Phototoxic aptamers selectively enter and kill epithelial cancer cells

Abstract

The majority of cancers arise from malignant epithelial cells. We report the design of synthetic oligonucleotides (aptamers) that are only internalized by epithelial cancer cells and can be precisely activated by light to kill such cells. Specifically, phototoxic DNA aptamers were selected to bind to unique short O-glycan-peptide signatures on the surface of breast, colon, lung, ovarian and pancreatic cancer cells. These surface antigens are not present on normal epithelial cells but are internalized and routed through endosomal and Golgi compartments by cancer cells, thus providing a focused mechanism for their intracellular delivery. When modified at their 5′ end with the photodynamic therapy agent chlorin e6 and delivered to epithelial cancer cells, these aptamers exhibited a remarkable enhancement (>500-fold increase) in toxicity upon light activation, compared to the drug alone and were not cytotoxic towards cell types lacking such O-glycan-peptide markers. Our findings suggest that these synthetic oligonucleotide aptamers can serve as delivery vehicles in precisely routing cytotoxic cargoes to and into epithelial cancer cells.

Self-assemble gene delivery system for molecular targeting using nucleic acid aptamer

“…aptamers were also developed and reported to show high selectivity (Ferreira, et al, 2009;Savla, et al, in press); however, there are few reports about gene delivery systems using MUC1 aptamer. In the previous study, we developed some ternary complexes of pDNA/PEI coated by polynucleic acid, such as polyadenylic acid (polyA) and polyinosinic-polycytidylic acid (polyIC) (Kurosaki, et al, 2009).…”

“…RPMI 1640, Opti-MEM I, antibiotics (penicillin 100 U/mL and streptomycin 100 g/mL), and other culture reagents were obtained from GIBCO BRL (Grand Island, NY, USA). MUC1 aptamer (5'-GAAGTGAAAATGACAGAACACAACA-3') and a non-specific 25 base-long DNA aptamer composed of GATC repeats, according to a previous report (Ferreira, et al, 2009), were purchased from Hokkaido System Science Co., Ltd. (Hokkaido, Japan). All other chemicals were of the highest purity available.…”

Clinical applications of nucleic acid aptamers in cancer

“…DNA aptamers directed against Muc1 (AptA and AptB) were identified in 2006 (84) and have since been implemented in ex vivo imaging and radiotherapy (85). In subsequent studies, when such an DNA aptamer was coupled to the light-activated photodynamic therapy agent chlorine e6, it specifically delivered chlorine e6 into epithelial cancer cells, with a significant enhancement in efficiency (>500-fold increase) compared to that of the drug alone, and achieved cancer-specific cytotoxicity (86). These results suggested the anti-Muc1 aptamers may function as drug carriers to specific epithelial cancer cells.…”

Anti-MUC1 nano-aptamers for triple-negative breast cancer imaging by single-photon emission computed tomography in inducted animals: initial considerations

“…21 In addition, they have been capable of detecting circulating MUC1 in sandwich enzyme-linked immunosorbent assays, improving current detection limits, 19 and have been extensively studied as radiopharmaceuticals for their potential in gamma-camera and single-photon emission computed tomography (SPECT) imaging. [21][22][23] Furthermore, they have been shown to be particularly promising agents in photodynamic therapy as phototoxic agents 24 and delivery agents of standard chemotherapy such as doxorubicin. 25 Finally, the MUC1 aptamers have been successfully used in nanoparticle (NP) formulation, described both from our own group 26 for silica NPs and from a different group for liposomal formulation in conjunction with paclitaxel.…”