Head-to-head comparison of in vitro and in vivo efficacy of pHLIP-conjugated anti-seed gamma peptide nucleic acids

Karishma Dhuri; Tibo Duran; Bodhisattwa Chaudhuri; Frank J Slack; Ajit Vikram; Peter M Glazer; Raman Bahal

doi:10.1016/j.xcrp.2023.101584

Head-to-head comparison of in vitro and in vivo efficacy of pHLIP-conjugated anti-seed gamma peptide nucleic acids

Cell Rep Phys Sci. 2023 Oct 18;4(10):101584. doi: 10.1016/j.xcrp.2023.101584. Epub 2023 Sep 15.

Authors

Karishma Dhuri¹, Tibo Duran¹, Bodhisattwa Chaudhuri^{1

2}, Frank J Slack³, Ajit Vikram⁴, Peter M Glazer⁵, Raman Bahal^{1

6}

Affiliations

¹ Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
² Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA.
³ HMS Initiative for RNA Medicine, Department of Pathology, BIDMC Cancer Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
⁴ Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
⁵ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁶ Lead contact.

Abstract

Gamma peptide nucleic acids (γPNAs) have recently garnered attention in diverse therapeutic and diagnostic applications. Serine and diethylene-glycol-containing γPNAs have been tested for numerous RNA-targeting purposes. Here, we comprehensively evaluated the in vitro and in vivo efficacy of pH-low insertion peptide (pHLIP)-conjugated serine and diethylene-based γPNAs. pHLIP targets only the acidic tumor microenvironment and not the normal cells. We synthesized and parallelly tested pHLIP-serine γPNAs and pHLIP-diethylene glycol γPNAs that target the seed region of microRNA-155, a microRNA that is upregulated in various cancers. We performed an all-atom molecular dynamics simulation-based computational study to elucidate the interaction of pHLIP-γPNA constructs with the lipid bilayer. We also determined the biodistribution and efficacy of the pHLIP constructs in the U2932-derived xenograft model. Overall, we established that the pHLIP-serine γPNAs show superior results in vivo compared with the pHLIP-diethylene glycol-based γPNA.

Abstract

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