Multifunctional Gold Nanoparticles Linked With Aptamers And Fluorophores For Breast Cancer Imaging And Therapy
CANCER RESEARCH(2012)
摘要
Breast cancer is a leading cause of mortality among women worldwide and there is a need for improved methods for early detection, new therapies that are more effective with fewer side effects, and personalized treatment options. Nucleic acid aptamers are synthetic oligonucleotides that bind to specific target proteins and have potential for both imaging and therapy. They have a targeting mechanism similar to monoclonal antibodies (i.e. shape-specific recognition), but may have substantial advantages, including easier synthesis and storage, better tumor penetration, and non-immunogenicity. Previously, we developed AS1411 (now renamed ACT-GRO-777), a nucleolin-binding DNA aptamer that has antiproliferative activity against cancer cells with little effect on non-malignant cells. AS1411 was the first anticancer aptamer to be tested in human clinical trials, which indicated promising activity with no evidence of serious side effects. The molecular target for AS1411 is nucleolin, a protein highly expressed on the surface of breast cancer cells and breast tumor-associated endothelial cells, suggesting the potential utility of AS1411 in this disease. Here we report on new research in which we conjugated gold nanoparticles (GNPs) to AS1411 and assessed their potential for breast cancer imaging and therapy. The antiproliferative activity of AS1411 linked to 5 nm gold nanoparticles (GNP) was determined by MTT and clonogenic assays. The GI50 value for AS1411-GNPs against breast cancer cell lines was less than 100 nM (aptamer concentration), which is at least 20-fold lower than unconjugated AS1411. Moreover, AS1411-GNPs retained the cancer-selectivity of AS1411 and had no effect on non-malignant breast cells. Confocal microscopy revealed increased uptake in breast cancer cells for GNP-AS1411 compared to GNP alone or GNP conjugated to a control oligonucleotide. In addition, GNP-AS1411 potently induced breast cancer cell vacuolization and death, similar to that seen at higher concentrations of AS1411. Furthermore, in vivo studies in nude mice with established MDA-MB-231 xenografts have shown that systemic administration of AS1411-GNPs for 12 days could completely inhibit tumor growth in a specific manner. We further examined if the GNP-AS1411 conjugated to fluorophore Cy5 has a potential for in-vivo optical imaging to specifically detect the tumor in established breast cancer xenograft model. Preliminary data from biodistribution studies suggest that GNP-AS1411 can very efficiently detect tumors using in vivo imaging modalities. Altogether, our data suggest that this strategy could be used to develop multifunctional tumor-targeting nanoparticles that can serve as imaging agents to detect breast cancers or monitor clinical response, as well as to specifically deliver therapeutic agents to the tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5688. doi:1538-7445.AM2012-5688
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关键词
multifunctional gold nanoparticles,gold nanoparticles,breast cancer imaging,fluorophores
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