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.

• Authors: Myrto Ischyropoulou, Kristina Sabljo, Leonie Schneider, Christof M Niemeyer, Joanna Napp, Claus Feldmann, Frauke Alves
• Journal: Advanced materials (Deerfield Beach, Fla.) (Adv Mater) Vol. 35 Issue 46 Pg. e2305151 (Nov 2023) ISSN: 1521-4095 [Electronic] Germany
• PMID: 37587542 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.

Chemical References

• Gemcitabine
• Deoxycytidine

Topics

• Humans
• Gemcitabine
• Cell Line, Tumor
• Pancreatic Neoplasms (diagnostic imaging, drug therapy, pathology)
• Deoxycytidine (pharmacology, therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, pathology)
• Drug Delivery Systems
• Nanoparticles