Aptamer-based targeted therapy

Abstract

Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers, neurodegenerative diseases, to cardiovascular diseases. The proteomic profiles resulting from the unique genetic and epigenetic signatures represent a class of relatively well accessible molecular targets for both interrogation (e.g., diagnosis, prognosis) and intervention (e.g., targeted therapy) of these diseases. Aptamers are promising for such applications by specific binding with cognate disease biomarkers. Nucleic acid aptamers are a class of DNA or RNA with unique three-dimensional conformations that allow them to specifically bind with target molecules. Aptamers can be relatively easily screened, reproducibly manufactured, programmably designed, and chemically modified for various biomedical applications, including targeted therapy. Aptamers can be chemically modified to resist enzymatic degradation or optimize their pharmacological behaviors, which ensured their chemical integrity and bioavailability under physiological conditions. In this review, we will focus on recent progress and discuss the challenges and opportunities in the research areas of aptamer-based targeted therapy in the forms of aptamer therapeutics and aptamer-drug conjugates (ApDCs).

Keywords: Aptamer; Aptamer-drug conjugate; Drug delivery; Nucleic acid therapeutics; Targeted immunotherapy.

Figure 1.

Workflow of SELEX. (A) Schematic illustration of in vitro SELEX for aptamer screening. (B) The oligonucleotide pool from the last round of SELEX was subject to sequencing and bioinformatic analysis of homology and frequency. (C) Exemplary sequences of library and primers used for SELEX. (D) An example of flow cytometry results that demonstrate the progressive enrichment of aptamer candidates to target cells.

Figure 2.

Mechanism of the development of aptamers as anticoagulants by targeting FIXa. Shown are a brief description of blood coagulation cascades, in which IXa can be inhibited by anti-FIXa aptamers, thereby inhibiting blood coagulation.

Figure 3.

ApDCs for chemotherapy. (A) Via noncovalent complexation of aptamer-tethered nanotrains and drugs, an ApDC was developed to deliver a large payload of DNA-intercalating drugs into target tumor cells. (B) An example of ApDCs that was programmably synthesized using a phosphoramidite that carried a 5-FU prodrug via a photocleavable linker (inset: molecular structure of a prodrugincorporating phosphoramidite). (C) As a mimic of bispecific antibody, a bi-specific ApDC was developed by simply linking two independent aptamers via a dsDNA linker, which was additionally harnessed for drug loading in bi-specific drug delivery. (D) A schematic representation of aptamerfunctionalized nanocarriers for targeted drug delivery.

Figure 4.

ApDCs for gene therapy. (A) Schematic representation of an aptamer-modified viral carrier for potential application in targeted gene delivery. (B) A schematic illustration of a chimeric aptamersiRNA as ApDC for targeted siRNA delivery.

Figure 5.

Aptamers for immunotherapy. (A) Aptamers as therapeutics that bind to and modulate the biological functions of immunomodulatory molecules. (B) ApDCs developed for targeted delivery of immunotherapeutic drugs.

Figure 6.

Improve the pharmacokinetics of aptamers by PEGylation. A 39-mer aptamer composing of 2’-deoxy purine and 2’-O-methyl pyrimidine was conjugated with PEG (20 kDa and 40 kDa, respectively). The resulting conjugates were administered intravenously to mice at 10 mg/kg. Pharmacokinetics profiles showed that PEGylation dramatically enhanced the half-lives of the aptamers [11].