Drug-loaded implantable surgical cavity-adaptive hydrogels for prevention of local tumor recurrence

Abstract

High local post-surgical cancer recurrence severely impairs the patients' prognosis and survival rates. Here, an injectable in situ forming hydrogel was designed to locally controlled release gemcitabine (GEM) and doxorubicin (DOX) to prevent local cancer recurrence. The hydrogel was rapidly formed at the post-surgical cavity after the aldehyde hyaluronic acid (HA-CHO) and the carboxymethyl chitosan (CM-CS) were mixed and immediately injected. Meanwhile, DOX was conjugated to HA-CHO and GEM was doped in CM-CS to obtain GD-HA/CS-Gel. The drug-free hydrogels showed low cytotoxicity on L929 cells and good in vivo biocompatibility. The hydrogels had appropriate viscoelasticity and rapid self-healing ability, favoring long-term local residence at the injected site where GEM quickly released and DOX slowly released. GEM and DOX showed the synergistic anticancer effect on 4T1 cells. Breast cancer 4T1-cell xenograft models were established and the tumors were surgically resected. GD-HA/CS-Gel was implanted in the post-surgical cavity and cancer recurrence and distant lung metastasis were completely prevented in comparison with the single drug-loaded hydrogel or drug solutions. The locally implanted dual drug-loaded cavity-adaptive hydrogel is a promising medication for prevention of post-surgical tumor recurrence.

Keywords: Controlled release; Hydrogel; Post-surgical; Recurrence; Synergistic effect.