Achieving successful delivery of oligonucleotides — From physico-chemical characterization to in vivo evaluation

Scomparin, Anna; Polyak, Dina; Krivitsky, Adva; Satchi‐Fainaro, Ronit

doi:10.1016/j.biotechadv.2015.04.008

Cited by 36 publications

(37 citation statements)

References 160 publications

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“…23 Most therapeutic applications of miRNA require packaging the nucleic acid in a vector or nanovehicle, example of which include adenovirus (AV), adeno-associated virus (AAV), liposomes, polycationic polymers, and organic/ inorganic nanoparticles. [24][25][26][27][28][29] Kota et al, for example, showed that miR-26a, a downregulated miRNA in hepatocellular carcinoma, could be delivered to liver cancer cells using AAV where it induced tumor-specific apoptosis in a mouse model of liver cancer. 30 Moreover, our group developed a poly(lactic-coglycolic acid)/polyetherimide/hyaluronan (PLGA/PEI/HA)-based vehicle as a carrier of miR-145 and further showed that PLGA/PEI/HA/miRNA complexes were delivered efficiently to tumor cells within colon carcinoma xenografts in mice where they exhibited significant antitumor effects.…”

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confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

207

152

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Introduction Exosomes are closed-membrane nanovesicles that are secreted by a variety of cells and exist in most body fluids. Recent studies have demonstrated the potential of exosomes as natural vehicles that target delivery of functional small RNA and chemotherapeutics to diseased cells. Methods In this study, we introduce a new approach for the targeted delivery of exosomes loaded with functional miR-26a to scavenger receptor class B type 1-expressing liver cancer cells. The tumor cell-targeting function of these engineered exosomes was introduced by expressing in 293T cell hosts, the gene fusion between the transmembrane protein of CD63 and a sequence from Apo-A1. The exosomes harvested from these 293T cells were loaded with miR-26a via electroporation. Results The engineered exosomes were shown to bind selectively to HepG2 cells via the scavenger receptor class B type 1–Apo-A1 complex and then internalized by receptor-mediated endocytosis. The release of miR-26a in exosome-treated HepG2 cells upregulated miR-26a expression and decreased the rates of cell migration and proliferation. We also presented evidence that suggest cell growth was inhibited by miR-26a-mediated decreases in the amounts of key proteins that regulate the cell cycle. Conclusion Our gene delivery strategy can be adapted to treat a broad spectrum of cancers by expressing proteins on the surface of miRNA-loaded exosomes that recognize specific biomarkers on the tumor cell.

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confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

207

152

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“…Subtle differences in architectures and the physicochemical properties of the NP complexes (i.e. size, stiffness, surface potential, morphology, hydrophobicity) [112,113] can have significant effects on the in vitro and in vivo delivery efficiency [85]. Thus polymer composition should be carefully considered when designing such delivery vehicles.…”

Section: Polymersmentioning

confidence: 99%

Polymers in the Delivery of siRNA for the Treatment of Virus Infections

2017

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Viral diseases remain a major cause of death worldwide. Despite advances in vaccine and antiviral drug technology, each year over three million people die from a range of viral infections. Predominant viruses include human immunodeficiency virus, hepatitis viruses, and gastrointestinal and respiratory viruses. Now more than ever, robust, easily mobilised and cost-effective antiviral strategies are needed to combat both known and emerging disease threats. RNA interference and small interfering (si)RNAs were initially hailed as a "magic bullet", due to their ability to inhibit the synthesis of any protein via the degradation of its complementary messenger RNA sequence. Of particular interest was the potential for attenuating viral mRNAs contributing to the pathogenesis of disease that were not able to be targeted by vaccines or antiviral drugs. However, it was soon discovered that delivery of active siRNA molecules to the infection site in vivo was considerably more difficult than anticipated, due to a number of physiological barriers in the body. This spurred a new wave of investigation into nucleic acid delivery vehicles which could facilitate safe, targeted and effective administration of the siRNA as therapy. Amongst these, cationic polymer delivery vehicles have emerged as a promising candidate as they are low-cost and easy to produce at an industrial scale, and bind to the siRNA by non-specific electrostatic interactions. These nanoparticles (NPs) can be functionally designed to target the infection site, improve uptake in infected cells, release the siRNA inside the endosome and facilitate delivery into the cell cytoplasm. They may also have the added benefit of acting as adjuvants. This chapter provides a background around problems associated with the translation of siRNA as antiviral treatments, reviews the progress made in nucleic acid therapeutics and discusses current methods and progress in overcoming these challenges. It also addresses the importance of combining physicochemical characterisation of the NPs with in vitro and in vivo data.

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“…The resulting complexes were predicted to induce endosomal escape via the 'proton sponge effect' subsequent to endosomal membrane rupture. Incorporation of five histidine's to dermaseptin derived CPP, S4 13 -PV showed effective gene silencing of survivin gene in HT1080 (human fibrosarcoma) cells [88].…”

Section: Cpps and Endosomolytic Agentsmentioning

confidence: 99%

Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

Gupta

Puri

Shapiro

2017

DNA and RNA Nanotechnology

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RNA interference (RNAi) has been regarded as a vital asset in the field of therapeutics as it has the capability to silence various disease causing genes including those that cause cancer. Small non-coding RNA molecules such as short interfering RNAs (siRNAs) are one of the extensively studied RNAi inducers for gene modulations. However, the delivery of RNAi inducers including siRNAs is compromised due to the barriers imposed by the biological system such as degradation by nucleases, rapid clearance, high anionic charge, immunogenicity and off-target effects. Viral vectors, in general exhibit high transfection efficiencies but are expensive and likely to confer immunological and safety issues. Therefore, non-viral cationic vectors (NVCVs) have received considerable attention to not only address these issues but also for developing efficacious siRNA delivery vectors. In this review, we will first discuss the historical development of various NVCVs and then will discuss functionalized NVCVs with linkers that provide stability, as well as respond to the cancer cell environment and with cancer cell receptor specific ligands to explicitly target them for improved siRNA efficacy. Multifunctional NVCVs (MNVCVs) that employ multiple synergistically working components to aid siRNA delivery efficacy are also discussed.

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Achieving successful delivery of oligonucleotides — From physico-chemical characterization to in vivo evaluation

Cited by 36 publications

References 160 publications

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Polymers in the Delivery of siRNA for the Treatment of Virus Infections

Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

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