Pullulan dialdehyde cross-linked dual-action adhesive with high adhesion to lung tissue and the capability of pH-responsive drug release

To address the main challenges for thoracoscopic lung cancer surgery, including persistent pulmonary air leaks and cancer recurrence, this study developed an in-situ adhesive that can effectively adhere to the lung and release the anticancer drug in response to pH. The adhesive was formulated using hydrophobically modified cold-water fish skin gelatin (hm-CFG) and cross-linking agent pullulan dialdehyde (PDA), in which succinic dihydrazide-modified doxorubicin (SDH-DOX) can be incorporated. Utilizing PDA could improve both cohesion and interfacial adhesion, while also offering drug-loading sites through the aldehyde groups that were not involved in cross-linking. The optimal adhesive formulation was 9C10-CFG/PDA (30 w/v% 9 mol% decanal modified CFG/20 w/v% PDA). The 9C10-CFG/PDA adhesive exhibited suitable cohesive strength, good mechanical flexibility (tensile strain over 170 %), and strong interface adhesion. The burst strength of 9C10-CFG/PDA adhesive (131.5 ± 22.2 mm Hg) was almost 6-fold higher than that of commercial fibrin sealant. In a rat pneumothorax model, 9C10-CFG/PDA adhesive displayed favorable wound-sealing properties, as evidenced by CT imaging and restored rat behavior. When combined with the anticancer drug, SDH-DOX@Adhesive could release the drug in response to pH more gradually than DOX@Adhesive. This dual-action adhesive is anticipated to mitigate post-surgical occurrences of lung air leaks and cancer recurrence.