Aptamers as radiopharmaceuticals for nuclear imaging and therapy

doi:10.1016/j.nucmedbio.2015.09.005

Nuclear Medicine and Biology

Volume 43, Issue 4, April 2016, Pages 253-271

https://doi.org/10.1016/j.nucmedbio.2015.09.005 Get rights and content

Abstract

Today, radiopharmaceuticals belong to the standard instrumentation of nuclear medicine, both in the context of diagnosis and therapy. The majority of radiopharmaceuticals consist of targeting biomolecules which are designed to interact with a disease-related molecular target. A plethora of targeting biomolecules of radiopharmaceuticals exists, including antibodies, antibody fragments, proteins, peptides and nucleic acids. Nucleic acids have some significant advantages relative to proteinaceous biomolecules in terms of size, production, modifications, possible targets and immunogenicity. In particular, aptamers (non-coding, synthetic, single-stranded DNA or RNA oligonucleotides) are of interest because they can bind a molecular target with high affinity and specificity. At present, few aptamers have been investigated preclinically for imaging and therapeutic applications. In this review, we describe the use of aptamers as targeting biomolecules of radiopharmaceuticals. We also discuss the chemical modifications which are needed to turn aptamers into valuable (radio-)pharmaceuticals, as well as the different radiolabeling strategies that can be used to radiolabel oligonucleotides and, in particular, aptamers.

Section snippets

Radiopharmaceuticals

Nuclear medicine was developed in the 1950s by the use of ¹³¹I to diagnose and treat thyroid cancer and disease. Soon afterwards, sodium iodine (Na¹³¹I) became the first radiopharmaceutical approved in 1951 for clinical use by the United States Food and Drug Administration (FDA). Today, tens of millions of nuclear medicine procedures using radiopharmaceuticals are performed each year in more than 10,000 hospitals worldwide [1]. The most common radionuclide used in diagnosis is ^99mTc, accounting

Aptamers

Aptamers are oligomers composed of ribonucleotides (RNA aptamers), deoxyribonucleotides (DNA aptamers) or amino acids (peptide aptamers). RNA or DNA aptamers are typically single-stranded and small (< 100-mer, 10 to 20 kDa). The term ‘aptamer’ was first introduced about 25 years ago, and is derived from the Latin word aptus (meaning ‘to fit’) and the Greek word meros (meaning ‘part or region’). Aptamers can form many three-dimensional structures (G-quartet, bulge loop, pseudoknot, hairpin, etc.)

How to turn aptamers into valuable (radio-)pharmaceuticals

Novel radiopharmaceuticals must meet a number of requirements concerning their pharmacokinetic and pharmacodynamics properties in order to become valuable radiopharmaceuticals for imaging or therapy. The major parameters which play a crucial role for systemic applications of radiopharmaceuticals are addressed in Table 2. The affinity (expressed by the affinity constant K_D = k_off/k_on) of the radiopharmaceutical for the target should be high (K_D in low nanomolar range) [79]. However, very high

Radiolabeling strategies for aptamers

The development of new radiopharmaceuticals is far from trivial and radiochemistry can be challenging. The success of radiolabeling can be expressed in terms of the efficiency of the radiolabeling process, specific activity (expressed in radioactivity per molar unit, e.g. Ci/μmol), radiochemical and chemical purity, radiochemical and chemical stability and shelf life of the final product. In order to ensure the patient safety and to obtain good therapeutic or diagnostic results, the

Aptamer-based radiopharmaceuticals

In this section, we will give an overview of aptamer-based radiopharmaceuticals developed for imaging and therapy of non-cancer disease and cancer (Fig. 5, Table 3). The majority has been radiolabeled with ^99mTc for SPECT imaging. Only few reports are published regarding radiolabeled aptamers for PET imaging, and, to the best of our knowledge, there is only one report describing the use of radiolabeled aptamers for therapy [197]. So far, all radiolabeled aptamers have only been tested for

Discussion and perspectives

The emergence of molecular medicine showing promising results, both for imaging and therapy, has changed the field of medicine of today.

Molecular nuclear imaging allows the non-invasive visualization of a disease in vivo at the molecular level with high sensitivity. As such, a disease can be carefully detected, localized, classified and quantified. As a result, it will assist in defining an accurate prognosis and in deciding which therapy to launch (curative or palliative). In addition,

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Aptamers as radiopharmaceuticals for nuclear imaging and therapy☆

Abstract

Section snippets

Radiopharmaceuticals

Aptamers

How to turn aptamers into valuable (radio-)pharmaceuticals

Radiolabeling strategies for aptamers

Aptamer-based radiopharmaceuticals

Discussion and perspectives

Trends Biotechnol

Mol Ther Nucleic Acids

Biomol Eng

Biosens Bioelectron

Ophthalmology

Curr Opin Pharmacol

Mol Ther Nucleic Acids

Eur J Pharm Sci

Cancer Lett

Chem Biol

Semin Nucl Med

Advancing Nuclear Medicine Through Innovation

Handbook of Nuclear Chemistry

Fundamentals of Nuclear Pharmacy

Biological carrier molecules of radiopharmaceuticals for molecular cancer imaging and targeted cancer therapy

Curr Pharm Des

Radiolabeled Nanoparticles for Molecular Imaging

Radiolabeled lipid nanoparticles for diagnostic imaging

Expert Opin Med Diagn

Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

J Clin Invest

Riboswitches: ancient and promising genetic regulators

Chembiochem

Gene regulation by riboswitches

Nat Rev Mol Cell Biol

Discovery and development of therapeutic aptamers

Annu Rev Pharmacol Toxicol

Aptamers the Chemical Antibodies

Aptamers as therapeutics

Nat Rev Drug Discov

The chemical biology of aptamers

Angew Chem Int Ed Engl

High-resolution molecular discrimination by RNA

Science

An RNA motif that binds ATP

Nature

RNA aptamers that bind l-arginine with sub-micromolar dissociation constants and high enantioselectivity

Nucleic Acids Res

Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase

Science

In vitro selection of RNA molecules that bind specific ligands

Nature

Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA

Nature

RNA aptamers and their therapeutic and diagnostic applications

Int J Biochem Mol Biol

Nucleic acid and peptide aptamers: fundamentals and bioanalytical aspects

Angew Chem Int Ed

Challenges and opportunities for small molecule aptamer development

J Nucleic Acids

Strategies for the discovery of therapeutic aptamers

Expert Opin Drug Discov

Selection of an RNA domain that binds Zn2 +

RNA

Aptamers evolved from live cells as effective molecular probes for cancer study

Proc Natl Acad Sci U S A

Development, screening, and analysis of DNA aptamer libraries potentially useful for diagnosis and passive immunity of arboviruses

BMC Res Notes

Molecular recognition of amino acids by RNA aptamers: an l-citrulline binding RNA motif and its evolution into an l-arginine binder

J Am Chem Soc

Functional aptamers and aptazymes in biotechnology, diagnostics, and therapy

Chem Rev

Aptamers in Bioanalysis

Therapeutic applications of aptamers

Expert Opin Investig Drugs

Aptamers as inhibitors of target proteins

Expert Opin Ther Pat

Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease

Nat Rev Drug Discov

A phase II randomized double-masked trial of pegaptanib, an anti–vascular endothelial growth factor aptamer, for diabetic macular edema

Ophthalmology

Selection of an RNA domain that binds Zn^2 +