Nucleic Acid Bioconjugates in Cancer Detection and Therapy

Abstract

Nucleoside- and nucleotide-based chemotherapeutics have been used to treat cancer for more than 50 years. However, their inherent cytotoxicities and the emergent resistance of tumors against treatment has inspired a new wave of compounds in which the overall pharmacological profile of the bioactive nucleic acid component is improved by conjugation with delivery vectors, small-molecule drugs, and/or imaging modalities. In this manner, nucleic acid bioconjugates have the potential for targeting and effecting multiple biological processes in tumors, leading to synergistic antitumor effects. Consequently, tumor resistance and recurrence is mitigated, leading to more effective forms of cancer therapy. Bioorthogonal chemistry has led to the development of new nucleoside bioconjugates, which have served to improve treatment efficacy en route towards FDA approval. Similarly, oligonucleotide bioconjugates have shown encouraging preclinical and clinical results. The modified oligonucleotides and their pharmaceutically active formulations have addressed many weaknesses of oligonucleotide-based drugs. They have also paved the way for important advancements in cancer diagnosis and treatment. Cancer-targeting ligands such as small-molecules, peptides, and monoclonal antibody fragments have all been successfully applied in oligonucleotide bioconjugation and have shown promising anticancer effects in vitro and in vivo. Thus, the application of bioorthogonal chemistry will, in all likelihood, continue to supply a promising pipeline of nucleic acid bioconjugates for applications in cancer detection and therapy.

Bioorthogonal Chemistry and Its Applications

“…Azide-modified nucleoside triphosphates have been shown to be incorporated into the DNA backbone providing bioorthogonal handles for further label-ing. 84,85 Alkenyl deoxynucleosides and alkynylnucleosides have been employed to label rat DNA and RNA. 82 Huang et al reported using 5-vinyl-2′-deoxyuridine as a bioorthogonal precursor for labeling viral genomes.…”

Conjugation Approaches for Peptide-Mediated Delivery of Oligonucleotides Therapeutics

“…remain bound within the target cell) (Fig. 2), [14,25,29,30] conjugation chemistry has a major role to play in the development of efficient peptide-oligonucleotide conjugates. This review focuses specifically on the various chemical approaches used to form oligonucleotide and peptide conjugates.…”

Covalent Fluorophore Labeling of Oligonucleotides and Generation of Other Oligonucleotide Bioconjugates

“…Among those, the use as probes for in situ hybridization, in microarrays, for some PCR applications, or the tracking of oligonucleotides in vitro or in vivo requires attachment of fluorescent or other labels to chemically synthesized oligonucleotides [5]. In addition, bioconjugation of various ligands has an important role in the development of therapeutically active oligonucleotide agents [6,7]. The tethering of proteins, peptides or small molecule receptor ligands for targeting applications may be instrumental for overcoming the inherent, yet not sufficiently solved issues of pharmaceutical development.…”

“…However, this approach is limited to hepatocyte targeting and thus directed to liver diseases, and other targeting moieties seem to be needed for expanding the target space of oligonucleotide therapeutics. Besides conferring receptor-targeting properties, the attachment of certain ligands to oligonucleotides may also influence pharmacokinetics and biodistribution in a nonspecific way, by increasing the molecular weight [12][13][14] or by modulating lipophilicity [7] or plasma protein binding. In addition, cellular uptake and endosomal escape are aimed to be increased by attaching cationic small molecules or peptides [15][16][17][18][19].…”