this work, the folic acid-modified calix[4]resorcinol was synthesized. The choice of calix[4]resorcinol as a modified molecule is due to the possibility of simultaneous attachment of four folic groups. However, this synthetic modification did not improve the water solubility of the calixarene skeleton; therefore, its water-soluble form was further prepared in the presence of N-methyl-D-glucamine and the ability of the resulting form to bind doxorubicin hydrochloride was studied. When studying a mixed system of folic acid-based calix[4]resorcinol with doxorubicin, the smallest particles were found at their equimolar ratio. The equimolar complex of the synthesized macrocycle with doxorubicin exhibits folic acid-receptor mediated selective uptake by M-HeLa cells and induces selective cancer death.