Purpose: As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. Materials and methods: We fabricated novel HApt aptamer-functionalized pH-sensitive β-cyclodextrin (β-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). β-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Results: Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 μg/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. Conclusion: MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer.
Keywords: HER2 aptamer; mesoporous silica nanoparticle; pH-sensitive nanovalve; synergistic cytotoxicity.