Sequential gemcitabine and panobinostat-loaded albumin nanoparticle delivery via thermosensitive hydrogel in pancreatic peritoneal metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by frequent peritoneal metastasis and a poor 5-year survival rate despite chemotherapy. The limited efficacy of current systemic therapies highlights the need for effective, localized chemotherapeutic strategies targeting peritoneal metastasis. We developed a thermosensitive PLGA-PEG-PLGA hydrogel co-loaded with gemcitabine (GEM) and panobinostat (PNB). PNB was loaded into bovine serum albumin (BSA) nanoparticles to improve its solubility and stability. The formulation was optimized using a Box-Behnken design, yielding uniform spherical nanoparticles (110 nm) with an encapsulation efficiency of 85.3%. The obtained PNB-BSA NPs were homogeneously dispersed within the thermosensitive hydrogel, forming a composite depot (PNB-BSA NPs@GEM hydrogel) that exhibited a sol-gel transition at 34 °C and maintained structural stability at physiological temperature. GEM was released rapidly via diffusion from the hydrogel, while nanoparticle-loaded PNB displayed delayed, controlled diffusion, enabling sequential drug delivery. In vitro cytotoxicity assays using Panc-1-luc2 cells revealed that the co-loaded hydrogel significantly enhanced cell death and suppressed migration and invasion compared with single-drug formulations. In three-dimensional tumor spheroids, PNB-BSA NPs@GEM hydrogel almost completely inhibited tumor growth within 5 days, whereas free drugs or single gels showed only partial inhibition. In vivo intraperitoneal administration reduced total flux and peritoneal metastatic nodules by 82.5% and 88.6%, respectively, compared with the control group, without body-weight loss or systemic toxicity. PNB-BSA NPs@GEM hydrogel provides localized, controlled, and synergistic chemotherapy against peritoneal metastatic PDAC, offering a promising intraperitoneal depot formulation for postoperative or recurrent pancreatic cancer therapy.