Co-delivery of 5-fluorodeoxyuridine and doxorubicin via gold nanoparticle equipped with affibody-DNA hybrid strands for targeted synergistic chemotherapy of HER2 overexpressing breast cancer

Abstract

Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. As an attractive component, gold nanoparticles (AuNPs) have been extensively studied as biosafety nanomaterials, but they are rarely explored as drug nanocarriers for targeted co-delivery of multiple chemotherapeutics. Herein, a novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). FUdRs were integrated into DNA hybrid strands decorated on AuNPs by DNA solid phase synthesis, and Dox molecules were intercalated into their duplex regions. Affibody molecules coupled to the DNA hybrid strands were distributed the surface of AuNPs, giving them targeting for HER2. The new dual-drug-containing affibody-DNA-AuNPs (Dox@affi-F/AuNPs) owned compact and stable spherical nanostructures, and precise drug loading. Cytotoxicity tests demonstrated that these nanoparticles caused a higher inhibition in HER2 overexpressing breast cancer cells, and showed better synergistic antitumor activity than simple mixture of the two drugs. The related mechanistic studies proved that Dox@affi-F/AuNPs achieved a remarkable combined antitumor activity of Dox and FUdR by promoting more cells to enter apoptosis pathway. Our work provided a nanomedicine platform for targeted co-delivery of nucleoside analog therapeutics and anthracycline anticancer drugs to achieve synergistic treatment of HER2+ cancer.

Affibody Modified G-quadruplex DNA Micelles Incorporating Polymeric 5-Fluorodeoxyuridine for Targeted Delivery of Curcumin to Enhance Synergetic Therapy of HER2 Positive Gastric Cancer

“…demonstrate that affibody molecule is an excellent target ligand that has the advantages of low molecular weight (7 kDa), stable structure and function, high selectivity and affinity [40][41][42]. In this regard, affibody as a targeting moiety will be employed to develop a variety of drug delivery systems for the treatment of HER2-positive tumors [43][44][45]. In this study, 5-fluorodeoxyuridine (FUdR, metabolite of 5-Fluorouracil) and curcumin (Cur) were chosen as a model hydrophobic drug and hydrophilic drug due to their good synergistic effect in cancer treatment [46][47][48].…”

PrPC Aptamer Conjugated–Gold Nanoparticles for Targeted Delivery of Doxorubicin to Colorectal Cancer Cells

“…Many studies on active targeting of drug-loaded AuNPs using cancer targeting ligands such as antibodies, peptides, and small molecules also have been reported [ 53 ]. Zhang et al developed 5-fluorodeoxyuridine (FUdR) and Dox co-delivery systems using HER2-specific affibody-functionalized AuNPs [ 54 ]. They conjugated FUdR containing DNA to HER2-specifc affibody and attached the affibody-DNA hybrid to AuNPs.…”

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

“…Notably, Yeom et al engineered BAX mRNA-loaded AuNP–DNA conjugates and then injected them into xenograft tumors in mice, resulting in highly efficient mRNA delivery and biologically functional BAX protein (a proapoptotic factor) production, subsequently inhibiting tumor growth [ 159 ]. Moreover, Zhang et al demonstrated that DNA-attached AuNPs are more easily taken up by cells and are highly stable in serum-containing solutions [ 160 ].…”