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. This article is protected by copyright. All rights reserved.