Intraperitoneal Delivery of Cisplatin via a Hyaluronan-Based Nanogel/in Situ Cross-Linkable Hydrogel Hybrid System for Peritoneal Dissemination of Gastric Cancer. 
Intraperitoneal administration of chemotherapeutics is expected for the treatment of peritoneally disseminated gastric cancer because of poor migration of the drugs from the systemic circulation to the peritoneal cavity.  In this study, for intraperitoneal delivery of cisplatin (CDDP), we developed a hyaluronan (HA)-based hybrid system in which CDDP-loaded HA nanogels were either physically encapsulated in or chemically conjugated to injectable HA hydrogels.  Physical encapsulation enabled sustained release of HA nanogels from the HA hydrogel matrix for over a week.  This was a longer release period than that of encapsulated free CDDP, which released 80% of the drug in 2 days.  The longer release was attributed to delayed diffusion of HA nanogels from the hydrogel matrix network.  The release profile could be tuned by modifying the chemical conjugation of HA nanogels to the HA hydrogel matrix, as well as the type of chelating ligands used to load CDDP to the nanogel.  Furthermore, intraperitoneally administered hybrid had significant antitumor activity in a mouse model of peritoneally disseminated gastric cancer, especially for nodules smaller than 1.0 mm.