The closer, the better: intratumoral delivery of a thermoresponsive gemcitabine-loaded hydrogel in preclinical PDAC models

Current treatments for pancreatic ductal adenocarcinoma (PDAC) patients are typically restricted to (neo)adjuvant chemotherapy, surgery or palliative care. Mainly due to a late diagnosis and highly desmoplastic environment, these treatments have limited efficacy and patient prognosis is very poor. Intratumoral delivery of chemotherapeutic agents using hydrogel technology might boost treatment efficacy and reduce side effects. Here, we aimed to investigate the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell, loaded with the chemotherapeutic agent gemcitabine. We explored this in vitro, using patient-derived organoids and surgically obtained tumor explants, and in vivo, using a human patient-derived xenograft (PDX) and syngeneic KPC3 mouse models. Upon intratumoral injections of gemcitabine-loaded ChemoGell, respective survival, peripheral blood and end-stage tumor histological analyses were performed. Intratumoral injection of gemcitabine-loaded ChemoGell in in vitro and in vivo models showed decreased tumor growth and increased cytotoxicity compared to blank ChemoGell and saline control intratumoral injections. In contrast, systemic administration of gemcitabine did not show therapeutic benefits. Intratumoral ChemoGell injections induced interesting lymphocyte and monocyte dynamics overtime, showing an intratumoral influx of NK cells and monocytes and an in-depot infiltration of activated fibroblasts, macrophages and activated CD8 + T cells. Our findings establish a foundation for integrating localized treatment modalities, addressing critical challenges in PDAC and improving patient prognosis through more effective, localized therapeutic strategies.