High-Load Core@Shell Nanocarriers with Irinotecan and 5-Fluorouracil for Combination Chemotherapy in Colorectal Cancer

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. A clinically relevant drug cocktail of irinotecan (ITC) and 5-fluorouridine (5-FU) is combined in a single nanocarrier with high drug payload (32%). The nanocarriers show efficient uptake and high efficacy in different human colon cancer and human rectal cancer cell lines as well as rectal cancer patient-derived organoids, also allowing to elucidate the membrane-trafficking pathway.image (c) 2024 WILEY-VCH GmbH