Researchers at creighton university and colleagues at other centers noted that vaginal gel leakage and poor tenofovir penetration of vaginal tissue may. Evidence of rnai in humans from systemically administered. Vaginal topical 1% tenofovir gel has been reported to reduce risk of hiv and. Pdf preexposure prophylaxis prep, 1% tenofovir tfv vaginal gel has failed in clinical trials. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation halflife and biodistribution, cellspecific internalization, excretion, toxicity and efficacy. Conjugated polymer nanoparticles for effective sirna. Development and in vivo safety assessment of tenofovirloaded. Vaginal tenofovir gel may lower the risk for hsv2 acquisition. Molecularly selfassembled nucleic acid nanoparticles for targeted in vivo sirna delivery hyukjin lee 1,4, abigail k. A gel containing 1% tenofovir, used before and after sexual intercourse, has reduced new hiv infections by 39% and the risk for herpes simplex virus infections by 51% in highrisk women in africa. The vaginal gel formulation of tenofovir will be particularly helpful in interfering with the sexual transmission of hiv in women. Rna interference rnai is a gene regulation mechanism initiated by rna molecules that enables sequencespecific gene silencing by promoting degradation of specific mrnas. Nucleic acid nanoparticles for triggering rna interference summary 1024character limit rna interference rnai is a naturally occurring cellular posttranscriptional gene regulation process. Effect of the nanoformulation of sirna lipid assemblies on their cellular uptake and immune stimulation kohei kubota,1,2 kohei onishi,3 kazuaki sawaki,3 tianshu li,4 kaoru mitsuoka,5 takaaki sato,6 shinji takeoka1,3,4 1cooperative major in advanced biomedical sciences, graduate school of advanced sciences and engineering, waseda university twins, tokyo, japan.
In vivo delivery of sirna nanoparticles against hsv2. Nucleic acid nanoparticles for triggering rna interference. Nanoparticlesinfilms as potential vaginal microbicide products. After penetration, punch biopsies were taken and the penetration depths of the particles were investigated by laser scanning microscopy. In this study, we investigated the conjugation of mirnas to gold nanoparticles and its cell transfection scheme 1. Herein, in order to identify the optimal size of nanocarriers for sirna delivery, different sized cationic micellar nanoparticles mnps 40, 90, and 180 nm are developed that exhibit similar sirna binding efficacies, shapes, surface charges, and surface chemistries pegylation to ensure size is. Met silenziatori genici sirna h, shrna e particelle lentivirali sono disegnati per il knockdown dellespressione genica di human met. All ordering options are in the available skupack sizes table. A phase i trial using the experimental therapeutic calaa01 was initiated, and the.
The sexual transmission of viruses such as herpes simplex virus type2 hsv2 and the human immunodeficiency virus type1 hiv1, has been especially difficult to control. Tenofovir vaginal gel first microbicide to prevent hiv, hsv. Here we examine the structure of lnp sirna systems containing dlinkc2dmaan ionizable cationic lipid, phospholipid, cholesterol and a polyethylene glycol peg lipid formed using a rapid. Lentiviral particles are provided as transductionready viral particles for gene silencing. Microrna conjugated gold nanoparticles and cell transfection. Optimizing the size of micellar nanoparticles for efficient. An effective vaccine against the virus that causes genital herpes has evaded researchers for decades. Although antiretroviral drugs have been remarkably. Ome modifications shown to significantly enhance serum stability as well as reduce immune stimulation potential was used in these experiments16. Jun 23, 20 detailed analyses of sirna delivery by lipid nanoparticles reveal major pathways of sirna internalization and endosomal escape. Ugcg sirna h, shrna and lentiviral particle gene silencers. In particular, a vaginal gel containing this ntrti has been shown useful in reducing the transmission of both hiv1 and herpes simplex virus type 2 hsv2 in the caprisa 004 clinical trial. Topical delivery of sirna based spherical nucleic acid nanoparticle conjugates for gene regulation dan zheng a,b, david a. Stability, intracellular delivery, and release of sirna from.
Native polyacrylamide gel electrophoresis page analysis shows the stepwise assembly of. In order to target the cancer cells preferentially, sirna nanoparticles have been formulated with ligands that are specific to the. Topical tenofovir disoproxil fumarate df nanoparticles. Prevention strategies play a key role in the fight against hivaids. Mar 21, 2010 the function of the stain has been previously confirmed using other cyclodextrincontaining particles 20, and is demonstrated here for the targeted nanoparticles carrying sirna in vitro. The role of nanotechnology in the treatment of viral. Nanomaterials designed for antiviral drug delivery. Engineered phagebased therapeutic materials inhibit chlamydia trachomatis intracellular infection shanta raj bhattaraia,b,c,1, so young yooa,b,c,1, seungwuk leeb,c, deborah deana,b,d, acenter for immunobiology and vaccine development, childrens hospital oakland research institute, 5700 martin luther king jr. Lentiviral particles generally contain three to five expression constructs each encoding targetspecific 1925 nt plus hairpin shrna designed to knockdown gene expression. Effect of the nanoformulation of sirnalipid assemblies on their cellular uptake and immune stimulation kohei kubota,1,2 kohei onishi,3 kazuaki sawaki,3 tianshu li,4 kaoru mitsuoka,5 takaaki sato,6 shinji takeoka1,3,4 1cooperative major in advanced biomedical sciences, graduate school of advanced sciences and engineering, waseda university twins, tokyo, japan. Topical delivery of sirnabased spherical nucleic acid nanoparticle conjugates for gene regulation. Preexposure prophylaxis with tenofovir disoproxil fumarate nearly halved 48.
Tenofovir nanoparticles in vaginal gel protect 10 of 10 blt. Polymer nanoparticles encapsulating sirna for treatment of. The voice trial was a multisite study of hiv1 prevention among women in sub saharan africa that compared tenofovir tfv. First, the unique properties of nanoparticles such as 1 small particle size. Patrick lu clinam 7 2014, 7th conference and exhibition, june 2325, 2014. Progress and perspectives on hiv1 microbicide development. Advancing sirna therapeutics with nanoparticle delivery youtube. Thus, tenofovir is efficiently converted to its antivirally active metabolite in multiple different cell types that represent relevant target cells for either hiv or hsv infection in vivo. A clinical trial conducted in south africa, using 1% tenofovir gel within 12 h before and after sex. Heterogeneous polymer composite nanoparticles loaded in situ gel for. To explore current developments in short interfering rna sirna delivery systems in nanooncology, in particular nanoparticles that encapsulate sirna for targeted treatment of cancer. Improved sirna delivery efficiency via solventinduced. Pdf nanoparticles in antiviral therapy researchgate. Notably, the effective dose of the targeted sirna that resulted in protective immunity was ten to 50fold lower than that of the nontargeted sirnadelivery systems.
Assembled viruslike particles vlps without genetic material, with structure similar to. Efficiency of sirna delivery by lipid nanoparticles is. Post transcriptional gene silencing ptgs is a mechanism harnessed by plant biologists to knock. Four different formulations ethanolic suspension, aqueous suspension, ethanolic gel and aqueous gel containing peptideloaded particles of 1 m in diameter were prepared and applied on porcine ear skin. Native polyacrylamide gel electrophoresis page analysis shows the stepwise assembly of dna tetrahedron particles as each strand is added. Topical delivery of sirnabased spherical nucleic acid. Pharmaceutics free fulltext pharmaceutical vehicles. The major challenges to application of sirna therapeutics include. Recent developments in nanoparticlebased sirna delivery. Topical delivery of sirnabased spherical nucleic acid nanoparticle conjugates for gene regulation dan zheng a,b, david a. Abstract nanoparticles are employed for delivering therapeutics into cells1,2. These nanoparticles are uniform in size typical size of 100 nm and can encapsulate and deliver sirna to the liver with very high levels of efficiency. The nanoparticles formed were mostly spherical in shape, as seen in fig. This characteristic of tenofovir allows sufficiently high hsv2suppressive tenofovir diphosphate metabolite levels upon 1% tenofovir 10 mgml gel application.
Development and in vivo safety assessment of tenofovir. Our group recently reported a very effective and safe hybrid. Nanogels are one of the techniques in nanotechnology which has been most prevalent in successful medication delivery inside the body and in addition topical treatment. The obtained gel formulation based on acvloaded ns proved an. In a recent study, sirnacontaining nanoparticles were synthesized that.
May 08, 2020 by delivering sirna molecules to the site of infection, these nanoparticles reduce the expression of the nectin1 protein involved in hsv2 infection and celltocell transmission. Still, less than optimal performance of simple dosage forms such as gels e. Additionally, these particles exhibited effective plasmid and sirna delivery, quantified through green fluorescent protein gfp expression and sod1 knockdown in western blots respectively. Nanogel as a novel platform for smart drug delivery system. Nter nanoparticle sirna transfection reagent is for the transfection of recalcitrant eukaryotic cells with sirna custom sirna and predesigned sirna to achieve transient knockdown of gene. Detailed analyses of sirna delivery by lipid nanoparticles reveal major pathways of sirna internalization and endosomal escape. The first targeted delivery of sirna in humans via a self. The role of nanotechnology in the treatment of viral infections. In the present research, tenofovir was incorporated into cross linked, biodegradable gelatin nanoparticles by double desolvation method kreuter et al. Advances in herpes prevention and treatment vaccines and. Recombinant hepatitis e virus like particles can function as rna nanocarriers subrat kumar panda, neeraj kapur, daizy paliwal and hemlata durgapal abstract background.
Tenofovir vaginal gel first microbicide to prevent hiv. Investigating organ toxicity profile of tenofovir and. We earlier described in vitro assembly, characterisation and tissue specific receptor dependent clathrin mediated entry of empty hev vlps, produced from escherichia coli expressed hev capsid protein porf2. Met sirna h, shrna and lentiviral particle gene silencers. Molecular therapy using small interfering rna sirna has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. Polymer nanoparticles encapsulating sirna for treatment of hsv2.
Pharmaceutics free fulltext pharmaceutical vehicles for. The caf 2shell particles had a greater working range, up to 50 gml at 80% cell viability, but did not demonstrate effective plasmid or sirna delivery. For example wheeler and colleagues engineered cd4aptamersirna chimeras cd4asics that. The function of the stain has been previously confirmed using other cyclodextrincontaining particles 20, and is demonstrated here for the targeted nanoparticles carrying sirna in vitro. Tenofovir reduces hiv infections in injection drug users. Recent developments in nanoparticlebased sirna delivery for. Despite efforts to understand the interactions between nanoparticles. Intravaginal 1% tenofovir gel applied before and after sex lowered hiv acquisition risk 39% in the caprisa 004 trial 2, but daily 1% tenofovir gel did not protect women in the voice trial 3. Measurement of sirna entrapment efficiency by nanoparticles is needed to determine if it will be an effective nanocarrier of sirna. To date, no effective vaccines have been developed to prevent the transmission of these stis. Nanoparticle fabrication methods, systems, and materials. Herein, in order to identify the optimal size of nanocarriers for sirna delivery, different sized cationic micellar nanoparticles mnps 40, 90, and 180 nm are developed that exhibit similar sirna binding efficacies, shapes, surface charges, and surface chemistries pegylation to ensure size is the only variable. Tenofovir international partnership for microbicides ipmcontraceptive.
Bioadhesive hpmc gel containing gelatin nanoparticles for. By delivering sirna molecules to the site of infection, these nanoparticles reduce the expression of the nectin1 protein involved in hsv2 infection and celltocell transmission. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide. Lipid nanoparticles lnp containing ionizable cationic lipids are the leading systems for enabling therapeutic applications of sirna. Nanoparticle transfection reagent all ordering options are in the available skupack sizes table. So far, only a tenofovir tfv gel and a dapivirine dpv ring were. The nano particles can include pharmaceutical compositions, taggants, contrast agents, biologic drugs, drug compositions, organic materials, and the like. Characterization of hpmc k15m gel containing tenofovir loaded gelatin nanoparticles determination of ph the ph of the prepared nanogel formulations were. Vaginal and rectal microbicides hold great promise in tackling sexual transmission of hiv1, but effective and safe products are yet to be approved and made available to those in need. The nanoparticulate frameworks are materials having under 100 nm in any event in one measurement. Proceedings of the national academy of sciences of the united states of. The patent landscape of sirna nanoparticle delivery. Nanoparticles hold promise as doubleedged sword against genital.
Assembled viruslike particles vlps without genetic material, with structure similar to infectious virions, have been successfully used as vaccines. Recombinant hepatitis e virus like particles can function as. The first targeted delivery of sirna in humans via a selfassembling, cyclodextrin polymerbased nanoparticle. Davis chemical engineering, california institute of technology, pasadena, california 91125. Loading efficiency of chitosantpp nanoparticles was evaluated using gel electrophoresis, sirna loading efficiency was 100% for all the entrapped sirna katas and alpar, 2006, beddoes et al. Recombinant hepatitis e virus like particles can function.
The global impact of sexually transmitted infections stis is significant. Conjugated polymer nanoparticles for effective sirna delivery to tobacco by2 protoplasts asitha t silva1, alien nguyen2, changming ye1, jeanmarie verchot1, joong ho moon2 abstract background. Proofofconcept for vaginal microbicides was recently achieved in a phase 2b clinical trial testing a gel containing 1% of the nucleotide reverse transcriptase inhibitor ntrti tenofovir 2. Chitosan cs nanoparticles have been extensively studied for sirna delivery. Engineered phagebased therapeutic materials inhibit. Most microbicide products developed and tested so far in human clinical trials have relied in semisolid dosage forms, particularly gels. The incorporation of sirna onto nanocarriers, however, can also overcome this limitation 39 to achieve successful inhibition of viral replication. Reductively responsive sirna conjugated hydrogel nanoparticles for gene silencing. Tenofovir tnf, 2r16amino9hpurin9ylpropan2yloxymethylphosphonic acid is a nucleotide analog hiv reverse transcriptase inhibitor whose prodrug tenofovir disoproxil fumarate, tdf is now marketed in an oral dosage form viread, gilead science, and its 1% vaginal gel formulation has recently been proven effective in clinical.
Tenofovir nanoparticles in vaginal gel protect 10 of 10. Nter nanoparticle sirna transfection reagent is for the transfection of recalcitrant eukaryotic cells with sirna custom sirna and predesigned sirna to achieve transient knockdown of gene expression. While most efforts have been placed in finding and testing suitable active drug candidates to be used in microbicide development, the last. Note that this strategy was successfully exploited for sirna delivery in which gold nanoparticles protected the sirna from rnases, showing. Way, oakland, ca 94609, usa b department of bioengineering, university of. Rna interference rnai is a costeffective means of suppressing the expression of virtually any gene in a sequence specific manner 84, 85. This is a pdf file of an unedited manuscript that has been.
Get article recommendations from acs based on references in your mendeley library. Molecularly selfassembled nucleic acid nanoparticles for. Lipid nanoparticles containing sirna synthesized by. Nevertheless, their clinical application has been limited by a lack of effective and safe nanotechnologybased delivery system that allows a controlled and safe transfection to cytosol of targeted cells without the associated adverse effects. This research achieved a sustained drug release period increased by 30% showing absolute drug release profiles over a 5day period with. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation halflife and biodistribution, cell specific internalization, excretion, toxicity, and efficacy37. Grant eb000244 nanoparticles are used for delivering therapeutics into cells. Sep 26, 2015 sirnas have a high potential for silencing critical molecular pathways that are pathogenic. Pdf in addition to general unavailability of specific antiviral therapeutics for a. The field began early in the 1990s, with the discovery that small rna molecules had the ability to regulate developmental timing in the nematode caenorhabditis elegans and trans gene expression in plants 8688.
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