Anti-nucleolin aptamer AS1411: an advancing therapeutic

Abstract

Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.

Keywords: AS1411; cancer; endocytosis; nucleolin; pathogens; targeted therapy.

FIGURE 1

1) The virus binds to nucleolin expressed on the cell surface. 2) Clathrin coats the intracellular plasma membrane around the virus-bound receptor. This leads to an invagination and ultimately a vesicle. 3) After the vesicle gets internalized, the clathrin dissociates. 4) The vesicle joins the endosome. 5) The virus evades the endosome and enters the cytoplasm. 6/7/8) The nucleolin is recycled to the extracellular domain.

FIGURE 2

1) Arp2/3 induces actin polymerization leading to membrane ruffling and the formation of a vesicle. 2/3) The AS1411 is released from the vesicle into the cytoplasm. 4) AS1411 leads to the inhibition of nucleolin. 5) The inhibited nucleolin leads to an upregulation of a guanosine exchange factor. 6) The activated GEF leads to the conversion of Rac1GDP to Rac1GTP. 7) rac1GTP leads to activation of the WAVE complex. 7) The WAVE complex upregulates Arp2/3 and more membrane ruffling.

FIGURE 3

HIV-1, Human Immunodeficiency Virus 1; RSV, Respiratory Syncytial Virus; HCV, Hepatitis C Virus; HSV-1, Herpes Simplex Virus 1; EBV, Epstein-Barr Virus; KSHV, Kaposi’s sarcoma-associated herpesvirus.