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.
Highlights
Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer
Based on the structural similarity between nucleoside analog therapeutics and natural nucleobases, an affibody modified DNA-AuNPs nanomedicine platform integrated with FUdRs was successfully constructed for the first time
When the nano-drugs entered the cell, DNase II triggered the degradation of exogenous DNA, which promoted the synchronous release of FUdR and Dox from Dox@affi-F/AuNPs
Summary
Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. A novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). 40–60% of HER2+ breast cancer patients do not respond to the treatment or develop primary and secondary drug resistance to antibody therapy[5,6]. To address these issues, many researchers have developed small peptide mimics of antibodies against HER2, such as affibody molecules, and exploited them for preparing various drug delivery systems to achieve targeted therapy. There is an urgent need to develop an improved drug loading strategy for the delivery of hydrophilic chemotherapeutic agents
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