High‐Load Gemcitabine Inorganic‐Organic Hybrid Nanoparticles as 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, we present inorganic‐organic hybrid nanoparticles (GMP‐IOH‐NPs) as 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 [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 to overcome cellular resistance induced by the down‐regulation of deoxycytidine kinase. GMP‐IOH‐NPs show high accumulation in tumor lesions and only minor liver trapping when given intraperitoneally. GMP‐IOH‐NPs result in a higher anti‐tumor efficacy compared to free GEM and 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, we anticipate GMP‐IOH‐NPs to have a high chance to significantly improve current PDAC‐patient outcome.

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