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Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics
Open accessAbstract
Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.
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“Strategies that have been applied for achieving functional siRNA delivery into the brain mainly rely on employing potent protein or peptide ligands to target the receptors, such as transferrin, insulin and LDL receptors, which are highly expressed on the blood brain barrier (BBB).[102]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [102]
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Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA
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Pulmonary delivery of therapeutic siRNA
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BackgroundCell-penetrating Peptides as Versatile Vehicles for Oligonucleotide Delivery
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BackgroundPolyethylenimines for siRNA and miRNA delivery in vivo
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BackgroundLipid nanoparticle delivery systems for siRNA-based therapeutics
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Comparison of five different targeting ligands to enhance accumulation of liposomes into the brain
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Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2 + Breast Cancer Growth and Metastasis
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BackgroundCD44 is the Principal Mediator of Hyaluronic-Acid-Induced Melanoma Cell Proliferation
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Antisense Drug Discovery and Development
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“RGD peptides were also attached to the surface of PAMAM dendrimers [129,130].”
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Extravasation of macromolecules
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“Besides intravenous injections, application routes to the blood stream include subcutaneous injection, delivery through the skin, lung [74], or nasal mucosa [75].”
BackgroundsiRNA Delivery to the lung: What's new?
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The Chemistry and Biology of Oligonucleotide Conjugates
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“Several ligands have been used to further increase hepatic accumulation and uptake, including lipids [181], steroids [182], tocopherol [183], and carbohydrates [184] (Figure 2).”
MethodBevasiranib for the Treatment of Wet, Age-Related Macular Degeneration
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Safety profile of RNAi nanomedicines
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“Furthermore, comprehensive drug safety assessments will have implications for the whole class of siRNA therapeutics [49,50].”
BackgroundMultivalent Cyclic RGD Conjugates for Targeted Delivery of Small Interfering RNA
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“The cyclic RGD peptide has been attached to siRNA for specific targeting of αvβ3 integrin-positive cells [131].”
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“The increased expression ofαVβ3 integrin on tumor endothelial cells was exploited for delivery of siRNA through a cationic lipid systemwith cyclic RGD grafted onto its surface [128].”
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“Therapeutic siRNAs can be coated onto those stainless steel needles, or injected with microneedle devices [76,77].”
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Designed Ankyrin Repeat Proteins (DARPins)
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“Oligonucleotides can be site-specifically attached to protein binders such as affibodies [161], anticalins [162], or DARPins [154,163].”
BackgroundDefined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing
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Liver as a target for oligonucleotide therapeutics
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“It is no surprise that all these clinically evaluated siRNA and miRNA drugs, as well asmany antisense agents, are tested for the antagonization of liver targets [48].”
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“Standard single and double stranded oligonucleotides (and their metabolites) fail to reach this limit, but increasing the molecular size by either attachment of ligands such as polyethylene glycol (PEG), incorporation into larger particles or significant binding to plasma proteins efficiently saves siRNA from eliminat…”
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“Transferrin receptor targeted delivery has shown some success for protein and drug uptake into the brain [102,106] but in other cases, trapping in the brain microvasculature has been reported [107,108].”
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“Based on disease areas with unmet medical need, functional siRNA delivery into tumors [100], the brain [101], and endothelium [99] is especially attractive.”
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“Instead of antibody fragments, alternative protein binder scaffolds offer easier production, higher stability, andmore facile derivatization [153].”
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Optimized siRNA-PEG Conjugates for Extended Blood Circulation and Reduced Urine Excretion in Mice
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“This can be avoided by increasing the molecular size, for example by PEGylation [178–180].”
BackgroundA Locked Nucleic Acid Oligonucleotide Targeting MicroRNA 122 Is Well-Tolerated in Cynomolgus Monkeys
Hildebrandt-Eriksen, E. S., Aarup, V., Persson, R., Hansen, H. F., Munk, M. E., & Ørum, H. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2011.0332 · Cited by 97 · cited 1×
“Modifications on the ribose (2′-methyl, methoxyethyl and other alkyl chains, as well as locked nucleic acids (LNA)) [23,24] aptly increase enzymatic stability, but are only efficacious in combination with at least a partial phosphorothioate backbone, which is necessary for protein binding and thus a certain amount of…”
BackgroundDelivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC
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“2 Lung indications Silence Therapeutics Phase I [63]”
BackgroundOff‐Target Effects Related to the Phosphorothioate Modification of Nucleic Acids
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“Both sequence-specific and sequence-unspecific off-target effects are well-documented [19,52–54].”
BackgroundEpithelial cell adhesion molecule-targeted drug delivery for cancer therapy
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“For siRNA delivery, frequently targeted receptors include Her2 [132], the epidermal growth factor receptor EGFR [133], and the epithelial cell adhesion molecule EpCAM [134].”
BackgroundEpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins
Winkler, J., Martin-Killias, P., Plückthun, A., & Zangemeister‐Wittke, U. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0402 · Cited by 93
Technology evaluation: fomivirsen, Isis Pharmaceuticals Inc/CIBA vision.
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Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides
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“Generally, particles above around 200 nm are rapidly cleared by phagocytic cells mainly found in the liver and spleen [80].”
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“− Liposomes [110] − Peptide/siRNA complexes [112]”
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“Other targets that have been used for BBB-targeting of siRNA include the insulin receptor [104], and the LDL receptor [105].”
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Click-Modified Anandamide siRNA Enables Delivery and Gene Silencing in Neuronal and Immune Cells
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“75NTR are possible targets − Peptide/siRNA complexes [113] − Polyethyleneimine complexes [115] − Liposomes [116] − PAMAM nanoparticles [117] − Targeted exosomes [114] − Protamine-antibody/siRNA complexes [126] − Liposomes [127] − Polythyleneimine complexes [135–137] − PEG–siRNA conjugate [138] − Self-assembled nanopar…”
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“Depending on their mechanism of action, therapeutic oligonucleotides are categorized into several classes: Antisense [6,7], aptamers [8], splice correcting oligonucleotide [9,10], siRNA [1], miRNA mimics and antagonists [11], immunomodulating agents [12] and decoys [13] are themost important ones.”
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Engineered Proteinticles for Targeted Delivery of siRNA to Cancer Cells
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“A fusion protein with an oligonucleotide complexing domain, a cell-penetrating peptide, and a targeting peptidewas recently developed for tumor-specific delivery of siRNA [156].”
BackgroundNano-enabled delivery systems across the blood–brain barrier
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“For therapeutic purposes, only highly lipophilic molecules with a molecular weight under 400 Da or those with an active transport system can access the brain [87].”
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New links between vesicle coats and Rab-mediated vesicle targeting
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BackgroundThe emerging role of new protein scaffold-based agents for treatment of cancer.
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“Other targets that have been used for BBB-targeting of siRNA include the insulin receptor [104], and the LDL receptor [105].”
BackgroundParis‐Robidas, S., Émond, V., Tremblay, C., Soulet, D., & Calon, F. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.071027 · Cited by 70 · cited 1×
“Transferrin receptor targeted delivery has shown some success for protein and drug uptake into the brain [102,106] but in other cases, trapping in the brain microvasculature has been reported [107,108].”
BackgroundBioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting
Yoon, H. Y., Kim, H. R., Saravanakumar, G., Heo, R., Chae, S. Y., Um, W., Kim, K., Kwon, I. C., Lee, J. Y., Lee, D. S., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.09.008 · Cited by 68
Nascimento, A. V., Singh, A., Bousbaa, H., Ferreira, D., Sarmento, B. F. C. C., & Amiji, M. M. (2014) · Molecular Pharmaceutics · doi:10.1021/mp5002894 · Cited by 68 · cited 2×
“For siRNA delivery, frequently targeted receptors include Her2 [132], the epidermal growth factor receptor EGFR [133], and the epithelial cell adhesion molecule EpCAM [134].”
BackgroundCyclodextrin-Containing Polymers: Versatile Platforms of Drug Delivery Materials
Heidel, J. D., & Schluep, T. (2012) · Journal of Drug Delivery · doi:10.1155/2012/262731 · Cited by 65 · cited 1×
“completed [59]”
Fluiter, K., Mook, O. R. F., & Baas, F. (2008) · Methods in molecular biology · doi:10.1007/978-1-60327-547-7_9 · Cited by 63 · cited 1×
“Rapid renal filtration and elimination are not avoided [33–36].”
BackgroundRicotta, D. N., & Frishman, W. H. (2012) · Cardiology in Review · doi:10.1097/crd.0b013e31823424be · Cited by 60 · cited 1×
“Mipomersen inhibits the transcription of apolipoprotein B 100 and reduces blood levels of cholesterol, LDL-C, and apolipoprotein B [16].”
BackgroundLi, J., Ji, Mao, Z., Wang, Zhang, W., & Su, H. (2013) · International Journal of Nanomedicine · doi:10.2147/ijn.s42440 · Cited by 60
Knockdown of β-catenin with Dicer-Substrate siRNAs Reduces Liver Tumor Burden In vivo
Dudek, H., Wong, D. H., Arvan, R., Shah, A., Wortham, K. A., Ying, B., Diwanji, R., Zhou, W. L., Holmes, B. R., Yang, H., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.233 · Cited by 56
Kim, J. S., Oh, M. H., Park, J. Y., Park, T. G., & Nam, Y. S. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2012.12.004 · Cited by 54
Developing microRNA Therapeutics: Approaching the Unique Complexities
Jackson, A. L., & Levin, A. A. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2012.0356 · Cited by 53 · cited 1×
“The recently expanding knowledge about microRNAs (miRNA) has quickly prompted the development of miRNA-mimicking oligonucleotides for therapeutic applications [45].”
BackgroundHenry, S. P., Johnson, M., Zanardi, T. A., Fey, R. A., Auyeung, D. J., Lappin, P. B., & Levin, A. A. (2012) · Toxicology · doi:10.1016/j.tox.2012.06.005 · Cited by 50 · cited 1×
“Modifications on the ribose (2′-methyl, methoxyethyl and other alkyl chains, as well as locked nucleic acids (LNA)) [23,24] aptly increase enzymatic stability, but are only efficacious in combination with at least a partial phosphorothioate backbone, which is necessary for protein binding and thus a certain amount of…”
BackgroundFriberg, T. R., Tolentino, M., & for the LEVEL Study Group (2010) · British Journal of Ophthalmology · doi:10.1136/bjo.2009.174946 · Cited by 50 · cited 1×
“Pegaptanib is an aptamer available for local therapy of age-related macular degeneration, and antagonizes the detrimental effects of the vascular endothelial growth factor (VEGF) [15].”
BackgroundLau, S., Graham, B., Cao, N., Boyd, B. J., Pouton, C. W., & White, P. J. (2011) · Molecular Pharmaceutics · doi:10.1021/mp2002522 · Cited by 46
Oligo Safety Working Group Exaggerated Pharmacology Subcommittee Consensus Document
Kornbrust, D. J., Cavagnaro, J. A., Levin, A. A., Foy, J. W.-D., Pavco, P. A., Gamba‐Vitalo, C., & Guimond, A. (2013) · Nucleic Acid Therapeutics · doi:10.1089/nat.2012.0399 · Cited by 45 · cited 1×
“Furthermore, comprehensive drug safety assessments will have implications for the whole class of siRNA therapeutics [49,50].”
BackgroundTao, Y., Han, J., & Dou, H. (2012) · Journal of Materials Chemistry · doi:10.1039/c2jm31675g · Cited by 42 · cited 4×
“75NTR are possible targets − Peptide/siRNA complexes [113] − Polyethyleneimine complexes [115] − Liposomes [116] − PAMAM nanoparticles [117] − Targeted exosomes [114] − Protamine-antibody/siRNA complexes [126] − Liposomes [127] − Polythyleneimine complexes [135–137] − PEG–siRNA conjugate [138] − Self-assembled nanopar…”
BackgroundMethodInfluentialManich, G., Cabezón, I., del Valle, J., Duran‐Vilaregut, J., Camins, A., Pallàs, M., Pelegrı́, C., & Vilaplana, J. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2013.05.027 · Cited by 39
Nishimura, Y., Mieda, H., Ishii, J., Ogino, C., Fujiwara, T., & Kondo, A. (2013) · Journal of Nanobiotechnology · doi:10.1186/1477-3155-11-19 · Cited by 39 · cited 2×
“For Her2-mediated targeting, a recent report used particles consisting of hepatitis B virus L protein, the viral surface antigen (HBsAg), a lipid bilayer, and a Her2-selective affibody [142].”
MethodTherapeutic Potential of Mipomersen in the Management of Familial Hypercholesterolaemia
Gelsinger, C., Steinhagen‐Thiessen, E., & Kassner, U. (2012) · Drugs · doi:10.2165/11635060-000000000-00000 · Cited by 35 · cited 1×
“Biological investigations and the clinical evaluation of mipomersen and other antisense agents have recently proven that these off-target effects are indeed translated to considerable relevant side effects [20,21].”
BackgroundRecent advances in small interfering RNA sensing by the immune system
Sioud, M. (2010) · New Biotechnology · doi:10.1016/j.nbt.2010.02.015 · Cited by 29 · cited 2×
“Both sequence-specific and sequence-unspecific off-target effects are well-documented [19,52–54].”
BackgroundChemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect
Gaziova, Z., Baumann, V., Winkler, A.-M., & Winkler, J. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.02.004 · Cited by 29
Self-assembled proteinticle nanostructures for 3-dimensional display of antibodies
Lee, E. J., Lee, E., Kim, H. J., Lee, J.-H., Ahn, K.-Y., Park, J.-S., & Lee, J. (2014) · Nanoscale · doi:10.1039/c4nr03635b · Cited by 29 · cited 1×
“Recombinant engineering of self-multiplexing proteins yields well-controlled particles, termed proteinticles, with a uniform size distribution [155].”
BackgroundStessl, M., Marchetti‐Deschmann, M., Winkler, J., Lachmann, B., Allmaier, G. M., & Noe, C. R. (2009) · Journal of Proteomics · doi:10.1016/j.jprot.2009.06.001 · Cited by 29 · cited 1×
“On the flip side, the high non-specific protein affinity results in significant off-target effects, meaning biological outcomes that are caused by interactions other than that on the targeted gene [18,19].”
BackgroundHickerson, R. P., Wey, W. C., Rimm, D. L., Speaker, T. J., Suh, S., Flores, M. A., González-González, E., Leake, D., Contag, C. H., & Kaspar, R. L. (2013) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2013.56 · Cited by 29 · cited 1×
“Therapeutic siRNAs can be coated onto those stainless steel needles, or injected with microneedle devices [76,77].”
BackgroundNanomedicines Based on Recombinant Fusion Proteins for Targeting Therapeutic siRNA Oligonucleotides
Winkler, J. (2011) · Therapeutic Delivery · doi:10.4155/tde.11.56 · Cited by 28 · cited 1×
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
BackgroundShokrzadeh, N., Winkler, A.-M., Dirin, M., & Winkler, J. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.10.045 · Cited by 27 · cited 1×
“This can be avoided by increasing the molecular size, for example by PEGylation [178–180].”
BackgroundMash, R. J. (2006) · South African Family Practice · doi:10.1080/20786204.2006.10873431 · Cited by 26
Lee, D. U., Huang, W., Rittenhouse, K. D., & Jessen, B. A. (2012) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2011.0116 · Cited by 26
Nakagawa, O., Ming, X., Carver, K. A., & Juliano, R. L. (2013) · Bioconjugate Chemistry · doi:10.1021/bc400500h · Cited by 24 · cited 2×
“n molecule − Nanocomplexes [154] − Chitosan nanoparticles [133] − Conjugate [146] − Proteinticle [156]”
BackgroundUckun, F. M., Qazi, S., Dıbırdık, İ., & Myers, D. E. (2012) · Integrative Biology · doi:10.1039/c2ib20114c · Cited by 22 · cited 1×
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
BackgroundReview of Phase II and Phase III clinical trials for Duchenne muscular dystrophy
Scully, M. A., Pandya, S., & Moxley, R. T. (2012) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2013.746939 · Cited by 21 · cited 1×
“The orphan disease Duchenne muscular dystrophy is caused by the expression of a non-functional dystrophin protein due to deletion of a section of its corresponding gene [26].”
BackgroundIs mipomersen ready for clinical implementation? A transatlantic dilemma
Sjouke, B., Balak, D., Beuers, U. H., Ratziu, V., & Stroes, E. S. G. (2013) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328362dfd9 · Cited by 20 · cited 3×
“The tendency of mipomersen to induce an elevation of the plasma levels of liver alanine transaminase (ALT) and aspartate transaminase (AST), and hepatosteatosis have triggered controversy during the approval processes on both sides of the atlantic [5].”
BackgroundTan, M., Vernes, J.-M., Chan, J. C. Y., Cuellar, T. L., Asundi, A., Nelson, C., Yip, V., Shen, B., VANDLEN, R. L., Siebel, C. W., et al. (2012) · Analytical Biochemistry · doi:10.1016/j.ab.2012.08.018 · Cited by 19 · cited 1×
“Genentech has recently reported the generation and development of analytical methodology for an siRNA–antibody conjugate [159], but to date no pharmacological data”
Zhang, T., Wang, C., Zhang, W., Gao, Y., Yang, S., Wang, T., Zhang, R.-Z., Qin, C., & Xia, X. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.03.045 · Cited by 16 · cited 2×
“Several antibody-mediated strategies made use of fusion proteins with basic peptides, such as protamine [126,147–151].”
BackgroundNucleic Acid Therapeutics: Concepts for Targeted Delivery to Solid Tumors
Ogris, M. (2010) · Therapeutic Delivery · doi:10.4155/tde.10.9 · Cited by 8 · cited 1×
“Based on disease areas with unmet medical need, functional siRNA delivery into tumors [100], the brain [101], and endothelium [99] is especially attractive.”
Background
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Emerging Frontiers in Drug Delivery
Tibbitt, M. W., Dahlman, J. E., & Langer, R. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.5b09974 · Cited by 1,009
The delivery of therapeutic oligonucleotides
Juliano, R. L. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw236 · Cited by 882
“This approach has been especially important for therapeutic use of siRNA (164) and good accounts of current clinical trials using siRNA LNPs are found in recent reviews (10,165).”
BackgroundAntisense Oligonucleotides: An Emerging Area in Drug Discovery and Development
Dhuri, K., Bechtold, C., Quijano, E., Pham, H. T. T., Gupta, A., Vikram, A., & Bahal, R. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9062004 · Cited by 586
Kim, S. M., Yang, Y., Oh, S. J., Hong, Y., Seo, M., & Jang, M. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.09.013 · Cited by 481
Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives
Poller, W. C., Dimmeler, S., Heymans, S. R. B., Zeller, T., Haas, J., Karakas, M., Leistner, D. M., Jakob, P., Nakagawa, S., Blankenberg, S., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx165 · Cited by 417
Metadata
- Authors
- Lorenzer, C., Dirin, M., Winkler, A.-M., Baumann, V., & Winkler, J.
- Affiliations
- University of Vienna (AT)
- Corresponding author
- Winkler, Johannes
- ORCID
- Winkler, Johannes
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 203
- Pages
- 1-15
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2019613864
- Cited by
- 284
- References
- 188
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 17 · 2023: 17 · 2022: 22 · 2021: 25 · 2020: 23 · 2019: 35 · 2018: 34 · 2017: 33 · 2016: 37 · 2015: 18
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Controlled Release (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- FWF (I519-B11)
- Innovative Medicines Initiative Joint Undertaking (115363)
- European Union's (FP7/2007–2013)
- EFPIA companies'
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- siRNA therapeutics, targeted delivery, gene silencing, liposomes, nanoparticle drug delivery, tumor targeting, blood-brain barrier, transcytosis, cellular uptake, pharmacokinetics, oligonucleotide therapeutics, liver-targeted drug delivery
- MeSH terms
- RNAi Therapeutics, Animals, Blood-Brain Barrier, Endothelium, Humans, Leukocytes, Liposomes, Liver, Models, Molecular, Neoplasms, Drug Delivery Systems, Gene Transfer Techniques, RNA, Small Interfering, Nanoparticles
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