Metastatic spread inhibition of cancer cells through stimuli-sensitive HPMA copolymer-bound actinonin nanomedicines

The unresolved task of modern medicine is to prevent metastatic spread during and after the treatment of primary tumors. Here, the design, controlled synthesis, in-depth physicochemical and biological characteristics of a novel panel of well-defined water-soluble copolymer conjugates bearing actinonin intended for advanced drug delivery and inhibition of metastatic spread are described. Three different synthetic approaches were employed to covalently attach actinonin to the N-(2-hydroxypropyl)methacrylamide copolymers to control the release of actinonin to its pharmacologically active form. Actinonin was attached to the polymers via hydroxamate group suppressing its activity during the delivery, with the activity restored after its release in the primary tumors or metastatic foci. Importantly, developed nanosystems with favorable drug release kinetics inhibited the metastatic spread of cancer cells from primary 4T1 tumors into the lungs as well as invasion of B16F10 melanoma cells from circulation into the lungs at the dosage without any sign of toxicity. Well-defined biocompatible and stimuli-sensitive polymer-actinonin conjugates were designed and their anti-metastatic efficacy was proved in two mice models. The silenced actinonin in the form of polymer conjugate is released and activated into the pharmacologically active form in the primary tumors or metastatic foci. The re-activation of the actinonin activity within the tumorous tissue enable to inhibit metastatic spread from the primary tumor. [Display omitted]