Canonical and non-canonical barriers facing antimiR cancer therapeutics

Abstract

Once considered genetic "oddities", microRNAs (miRNAs) are now recognized as key epigenetic regulators of numerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer. The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming of the field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept, but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describes the canonical (e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localization and accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges to the delivery of antisense-based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will be placed on how the current leading antimiR platforms-ranging from naked chemically modified oligonucleotides to nanoscale delivery vehicles-are affected by and overcome these barriers. The perplexity of antimiR delivery presents both engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacological benefits of antagonizing tumor-associated miRNAs.

Fig. (1)

Physiological fates of systemically administered antimiRs. Chemically-modified antimiRs are generally removed from circulation by renal excretion and RES clearance; interaction with certain serum proteins leads to avoidance of these barriers, e.g. binding to albumin can prevent renal excretion. Nanovehicles that deliver antimiRs are typically removed from circulation by opsonization and subsequent RES clearance; this can be prevented by certain functional modifications, e.g. PEGylation obstructs recognition by the RES system. Although albumin binding and PEGylation improve circulation, it is unclear if these modifications directly facilitate tumor targeting. However, tumors are characterized by a leaky vasculature and poor lymphatic drainage, which facilitates passive accumulation of macromolecules and nanovehicles.

Fig. (2)

Cellular uptake and miRNA availability. AntimiR oligos and nanovehicles typically enter cells via endocytosis, which principally results in endolysosomal degradation or recycling. Therefore, escape from endocytic vesicles is necessary to inhibit cytosolic miRNAs. However, target accessibility may be obstructed by miRNA association with P-bodies and GW-bodies, as well as sequestration of miRNAs within cell-derived vesicles, such as exosomes.