Numerous first generation phosphorothioates (PS) and their derivatives have shown promise targeting mRNA for therapeutic applications and also gained market approval for their use as a drug. However, PS have not been explored for targeting microRNAs (miRNAs or miRs). In particular, efficient delivery remains a critical cog in PS-based antimiR applications. In this study, we tested and characterized a series of poly-lactic-co-glycolic-acid (PLGA) polymers of different molecular weights that can encapsulate the optimum amount of antimiR-155 PS with uniform morphology and surface charge density. We found that nuclear localization sequence substantially increases loading of antimiR-155 PS in PLGA nanoparticles. Further, in a battery of cell culture studies, we confirmed that PLGA nanoparticles encapsulated nuclear localization sequence/antimiR-155 PS combination undergoes significant intracellular delivery and results in reduced expression of miR-155. In conclusion, we successfully demonstrate the feasibility and promise of optimized PLGA nanoparticles based PS delivery in combination with nuclear localization sequence for antimiRs based therapeutics.
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Background:
Peptide nucleic acids (PNAs) belong to the next generation of synthetic nucleic acid
analogues. Their high binding affinity and specificity towards the target DNA or RNA make them the reagent of
choice for gene therapy-based applications.
Objective:
To review important gene therapy based applications of regular and chemically modified peptide nucleic
acids in combination with nanotechnology.
Method:
Selective research of the literature.
Results:
Poor intracellular delivery of PNAs has been a significant challenge. Among several delivery strategies
explored till date, nanotechnology-based strategies hold immense potential. Recent studies have shown that advances
in nanotechnology can be used to broaden the range of therapeutic applications of PNAs. In this review,
we discussed significant advances made in nanoparticle-based on PLGA polymer, silicon, oxidized carbon and
graphene oxide for the delivery of PNAs.
Conclusion:
Nanoparticles delivered PNAs can be implied in diverse gene therapy based applications including
gene editing as well as gene targeting (antisense) based strategies.
Cationic polymeric nanoformulations have been explored to increase the transfection efficiency of small molecules and nucleic acid-based drugs. However, an excessive positive charge density often leads to severe cell and tissue-based toxicity that restricts the clinical translation of cationic polymeric nanoformulations. Herein, we investigate a series of cationic poly(lactic-coglycolic acid) (PLGA)-histidine-based nanoformulations for enhanced cytoplasmic delivery with minimal toxicity. PLGA/poly-Lhistidine nanoparticles show promising physico-biochemical features and transfection efficiency in a series of in vitro and cell culturebased studies. Further, the use of acetone/dichloromethane as a solvent mixture during the formulation process significantly improves the morphology and size distribution of PLGA/poly-L-histidine nanoparticles. PLGA/poly-L-histidine nanoformulations undergo clathrin-mediated endocytosis. A contrast-matched small-angle neutron scattering experiment confirmed poly-L-histidine's distribution on the PLGA nanoformulations. PLGA/poly-L-histidine formulations containing paclitaxel as a small molecule-based drug and peptide nucleic acids targeting microRNA-155 as nucleic acid analog are efficacious in in vitro and in vivo studies. PLGA/ poly-L-histidine NPs significantly decrease tumor growth in PNA-155 (∼6 fold) and paclitaxel (∼6.5 fold) treatment groups in a lymphoma cell line derived xenograft mice model without inducing any toxicity. Hence, PLGA/poly-L-histidine nanoformulations exhibit substantial transfection efficiency and are safe to deliver reagents ranging from small molecules to synthetic nucleic acid analogs and can serve as a novel platform for drug delivery.
The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.
Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.
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