Abstract
Colorectal cancer (CRC) is the third most common cancer type and second leading cause of cancer-related deaths worldwide, requiring novel drug-delivery concepts. ITC@ZrO(TocP)/ZrO(FdUMP) core@shell nanocarriers (designated ITC-FdUMP-NC) with the clinically relevant chemotherapeutics irinotecan (ITC) and fluoro-2'-deoxyuridine-5'-phosphate (FdUMP) (active derivative of 5'-fluorouracil/5-FU) are a new type of nanocarrier with high drug payload (22 wt% of lipophilic ITC: particle core; 10 wt% of hydrophilic FdUMP: particle shell). The nanocarriers are tested in different CRC cell lines, a normal cell line, and rectal cancer patient-derived organoids (PDOs). Fluorescence-labeled nanocarriers show efficient uptake by all CRC cells and allow to distinctly track the intracellular trafficking toward endolysosomal compartments. Although free chemotherapeutic drugs exhibit a greater potency in 2D cell cultures, ITC-FdUMP-NC demonstrate equivalent cytotoxic efficacies as the freely dissolved drugs in the more complex 3D rectal cancer PDOs. The sustained drug-release profile of the nanocarriers contrasts favorably with conventional free drugs, potentially enhancing the therapeutic outcome in vivo. With a chemotherapeutic cocktail comparable to the clinically applied FOLFIRI (ITC + 5-FU), the ITC-FdUMP-NC represent a novel type of nanocarrier with high anti-tumor effect and high drug payload, offering a promising strategy to circumvent chemoresistance and to improve therapy efficacy in vivo with less side effects.