Nanotechnology for delivery of peptide nucleic acids (PNAs)

Gupta, Anisha; Bahal, Raman; Gupta, Meera; Glazer, Peter M.; Saltzman, W. Mark

doi:10.1016/j.jconrel.2016.01.005

Cited by 59 publications

(54 citation statements)

References 122 publications

(121 reference statements)

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“…Extensive studies have been done for facilitating the cellular uptake bioactive PNAs and other peptides and nucleic acids (32,34,(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100). We focused on testing the effect of bromination of PNA on cellular uptake as previous studies suggest that fluorination of PNA T base does not significantly enhance cellular uptake of PNAs (101,102).…”

Section: Targeting Hiv-1 Ribosomal Frameshift Inducing Mrna Hairpinmentioning

confidence: 99%

Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAs

Patil

Toh

Yuan

et al. 2018

Nucleic Acids Research

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Double-stranded RNA (dsRNA) structures form triplexes and RNA-protein complexes through binding to single-stranded RNA (ssRNA) regions and proteins, respectively, for diverse biological functions. Hence, targeting dsRNAs through major-groove triplex formation is a promising strategy for the development of chemical probes and potential therapeutics. Short (e.g., 6–10 mer) chemically-modified Peptide Nucleic Acids (PNAs) have been developed that bind to dsRNAs sequence specifically at physiological conditions. For example, a PNA incorporating a modified base thio-pseudoisocytosine (L) has an enhanced recognition of a G–C pair in an RNA duplex through major-groove L·G–C base triple formation at physiological pH, with reduced pH dependence as observed for C+·G–C base triple formation. Currently, an unmodified T base is often incorporated into PNAs to recognize a Watson–Crick A–U pair through major-groove T·A–U base triple formation. A substitution of the 5-methyl group in T by hydrogen and halogen atoms (F, Cl, Br, and I) causes a decrease of the pKa of N3 nitrogen atom, which may result in improved hydrogen bonding in addition to enhanced base stacking interactions. Here, we synthesized a series of PNAs incorporating uracil and halouracils, followed by binding studies by non-denaturing polyacrylamide gel electrophoresis, circular dichroism, and thermal melting. Our results suggest that replacing T with uracil and halouracils may enhance the recognition of an A–U pair by PNA·RNA2 triplex formation in a sequence-dependent manner, underscoring the importance of local stacking interactions. Incorporating bromouracils and chlorouracils into a PNA results in a significantly reduced pH dependence of triplex formation even for PNAs containing C bases, likely due to an upshift of the apparent pKa of N3 atoms of C bases. Thus, halogenation and other chemical modifications may be utilized to enhance hydrogen bonding of the adjacent base triples and thus triplex formation. Furthermore, our experimental and computational modelling data suggest that PNA·RNA2 triplexes may be stabilized by incorporating a BrUL step but not an LBrU step, in dsRNA-binding PNAs.

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Section: Targeting Hiv-1 Ribosomal Frameshift Inducing Mrna Hairpinmentioning

confidence: 99%

Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAs

Patil

Toh

Yuan

et al. 2018

Nucleic Acids Research

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“…The limited efficiency of transfection of Peptide Nucleic Acids in cells severely hampers their application in vivo. In the last few years the challenge has been tackled in many different ways (8). A recently proposed strategy entails the conjugation of PNAs to polyanionic molecules, such as polyaspartic acid peptides, followed by the packing with polycations, including polyethylenimine (PEI) and lipofectamine (5).…”

Section: Introductionmentioning

confidence: 99%

The influence of liposomal formulation on the incorporation and retention of PNA oligomers

Ringhieri

Avitabile

Morelli

et al. 2016

Colloids and Surfaces B: Biointerfaces

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Liposomal formulations composed of phospholipids with different unsaturation degrees, head groups and at different cholesterol content have been tested for the encapsulation of Peptide Nucleic Acid (PNA) oligomers. The best loading capability (177μg, ER%=87.2) was obtained for pure liposomes of phosphatidylglycerol (DOPG) with negatively charged head group. The insertion of a 10-20% of cholesterol in DOPG based liposomes provides a slight decrease (∼160μg) of the PNA loading. On the other hand, the cholesterol addition (20-30%) slows down the PNA's release (∼27%) in fetal bovine serum from the liposomal formulation. Based on the encapsulation and the release properties, PEGylated DOPG liposomes with a percentage of cholesterol of 10-20% are the optimal formulation for the loading of PNA-a210.

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“…As an alternative to peptide-mediated delivery of PNAs, several groups have investigated the use of NPs. While many of these delivery systems have been reviewed elsewhere [80], efforts have focused on developing NPs from poly(lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer, well-known to the FDA [81]. In addition to their favorable safety profiles [82,83], drug release from PLGA NPs is highly tunable by adjusting polymer molecular weight and ratio of lactic to glycolic acid [84].…”

Section: Plga Nanoparticle-mediated Delivery Of Pnasmentioning

confidence: 99%

Peptide Nucleic Acids and Gene Editing: Perspectives on Structure and Repair

et al. 2020

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Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct multiple human disease-relevant mutations with low off-target effects. Advances in molecular design, chemical modification, and delivery have enabled systemic in vivo application of PNAs resulting in detectable editing in preclinical mouse models. In a model of β-thalassemia, treated animals demonstrated clinically relevant protein restoration and disease phenotype amelioration, suggesting a potential for curative therapeutic application of PNAs to monogenic disorders. This review discusses the rationale and advances of PNA technologies and their application to gene editing with an emphasis on structural biochemistry and repair.

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Nanotechnology for delivery of peptide nucleic acids (PNAs)

Cited by 59 publications

References 122 publications

Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAs

Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A–U pairs in dsRNAs

The influence of liposomal formulation on the incorporation and retention of PNA oligomers

Peptide Nucleic Acids and Gene Editing: Perspectives on Structure and Repair

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