Native polyacrylamide gel electrophoresis page analysis shows the stepwise assembly of. Recombinant hepatitis e virus like particles can function as rna nanocarriers subrat kumar panda, neeraj kapur, daizy paliwal and hemlata durgapal abstract background. Conjugated polymer nanoparticles for effective sirna. 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. Assembled viruslike particles vlps without genetic material, with structure similar to infectious virions, have been successfully used as vaccines. Despite efforts to understand the interactions between nanoparticles.
In vivo delivery of sirna nanoparticles against hsv2. Tenofovir international partnership for microbicides ipmcontraceptive. Jun 23, 20 detailed analyses of sirna delivery by lipid nanoparticles reveal major pathways of sirna internalization and endosomal escape. Recombinant hepatitis e virus like particles can function. 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 sirna h, shrna and lentiviral particle gene silencers. 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. 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. 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. In this study, we investigated the conjugation of mirnas to gold nanoparticles and its cell transfection scheme 1.
Tenofovir nanoparticles in vaginal gel protect 10 of 10 blt. Nanoparticle fabrication methods, systems, and materials. 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 major challenges to application of sirna therapeutics include. Optimizing the size of micellar nanoparticles for efficient. Nanogel as a novel platform for smart drug delivery system. 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. This characteristic of tenofovir allows sufficiently high hsv2suppressive tenofovir diphosphate metabolite levels upon 1% tenofovir 10 mgml gel application. The nanoparticulate frameworks are materials having under 100 nm in any event in one measurement. Tenofovir reduces hiv infections in injection drug users. Evidence of rnai in humans from systemically administered. Lipid nanoparticles containing sirna synthesized by. The voice trial was a multisite study of hiv1 prevention among women in sub saharan africa that compared tenofovir tfv.
Tenofovir vaginal gel first microbicide to prevent hiv. Abstract nanoparticles are employed for delivering therapeutics into cells1,2. In the present research, tenofovir was incorporated into cross linked, biodegradable gelatin nanoparticles by double desolvation method kreuter et al. The role of nanotechnology in the treatment of viral infections. The role of nanotechnology in the treatment of viral.
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. Although antiretroviral drugs have been remarkably. Effect of the nanoformulation of sirnalipid assemblies on. Topical delivery of sirnabased spherical nucleic acid nanoparticle conjugates for gene regulation dan zheng a,b, david a. 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. Pdf preexposure prophylaxis prep, 1% tenofovir tfv vaginal gel has failed in clinical trials. 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.
Recent developments in nanoparticlebased sirna delivery. All ordering options are in the available skupack sizes table. Chitosan cs nanoparticles have been extensively studied for sirna delivery. Topical delivery of sirnabased spherical nucleic acid. For example wheeler and colleagues engineered cd4aptamersirna chimeras cd4asics that. 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. A phase i trial using the experimental therapeutic calaa01 was initiated, and the. 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. Nanomaterials designed for antiviral drug delivery. Additionally, these particles exhibited effective plasmid and sirna delivery, quantified through green fluorescent protein gfp expression and sod1 knockdown in western blots respectively. 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.
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. Note that this strategy was successfully exploited for sirna delivery in which gold nanoparticles protected the sirna from rnases, showing. The global impact of sexually transmitted infections stis is significant.
Molecularly selfassembled nucleic acid nanoparticles for targeted in vivo sirna delivery hyukjin lee 1,4, abigail k. Vaginal tenofovir gel may lower the risk for hsv2 acquisition. Davis chemical engineering, california institute of technology, pasadena, california 91125. Progress and perspectives on hiv1 microbicide development. Most microbicide products developed and tested so far in human clinical trials have relied in semisolid dosage forms, particularly gels. Advancing sirna therapeutics with nanoparticle delivery youtube. Efficiency of sirna delivery by lipid nanoparticles is.
Our group recently reported a very effective and safe hybrid. 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. This is a pdf file of an unedited manuscript that has been. 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. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide. After penetration, punch biopsies were taken and the penetration depths of the particles were investigated by laser scanning microscopy. 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. Bioadhesive hpmc gel containing gelatin nanoparticles for. An effective vaccine against the virus that causes genital herpes has evaded researchers for decades. Recent developments in nanoparticlebased sirna delivery for. Patrick lu clinam 7 2014, 7th conference and exhibition, june 2325, 2014. 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. 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.
In order to target the cancer cells preferentially, sirna nanoparticles have been formulated with ligands that are specific to the. 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. The incorporation of sirna onto nanocarriers, however, can also overcome this limitation 39 to achieve successful inhibition of viral replication. Lentiviral particles generally contain three to five expression constructs each encoding targetspecific 1925 nt plus hairpin shrna designed to knockdown gene expression. 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.
Tenofovir vaginal gel first microbicide to prevent hiv, hsv. 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. Conjugated polymer nanoparticles for effective sirna delivery. Still, less than optimal performance of simple dosage forms such as gels e. Rna interference rnai is a costeffective means of suppressing the expression of virtually any gene in a sequence specific manner 84, 85. While most efforts have been placed in finding and testing suitable active drug candidates to be used in microbicide development, the last. 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. Development and in vivo safety assessment of tenofovir.
Assembled viruslike particles vlps without genetic material, with structure similar to. Polymer nanoparticles encapsulating sirna for treatment of hsv2. 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. Polymer nanoparticles encapsulating sirna for treatment of. 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. Prevention strategies play a key role in the fight against hivaids. Nano particles are molded in nano scale molds fabricated from nonwetting, low surface energy polymeric materials. Researchers at creighton university and colleagues at other centers noted that vaginal gel leakage and poor tenofovir penetration of vaginal tissue may. Lentiviral particles are provided as transductionready viral particles for gene silencing. 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. 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. To date, no effective vaccines have been developed to prevent the transmission of these stis. Preexposure prophylaxis with tenofovir disoproxil fumarate nearly halved 48.
Tenofovir nanoparticles in vaginal gel protect 10 of 10. Post transcriptional gene silencing ptgs is a mechanism harnessed by plant biologists to knock. Stability, intracellular delivery, and release of sirna from. Nucleic acid nanoparticles for triggering rna interference. The first targeted delivery of sirna in humans via a selfassembling, cyclodextrin polymerbased nanoparticle. First, the unique properties of nanoparticles such as 1 small particle size. The patent landscape of sirna nanoparticle delivery. 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.
Pdf in addition to general unavailability of specific antiviral therapeutics for a. Topical tenofovir disoproxil fumarate df nanoparticles. 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. Pharmaceutics free fulltext pharmaceutical vehicles for. Sep 26, 2015 sirnas have a high potential for silencing critical molecular pathways that are pathogenic.
Native polyacrylamide gel electrophoresis page analysis shows the stepwise assembly of dna tetrahedron particles as each strand is added. Advances in herpes prevention and treatment vaccines and. Lipid nanoparticles lnp containing ionizable cationic lipids are the leading systems for enabling therapeutic applications of sirna. Engineered phagebased therapeutic materials inhibit. Nanoparticlesinfilms as potential vaginal microbicide products. The first targeted delivery of sirna in humans via a self. Microrna conjugated gold nanoparticles and cell transfection. Molecular therapy using small interfering rna sirna has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. 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. Vaginal topical 1% tenofovir gel has been reported to reduce risk of hiv and. Ugcg sirna h, shrna and lentiviral particle gene silencers.
Improved sirna delivery efficiency via solventinduced. Development and in vivo safety assessment of tenofovirloaded. Get article recommendations from acs based on references in your mendeley library. 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. Detailed analyses of sirna delivery by lipid nanoparticles reveal major pathways of sirna internalization and endosomal escape. Molecularly selfassembled nucleic acid nanoparticles for.
The nanoparticles formed were mostly spherical in shape, as seen in fig. 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 nano particles can include pharmaceutical compositions, taggants, contrast agents, biologic drugs, drug compositions, organic materials, and the like. Rna interference rnai is a gene regulation mechanism initiated by rna molecules that enables sequencespecific gene silencing by promoting degradation of specific mrnas. Recombinant hepatitis e virus like particles can function as. Pharmaceutics free fulltext pharmaceutical vehicles. The vaginal gel formulation of tenofovir will be particularly helpful in interfering with the sexual transmission of hiv in women. Topical delivery of sirna based spherical nucleic acid nanoparticle conjugates for gene regulation dan zheng a,b, david a. The obtained gel formulation based on acvloaded ns proved an. Ome modifications shown to significantly enhance serum stability as well as reduce immune stimulation potential was used in these experiments16.
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. Measurement of sirna entrapment efficiency by nanoparticles is needed to determine if it will be an effective nanocarrier of sirna. This research achieved a sustained drug release period increased by 30% showing absolute drug release profiles over a 5day period with. Pdf nanoparticles in antiviral therapy researchgate. Characterization of hpmc k15m gel containing tenofovir loaded gelatin nanoparticles determination of ph the ph of the prepared nanogel formulations were. Met silenziatori genici sirna h, shrna e particelle lentivirali sono disegnati per il knockdown dellespressione genica di human met. To explore current developments in short interfering rna sirna delivery systems in nanooncology, in particular nanoparticles that encapsulate sirna for targeted treatment of cancer. Nanoparticles hold promise as doubleedged sword against genital. Reductively responsive sirna conjugated hydrogel nanoparticles for gene silencing. Nucleic acid nanoparticles for triggering rna interference summary 1024character limit rna interference rnai is a naturally occurring cellular posttranscriptional gene regulation process.
Proceedings of the national academy of sciences of the united states of. In a recent study, sirnacontaining nanoparticles were synthesized that. Grant eb000244 nanoparticles are used for delivering therapeutics into cells. Way, oakland, ca 94609, usa b department of bioengineering, university of. Topical delivery of sirnabased spherical nucleic acid nanoparticle conjugates for gene regulation.
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