Inhibition of nucleotide metabolism with dual-template epitope imprinted nanoparticles for targeted HER2+ tumor therapy

Abstract

Nucleotide metabolism therapeutics, aimed at disrupting nucleic acid production, have proven to be an effective strategy against cancers. Traditionally, these therapies rely on classical antimetabolites such as fluorouracil and mercaptopurine; however, they suffer from the drawback of high biotoxicity. In this study, we introduced a novel approach using dual-template epitope molecularly imprinted polymers (D-EMIPs), designed with the nucleotide metabolism therapy strategy in mind for precise targeting and cancer treatment. The imprinting process comprised two key template peptides: the active center peptide of inosine 5′-monophosphate dehydrogenase (IMPDH) and epitope of the human epidermal growth factor receptor-2 (HER2). The D-EMIPs could selectively bind to IMPDH and occupy its catalytic active sites, thereby suppressing enzymatic reactions and inhibiting DNA and RNA synthesis, ultimately impeding tumor growth. Furthermore, by specifically targeting HER2, an overexpressed protein in certain cancer types, D-EMIPs enhanced the therapeutic efficacy for HER2-positive (HER2+) cancers. In vitro experiments suggested that D-EMIPs could selectively target HER2+ tumor cells, leading to a substantial 41% reduction in cell proliferation. In vivo experiments further confirmed the tumor-specific targeting capability of D-EMIPs, resulting in smaller tumor volumes compared to the control group treated with phosphate-buffered saline (PBS). These findings emphasize the promise of combining nucleotide metabolism therapeutics with the dual-template imprinted technique as a comprehensive strategy to establish an integrated platform for cancer diagnosis and treatment.