A Self-Healing Metal-Organic gel (MOG) exhibiting pH-Responsive release of a chemotherapeutic agent, doxorubicin: modulation of release kinetics by partial dehydration of matrix

Abstract

Use of soft and porous metal−organic gels (MOGs), formed by metal−ligand coordination, has generated immense research interest in fields like conductance, catalysis, chemical sensing, and dye adsorption, but there are only few reports on their use in drug delivery, particularly cancer drug delivery. Consequently, a Cr3+-based metal− organic gel (MOG1) was synthesized from Cr(NO3)3·9H2O and 2,2′- bipyridine-4,4′-dicarboxylic acid (BPDA) in DMF, using a solvothermal route. The gel exhibited strong resilience when subjected to a dynamic frequency sweep from 1−100 rad/sec at a constant strain of 0.1% and minimal loss of storage modulus when subjected to repeated cycles of 0.1 and 100% strain for 60 s, and it exhibited self-healing characteristics. The doxorubicin (DOX)-loaded gels were developed to assess the drug release profiles at physiological (7.4) and intratumoral (6.4) pH and found to be pH-dependent. A sustained zero-order release of 54% drug was obtained after 48 h at pH 7.4 and, a faster release, with 87.4% of the drug being released in 12 h following pseudo-Fickian diffusion at pH 6.4. The most unique feature of the gel, not reported earlier, was the transformation of the drug release kinetics from zero order to exponential decay upon dehydration to 80% of its original weight. The drug release slowed down further when the gel was dehydrated to 50% of its original weight. The cell viability assay showed no significant toxicity of MOG1 to mdck (kidney epithelial) cell lines, and more than 75% cells were viable, even after 72 h, with concentrations up to 100 μg/mL, whereas the DOX-loaded MOG1 demonstrated dose-dependent toxicity to cancer cell lines (A549) in the concentration range investigated (0.1−5 μg/mL equivalent DOX). Fluorescence microscopy studies revealed efficient internalization of DOX released from MOG1 into cancer cells. The gel may be employed as an injectable depot for quick and selective delivery of a chemotherapeutic agent to tumoral sites.