High Drug-Loading Rucaparib-FdUMP Nanocarriers for Colorectal Cancer Combination Therapy

Combination chemotherapy remains the standard of care for advanced colorectal cancer, yet the clinical benefit is limited by off-target toxicity and insufficient tumor drug exposure. Co-administration of 5-fluorouracil (5-FU) with poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib (RUC) can potentiate 5-FU-induced DNA damage by suppressing DNA repair but achieving robust co-delivery at defined ratios and high payload remains challenging. Here, we report high drug-loading core@shell nanocarriers (RUC@[ZrO][FdUMP]) that co-deliver RUC and the active 5-FU metabolite fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP). Nanocarriers were synthesized via a solvent-antisolvent approach to form a tocopherol phosphate (TocP)-stabilized RUC core followed by the growth of an amorphous [ZrO][FdUMP] shell, yielding an overall drug load of 59 wt%. Dual fluorescence (shell incorporation of DUT647 and intrinsic RUC emission) enabled quantitative tracking and revealed rapid uptake in HCT116 and HT29 colorectal cancer cells and tumor accumulation in a subcutaneous HT29 xenograft. In vitro, RUC@[ZrO][FdUMP] showed cytotoxicity comparable to the free-drug combination, induced S-phase arrest, and increased γH2AX foci, consistent with replication stress and DNA double-strand break formation. Drug–drug interaction analysis demonstrated synergistic activity of the RUC/FdUMP pair in colorectal cancer cells. Together, these results establish RUC@[ZrO][FdUMP] as a high-payload nanocarrier platform for co-delivering synergistic PARP inhibitor/fluoropyrimidine combinations, supporting further development and in vivo evaluation of this co-delivery strategy for colorectal cancer therapy.