Therapeutic Potential of Chemically Modified, Synthetic, Triplex Peptide Nucleic Acid–Based Oncomir Inhibitors for Cancer Therapy

Abstract

miRNA-155 (miR-155) is overexpressed in various types of lymphomas and leukemias, suggesting that targeting miR-155 could be a potential platform for the development of precision medicine. Here, we tested the anticancer activity of novel, chemically modified, triplex peptide nucleic acid (PNA)–based antimiRs compared with the current state-of-the-art conventional full-length antimiRs. Next-generation modified PNAs that bound miR-155 by Watson–Crick and Hoogsteen domains possessed superior therapeutic efficacy in vivo and ex vivo compared with conventional full-length anti–miR-155. The efficacy of anti–miR-155 targeting in multiple lymphoma cell lines was comprehensively corroborated by gene expression, Western blot analysis, and cell viability–based functional studies. Finally, preclinical testing in vivo in xenograft mouse models containing lymphoma cell lines demonstrated that treatment with the miR-155-targeting next-generation antimiR resulted in a significant decrease in miR-155 expression, followed by reduced tumor growth. These findings support the effective therapeutic application of chemically modified triplex PNAs to target miR-155 to treat lymphoma. Overall, the present proof-of-concept study further implicates the potential for next-generation triplex gamma PNAs to target other miRNAs for treating cancer. Significance: This study demonstrates the utility of novel oncomiR inhibitors as cancer therapeutics, providing a new approach for targeting miRNAs and other noncoding RNAs.

LNA-anti-miR-150 alleviates renal interstitial fibrosis by reducing pro-inflammatory M1/M2 macrophage polarization

“…Chemically modified oligonucleotide small interfering RNAs and anti-miRs have been used to block the actions of specific endogenous genes and miRNA (25). More recently, LNA-anti-miR-132 has reduced liver fibrosis in a mouse model (26) LNA-anti-miR-150 reduced the renal infiltration of macrophages and polarization of M1/M2 macrophages in renal interstitial fibrosis mice.…”

The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint

“…Gupta et al showed that γPNA delivered via polymeric nanoparticles antagonized the expression of miR-210 in a HeLa cancer model, resulting in an anticancer effect with no observed toxicities [154]. Our recent study has explored the potential of tail-clamp γPNA to improve the miR inhibition efficacy and decrease tumor progression in vivo [150].…”

“…γPNA is the only molecule known to invade duplex RNA/DNA composed of up to 100% CG content in a sequence-specific manner [53]. Another attractive γPNA design is tail-clamp modifications, which can be used to target miRNA-containing homopurine stretches [150].…”

Perspectives on conformationally constrained peptide nucleic acid (PNA): insights into the structural design, properties and applications

“…A tetra-arginine-modified tail-clamp L Ser γPNA designed to target miRNA-155 was shown to exhibit superior anticancer activities in lymphoma cell lines and in mouse models over anti-miR-155 aegPNA and a control γPNA sequence. 313 Likewise, a 22nt miniPEG γPNA designed to target miRNA-210 can suppress tumor growth in mice much better than aegPNA with the same sequence and another miniPEG γPNA with a scrambled sequence when co-delivered with PLGA nanoparticles. 314 In a more elaborated control, an antisense miniPEG γPNA conjugated with pH-low insertion peptides (pHLIP) was shown to selectively target the DNA double-strand break repair factor KU80 in tumor cells thereby making them susceptible to irradiation.…”