<p>A dual-functional HER2 aptamer-conjugated, pH-activated mesoporous silica nanocarrier-based drug delivery system provides in vitro synergistic cytotoxicity in HER2-positive breast cancer cells</p>

Abstract

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 βcyclodextrin (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 stimuliresponsive 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.

Delivery of Natural Agents by Means of Mesoporous Silica Nanospheres as a Promising Anticancer Strategy

“…These include antibodies, proteins, peptides, aptamers, small molecules, and saccharides [221]. For example, transferrin [237], folic acid [42], epidermal growth factor (EGF) [253], methotrexate [254], RGD-type peptide [255], anti-HER2/neu [256], hyaluronic acid [257], and mannose [258]. As an example, Kundu et al [203] designed targeted delivery for umbelliferone prodrug, with the system consisting of umbelliferone loaded in MSNs and capped with a pH-sensitive poly acrylic acid and further grafted with folic acid on the surface.…”

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

“…123 Some recent case studies of the CDs in the optimal drug delivery of drugs, proteins, peptides and aptamers are reported in the Table 3. [124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140] CDs can be moulded into various types of formulation for proving ease the drug delivery by diverse routes of administration.…”

<p>Hybrid Hydrogels for Synergistic Periodontal Antibacterial Treatment with Sustained Drug Release and NIR-Responsive Photothermal Effect</p>

“…Because of the ordered pores and highly specific surface area, MSNs can carry large antibiotic loads and achieve sustained release. 8,9 Further, nanovalves and polymers are applied on the surface of MSNs to protect the antibiotics loaded in the pores and target the lesion this structure on the surface can be activated by pH, 10 light, 11 radical 12 and enzyme. 13 However, when the concentration of antibiotics loaded onto the MSNs decreases to below the lowest effective concentration, subgingival pathogens resume proliferation, leading to recurrence of infection.…”