High‐Load Gemcitabine Inorganic–Organic Hybrid Nanoparticles as an Image‐Guided Tumor‐Selective Drug‐Delivery System to Treat Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a devastating prognosis without effective treatment options. Thus, there is an urgent need for more effective and safe therapies. Here, inorganic–organic hybrid nanoparticles (GMP‐IOH‐NPs) are presented as a novel drug‐delivery system for the selective delivery of extraordinarily high concentrations of gemcitabine monophosphate (GMP), not only to the primary tumor but also to metastatic sites. GMP‐IOH‐NPs have a composition of [ZrO]²⁺[GMP]²⁻ with GMP as drug anion (76% of total IOH‐NP mass). Multiscale fluorescence imaging confirms an efficient uptake in tumor cells, independent of the activity of the human‐equilibrative‐nucleoside transporter (hENT1), being responsible for gemcitabine (GEM) transport into cells and a key factor for GEM resistance. Delivering already phosphorylated GMP via GMP‐IOH‐NPs into tumor cells also allows the cellular resistance induced by the downregulation of deoxycytidine kinase to be overcome. GMP‐IOH‐NPs show high accumulation in tumor lesions and only minor liver trapping when given intraperitoneally. GMP‐IOH‐NPs result in a higher antitumor efficacy compared to free GEM, which is further enhanced applying cetuximab‐functionalized GMP‐CTX‐IOH‐NPs. By maximizing the therapeutic benefits with high drug load, tumor‐specific delivery, minimizing undesired side effects, overcoming mechanisms of chemoresistance, and preventing systemic GEM inactivation, GMP‐IOH‐NPs are anticipated to have a high chance to significantly improve current PDAC‐patient outcome.