Delivering cargoes into cancer cells using DNA aptamers targeting internalized surface portals

Abstract

Many evolving treatments for cancer patients are based on the targeted delivery of therapeutic cargoes to and into cancer cells. The advent of monoclonal antibodies and the use of peptide hormones, growth factors and cytokines have historically provided a spectrum of ligands needed to selectively target tumor-associated antigens on cancer cells. However, issues linked to the size, cost and immunogenicity of protein-based ligands have led to the search for alternate ligand families. The advent of short synthetic oligonucleotide ligands known as aptamers now provides a simple strategy to select for membrane-impermeant aptamers tailored to precisely target internalized surface markers present on cancer cells. Here we described how 25-base long, synthetic single-stranded DNA aptamers were derived to bind to known internalized tumor markers such as CD33, CEA, MUC1 and Tn antigens and are imported through these surface portals into cancer cells. The key consequence of using internalized aptamers is their ability to accumulate inside the cells, thus routing their therapeutic cargoes to intracellular sites relevant to their action. Internalized aptamers are discussed in the context of how such ligands have been used to create a range of guided therapeutic agents ranging from drug-based conjugates up to targeted nanoparticles.

c-Src Antisense Complexed with PAMAM Denderimes Decreases of c-Src Expression and EGFR-Dependent Downstream Genes in the Human HT-29 Colon Cancer Cell Line

“…Polyamidoamin polymers, PAMAM nanoparticals, have been developed as a novel nonviral DNA delivery vector in the recent years. They are highly effective cationic delivery vehicles used and formed PAMAM-antisense complex by electrostatic interaction, as well as they carry the antisense into nucleus of target cells (Eichman et al, 2000;Baker et al, 2004;Orava et al, 2010;Wang et al, 2010). In addition, PAMAM polymer's ability in protection of antisense from digestion in cytoplasm had been investigated using restriction enzymes (Baker et al, 2004;Orava et al, 2010;Wang et al, 2010), so in this work we used G5 PAMAM polymer as delivery system.…”

Bi-specific Aptamers Mediating Tumor Cell Lysis

“…to enhance T cell reactivity (5,6). Finally, aptamers can be applied in ligand-based targeted therapies to specifically deliver cytotoxic payloads (7,8) or siRNA (9) to tumor cells. Monoclonal antibodies serve as established and successful tumor therapeutics.…”

EGFR Antisense Oligonucleotides Encapsulated with Nanoparticles Decrease EGFR, MAPK1 and STAT5 Expression in a Human Colon Cancer Cell Line

“…As antisense oligonucleotides have anionic charge and unable to pass into the cells, thus delivery systems should be employed for antisense transfection. For this aim we used polyamidoamin polymers, because they are highly effective cationic delivery vehicles and can form PAMAM-antisense complex by electrostatic interaction, as well as they transfer the antisense into nucleus of target cells and have ability to protect the antisense from digestion in cytoplasm (Eichmanet al, 2000;Baker et al, 2004;Orava et al, 2010;Wang et al, 2010).…”