Pancreatic cancer has an urgent need for more effective and safe therapies to overcome its poor prognosis. Pre-clinically we demonstrate that our novel Hybrid-Nanoparticle system not only delivers extraordinarily high concentrations of gemcitabine monophosphate (GMP) to the primary tumor but also to metastatic sites. Multiscale fluorescence imaging confirms an efficient uptake in tumor cells, independent of the activity of the transporter, being responsible for gemcitabine (GEM) transport into cells and a key factor for GEM resistance. Delivering already phosphorylated GMP into tumor cells allows to overcome cellular resistance induced by the down-regulation of the enzyme required for gemcitabine activation within cells. GMP-Hybrid-Nanoparticle result in a higher anti-tumor efficacy compared to the free drug. By maximizing the therapeutic benefits with high drug load, tumor-specific delivery, minimizing undesired side effects, bypass drug resistance mechanisms and preventing systemic GEM inactivation, we anticipate GMP-Hybrid-Nanoparticle to have a high potential to significantly improve current outcome pf patients with pancreatic cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, requiring novel therapeutic concepts. Our Dual-Hybrid-Nanoparticle drug-delivery system consisting of the clinically relevant chemotherapeutics irinotecan (ITC) and fluoro-2'-deoxyuridine-5'-phosphate (FdUMP) with high drug payload demonstrated strong efficacy in eliminating tumor cells within the rectal cancer organoids, highlighting their potential as effective drug delivery system. Fluorescent-labeling show efficient uptake of Dual-Hybrid-NP by CRC cells distinctly monitor their intracellular trafficking towards endolysosomal compartments, where they are expected to be dissolved within the acidic environment, underscoring the versatility of the technology in transporting chemically diverse drug molecules within a single nanoparticle formulation.

We have demonstrated the high therapeutic efficiency of glucocorticoid-loaded Hybrid-Nanoparticle, which consist of the anti-inflammatory drug betamethasone phosphate (BMP) and a fluorescent dye. When administered intranasally to asthmatic mice, they accumulate in the lungs already after four hours, where they were almost exclusively taken up by bronchio-alveolar macrophages, suggesting that these cells act as a reservoir from which the drug is released into the surrounding tissue. Their delivery can be simultaneously tracked in vivo by fluorescence imaging. Treatment of asthmatic mice with BMP-Hybrid-NP resulted in improved anti-inflammatory efficacy compared to the equivalent free drug, at least equal to that of the gold standard dexamethasone, showing the potential to reach clinical applications.