Multi-Biofunctional Silver-Containing Metallosupramolecular Nanogels for Efficient Antibacterial Treatment and Selective Anticancer Therapy

Abstract

We develop a simple and efficient route for the fabrication of water-soluble metallosupramolecular polymers. We demonstrate that the introduction of environment-responsive metal-organic complexes within supramolecular polymers endows the resulting self-assembled nano-objects with outstanding antibacterial activity and may significantly improve the efficacy and safety of selective cancer therapy. Herein, we successfully developed a silver-containing supramolecular polymer (Ag-Cy-J) possessing a hydrophilic Jeffamine backbone and highly sensitive pH-responsive cytosine-silver-cytosine (Cy-Ag-Cy) linkages, which spontaneously self-assemble to produce sterically stabilized spherical nanogels in water. The resulting nanogels exhibit several attractive features such as unique fluorescence behavior in water, highly stable self-assembled structures in biological media, significant antihemolytic capability, highly sensitive pH-responsiveness and broad-spectrum antibacterial activity against various bacteria strains. Importantly, in vitro cellular assays clearly demonstrated Ag-Cy-J nanogels highly selectively target and induce cytotoxicity in cancer cells, without affecting normal cells. The selective cytotoxic activity in cancer cells is attributed to rapid dissociation of the Cy-Ag-Cy complexes within the nanogels in the cancer cell microenvironment, followed by the intracellular release of silver ions and induction of rapid, massive apoptosis. Overall, the pH-sensitive Cy-Ag-Cy complexes within this supramolecular nanogel system may provide a route to remarkably improve the efficacy of both antibacterial and cancer drug therapies. STATEMENT OF SIGNIFICANCE: We present a significant breakthrough in the development of a water-soluble silver-containing metallosupramolecular polymer (Ag-Cy-J) that spontaneously self-assembles in water into a spherical nanogel with unique physical characteristics due to the existence of highly sensitive pH-responsive cytosine-silver-cytosine (Cy-Ag-Cy) linkages within the nanogels. Importantly, a series of in vitro antibacterial and anticancer assays demonstrated the Ag-Cy-J nanogels not only exert strong antibacterial activity against various bacterial strains, but also exhibit a high degree of selective uptake and rapidly induce massive apoptosis in cancer cells without harming normal cells. Thus, this newly discovered supramolecular system may potentially provide a multi-biofunctional soft nanomaterial for efficient and safe antibacterial and cancer therapies.

Keywords: Antibacterial activity; Metallosupramolecular polymers; Selective cytotoxicity; Silver-based supramolecular nanogels; pH responsiveness.