Our Science
Extrahepatic Delivery
of Therapeutic Nucleic Acids
RNA-based therapies are currently one of the most promising fields in medical research. However, effective and robust nucleic acid delivery remains the key rate-limiting step for unlocking the full potential of RNA therapeutics. Our OligoPhore™ / SemaPhore™ technology is a highly versatile platform that allows for delivery of nucleic acids into cells, notably into non-liver tissues, using systemic or local administration.
Current Challenges with RNA Delivery
There exist various carriers for delivering nucleic acids into cells, such as viral-based vectors, lipid nanoparticles (LNPs), and ligand conjugates. Although each of these system exhibits promising features, robust nucleic acid delivery remains the key rate-limiting step for unlocking the full potential of RNA therapeutics. For example, LNPs and currently available ligand conjugates using GalNac technology preferentially target the liver, which essentially precludes their use for targeting non-liver tissues.
Our Solution
Altamira Therapeutics is developing OligoPhore™ / SemaPhore™ as a versatile platform for delivery of nucleic acid payloads such as siRNA (small interfering ribonucleic acid), mRNA (messenger ribonucleic acid) into target cells, using systemic or local administration.
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siRNA is one type of oligonucleotide which can be used therapeutically to silence disease-related genes in a specific manner.
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mRNA can be used therapeutically to translate genetic code from DNA into proteins, which then can be used to replace abnormal or deficient proteins or make proteins to fight or prevent disease.
OligoPhore™ / SemaPhore™ are based on a proprietary 21 amino acid peptide that rapidly condenses peptide and nucleotide components into a polyplex. The polyplex has a size, charge, and other physical features that allow it to escape hepatic clearance and thus to reach other target tissues than the liver. It readily escapes the leaky vasculature of various pathologies, and is taken up avidly by cells that are capable of macropinocytosis (“cell drinking”), such as cancer cells or macrophages. However, OligoPhore™ / SemaPhore™ polyplexes have also been shown to transfect endothelium, smooth muscle, and other cell types.
Once in the endosome, the natural process of acidification breaks strong bonds between the RNA and the peptide to disassemble the polyplex. The released peptide interacts with the endosomal membrane to permeabilize it and release the RNA into the cytoplasm. The peptide is then diluted quickly and broken down, and has been designed to cause no unintentional damage to the targeted cell.
Technology Status
Our OligoPhore™ / SemaPhore™ technology has been tested in numerous standard murine models, both with siRNA and mRNA payloads. Several key features of the nanoparticles have emerged from these studies:
High stability
RNA complexed in nanoparticle format remains stable in the blood circulation and is only released inside of cells after uptake
Extrahepatic delivery
The nanoparticles are not sequestered in the liver, but reach other tissues
Efficient endosomal escape
pH-dependent nanoparticle disassembly, followed by full release of RNA into the cytoplasm
High selectivity
The nanoparticles can be administered systemically, but target only diseased tissues
Safety
No cellular or adaptive immune responsivity to nanoparticle components or RNA after multiple serial doses and no organ toxicities have been observed
Information Resources
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Kabir AU, Zeng C, Subramanian M, Wu J, Kim M, Krchma K, Wang X, Halabi CM, Pan H, Wickline SA, Fremont DH, Artyomov MN, Choi K. (2024):ZBTB46 coordinates angiogenesis and immunity to control tumor outcome, Nature Immunology.
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Wickline SA, Hou KK, Pan H (2023):Peptide-Based Nanoparticles for Systemic Extrahepatic Delivery of Therapeutic Nucleotides, International Journal of Molecular Sciences, 24(11), 9455.
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Yan H, Hu Y, Akk A, Wickline SA, Pan H, Pham Ch (2022):Peptide-siRNA Nanoparticles Targeting NF-κB p50 Mitigate Experimental Abdominal Aortic Aneurysm (AAA) Progression and Rupture, Biomaterials Advances, Volume 139, 213009.
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Yu J, Zhen L, Zhenxia L, Hairui L, Cheng Z, Ruomei L, Ting Z, Bing F (2022):Histone Demethylase JMJD3 Downregulation Protects against Aberrant Force-Induced Osteoarthritis through Epigenetic Control of NR4A1, International Journal of Oral Science, 14, Article nr. 34.
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Kim Y, Kim H, Kim EH, Jang H, Jang Y, Chi SG, Yang Y, Jim SH (2022):The Potential of Cell-Penetrating Peptides for mRNA Delivery to Cancer Cells, Pharmaceutics, 14(6), 1271.
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Yan H, Hu Y, Akk A, Pan H, Wickline SA, Pham Ch (2021):Systemic Delivery of SOD2 mRNA to Experimental Abdominal Aortic Aneurysm Mitigates Expansion, AHA Scientific Sessions, Circulation, Volume 144, Abstract 14026.
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Yan H, Hu Y, Akk A, Pan H, Wickline SA, Pham Ch (2021):Nanoparticles Targeting NF-kB Subunit p50 Suppress Experimental Abdominal Aortic Aneurysm Progression and Prevent Rupture, AHA Scientific Sessions, Circulation, Volume 144, 16 Nov. 2021, Abstract 14198.
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Rauch DA, Harding JC, Ratner L, Wickline SA, Pan H (2021):Targeting NF-κB with Nanotherapy in a Mouse Model of Adult T-Cell Leukemia/Lymphoma, Nanomaterials 11(6).
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Duan X, Cai L, Pham CTN, Abu-Amer Y, Pan H, Brophy RH, Wickline SA and Rai MF (2021):Intra-articular Silencing of Periostin via Nanoparticle-based siRNA Ameliorates Post-traumatic Osteoarthritis in Mice, Arthritis Rheumatology 10.
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Lockhart JH, VanWye J, Banerjee R, Wickline SA, Pan H and Totary-Jain H. (2021):Self-assembled miRNA-switch Nanoparticles Target Denuded Regions and Prevent Restenosis, Molecular Therapy 29(5), 1744-1757.
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Stansel T, Wickline SA and Pan H. (2020):NF-kappaB Inhibition Suppresses Experimental Melanoma Lung Metastasis, Journal of Cancer Science and Clinical Therapeutics 4(3), 256-265.
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Yan H, Hu Y, Akk A, Rai MF, Pan H, Wickline SA and Pham CTN (2020):Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis, Pharmaceutics 12(1).
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MohanKumar K, Namachivayam K, Song T, Jake Cha B, Slate A, Hendrickson JE, Pan H, Wickline SA, Oh JY, Patel RP, He L, Torres BA and Maheshwari A. (2019):A Murine Neonatal Model of Necrotizing Enterocolitis Caused by Anemia and Red Blood Cell Transfusions, Nature Communications 10(1).
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Zou W, Rohatgi N, Brestoff JR, Moley JR, Li Y, Williams JW, Alippe Y, Pan H, Pietka TA, Mbalaviele G, Newberry EP, Davidson NO, Dey A, Shoghi KI, Head RD, Wickline SA, Randolph GJ, Abumrad NA and Teitelbaum SL (2020):Myeloid-specific Asxl2 Deletion Limits Diet-induced Obesity by Regulating Energy Expenditure, Journal of Clinical Investigation 130(5), 2644-2656.
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Rai MF, Pan H, Yan H, Sandell LJ, Pham CTN and Wickline SA (2019):Applications of RNA Interference in the Treatment of Arthritis, Translational Research 1-16.
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Strand MS, Krasnick BA, Pan H, Zhang X, Bi Y, Karnish C, Wetzel C, Sankpal N, Goedegebuure P, Fleming T, DeNardo DG, Gillanders WE, Hawkins WG, Wickline SA, Fields RC (2019):Precision Delivery of RAS-inhibiting siRNA to KRAS Driven Cancer via Peptide-based Nanoparticles, OncoTarget 10(46), 4761-75.
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Yan H, Duan X, Collins KH, Springer LE, Guilak F, Wickline SA, Rai MF, Pan H and Pham CTN (2019):Nanotherapy Targeting NF-kappaB Attenuates Acute Pain After Joint Injury, Precis Nanomed 2(1), 245-248.
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Mills KA, Quinn JM, Roach ST, Palisoul M, Nguyen M, Noia H, Guo L, Fazal J, Mutch DG, Wickline SA, Pan H and Fuh KC (2019):p5RHH Nanoparticle-mediated Delivery of AXL siRNA Inhibits Metastasis of Ovarian and Uterine Cancer Cells in Mouse Xenografts, Scientific Reports 9(1):4762.
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Yan H, Duan X, Pan H, Akk A, Sandell LJ, Wickline SA, Rai MF and Pham CTN (2019):Development of a Peptide-siRNA Nanocomplex Targeting NF-kappaB for Efficient Cartilage Delivery, Scientific Reports 9(1):442.
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Kabir AU, Lee TJ, Pan H, Berry JC, Krchma K, Wu J, Liu F, Kang HK, Hinman K, Yang L, Hamilton S, Zhou Q, Veis DJ, Mecham RP, Wickline SA, Miller MJ and Choi K. (2018):Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis, JCI Insight.
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Pan H, Palekar RU, Hou KK, Bacon J, Yan H, Springer LE, Akk A, Yang L, Miller MJ, Pham CT, Schlesinger PH and Wickline SA (2018):Anti-JNK2 Peptide-siRNA Nanostructures Improve Plaque Endothelium and Reduce Thrombotic Risk in Atherosclerotic Mice, International Journal of Nanomedicine 13, 5187-5205.
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Lozhkin A, Vendrov AE, Pan H, Wickline SA, Madamanchi NR and Runge MS (2017):NADPH Oxidase 4 Regulates Vascular Inflammation in Aging and Atherosclerosis, Journal of Molecular and Cellular Cardiology 102, 10-21.
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Vendrov AE, Stevenson MD, Alahari S, Pan H, Wickline SA, Madamanchi NR and Runge MS (2017):Attenuated Superoxide Dismutase 2 Activity Induces Atherosclerotic Plaque Instability During Aging in Hyperlipidemic Mice, Journal of the American Heart Association 6(11).
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Yan H, Duan X, Pan H, Holguin N, Rai MF, Akk A, Springer LE, Wickline SA, Sandell LJ and Pham CT (2016):Suppression of NF-kappaB Activity via Nanoparticle-based siRNA Delivery Alters Early Cartilage Responses to Injury, Proceedings of the National Academy of Sciences of the United States of America 113(41), E6199-E6208.
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Hou KK, Pan H, Schlesinger PH and Wickline SA (2015):A Role for Peptides in Overcoming Endosomal Entrapment in siRNA Delivery - A Focus on Melittin, Biotechnology advances, 33(6PT1), 931-40.
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Pham CT, Pan H and Wickline SA (2015):Peptide-siRNA Nanotherapeutics in Arthritis, Oncotarget 6(17), 14731-2.
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Zhou HF, Yan H, Pan H, Hou KK, Akk A, Springer LE, Hu Y, Allen JS, Wickline SA and Pham CT (2014):Peptide-siRNA Nanocomplexes Targeting NF-kappaB Subunit p65 Suppress Nascent Experimental Arthritis, Journal of Clinical Investigation 124(10), 4363-74.
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Hou KK, Pan H, Ratner L, Schlesinger PH and Wickline SA (2013):Mechanisms of Nanoparticle-mediated siRNA Transfection by Melittin-derived Peptides, ACS Nano 7(10), 8605-15.
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Hou KK, Pan H, Lanza GM and Wickline SA (2013):Melittin Derived Peptides for Nanoparticle Based siRNA Transfection, Biomaterials 34(12), 3110-9.
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Pan H, Myerson JW, Ivashyna O, Soman NR, Marsh JN, Hood JL, Lanza GM, Schlesinger PH and Wickline SA (2010):Lipid Membrane Editing with Peptide Cargo Linkers in Cells and Synthetic Nanostructures, FASEB Journal 24(8), 2928-37.