Production of Cisplatin-Incorporating Hyaluronan Nanogels via Chelating Ligand–Metal Coordination

Abstract

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand-metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or malonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand-platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.

Diverse properties of the mesothelial cells in health and disease

“…Increased HA levels can induce EMT in MC under physiological conditions, which is essential for cell migration during wound healing and re-mesothelialization [79,96]. Meanwhile, CD44, the principal receptor for HA [97] is involved in binding gastric cancer [98,99] and ovarian cancer cells [100] to the mesothelium. HA-CD44 interaction is required for the extravasation of activated T cells from circulating blood to inflammatory sites [101].…”

Redox‐responsive core cross‐linked micelles of poly(ethylene oxide)‐b‐poly(furfuryl methacrylate) by Diels‐Alder reaction for doxorubicin release

“…Various techniques have been applied to prepare CCL micelles including photo‐cross‐linkable dimethylmaleide‐containing cores, phototriggered disulfide cross‐links, and metal‐coordination complexes . The cross‐linked micelles could release the entrapped therapeutic agents under UV/redox‐responsive, photothermo‐sensitive, or acidic environment . A typical method for this purpose is using a bifunctional group reagent which can be reacted with pendant groups on the polymer chains .…”

Dynamic Coordination of Eu–Iminodiacetate to Control Fluorochromic Response of Polymer Hydrogels to Multistimuli

“…Our design strategy is to use iminodiacetate (IDA) ligands as binding motifs ( Figure a; Figure S1a, Supporting Information) to coordinate Eu 3+ ions that further act as cross‐linkers to construct hydrogel networks. IDA is known to have large binding constant to various metals, while large lanthanide ions are able to coordinate with three IDA ligands simultaneously (Figure a) . In the presence of a large number of IDA ligands, water molecule is hypothesized to be effectively excluded from the coordination sphere of Eu 3+ ions that enhance the luminescence of Eu 3+ ions.…”