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 0-deoxyuridine-5 0-phosphate (FdUMP) (active derivative of 5 0-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 ompartments. 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. ... mehrWith a chemotherapeutic cocktail comparable to the clinically applied FOLFIRI (ITC þ 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.