A Self-assembled, Modular Nucleic Acid-based Nanoscaffold for Multivalent Theranostic Medicine

Overview

Journal Theranostics

Date 2019 May 28

PMID 31131060

Citations 12

Authors

Veronica Liv Andersen

Mathias Vinther

Rajesh Kumar

Annika Ries

Jesper Wengel

Jesper Sejrup Nielsen

Jorgen Kjems

Affiliations

Soon will be listed here.

Abstract

: Within the field of personalized medicine there is an increasing focus on designing flexible, multifunctional drug delivery systems that combine high efficacy with minimal side effects, by tailoring treatment to the individual. : We synthesized a chemically stabilized ~4 nm nucleic acid nanoscaffold, and characterized its assembly, stability and functional properties and . We tested its flexibility towards multifunctionalization by conjugating various biomolecules to the four modules of the system. The pharmacokinetics, targeting capability and bioimaging properties of the structure were investigated in mice. The role of avidity in targeted liver cell internalization was investigated by flow cytometry, confocal microscopy and by fluorescent scanning of the blood and organs of the animals. : We have developed a nanoscaffold that rapidly and with high efficiency can self-assemble four chemically conjugated functionalities into a stable, -applicable system with complete control of stoichiometry and site specificity. The circulation time of the nanoscaffold could be tuned by functionalization with various numbers of polyethylene glycol polymers or with albumin-binding fatty acids. Highly effective hepatocyte-specific internalization was achieved with increasing valencies of tri-antennary galactosamine (triGalNAc) and . : With its facile functionalization, stoichiometric control, small size and high serum- and thermostability, the nanoscaffold presented here constitutes a novel and flexible platform technology for theranostics.

Citing Articles

Plug-and-play nucleic acid-mediated multimerization of biparatopic nanobodies for molecular imaging.

Teodori L, Ochoa S, Omer M, Andersen V, Bech P, Su J Mol Ther Nucleic Acids. 2024; 35(3):102305.

PMID: 39281705 PMC: 11402398. DOI: 10.1016/j.omtn.2024.102305.

Targeted anti-angiogenesis therapy for advanced osteosarcoma.

Zhang Q, Xia Y, Wang L, Wang Y, Bao Y, Zhao G Front Oncol. 2024; 14:1413213.

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RNA nanostructures for targeted drug delivery and imaging.

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An Albumin-Holliday Junction Biomolecular Modular Design for Programmable Multifunctionality and Prolonged Circulation.

Dinesen A, Andersen V, Elkhashab M, Pilati D, Bech P, Fuchs E Bioconjug Chem. 2024; 35(2):214-222.

PMID: 38231391 PMC: 10886128. DOI: 10.1021/acs.bioconjchem.3c00491.

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References

de Bono J, Ashworth A . Translating cancer research into targeted therapeutics. Nature. 2010; 467(7315):543-9. DOI: 10.1038/nature09339. View

Prakash T, Graham M, Yu J, Carty R, Low A, Chappell A . Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014; 42(13):8796-807. PMC: 4117763. DOI: 10.1093/nar/gku531. View

Srinivasarao M, Galliford C, Low P . Principles in the design of ligand-targeted cancer therapeutics and imaging agents. Nat Rev Drug Discov. 2015; 14(3):203-19. DOI: 10.1038/nrd4519. View

Beck A, Goetsch L, Dumontet C, Corvaia N . Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017; 16(5):315-337. DOI: 10.1038/nrd.2016.268. View

Ho P . Structure of the Holliday junction: applications beyond recombination. Biochem Soc Trans. 2017; 45(5):1149-1158. DOI: 10.1042/BST20170048. View

Vester B, Wengel J . LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry. 2004; 43(42):13233-41. DOI: 10.1021/bi0485732. View

Douglas S, Bachelet I, Church G . A logic-gated nanorobot for targeted transport of molecular payloads. Science. 2012; 335(6070):831-4. DOI: 10.1126/science.1214081. View

Zhang Q, Jiang Q, Li N, Dai L, Liu Q, Song L . DNA origami as an in vivo drug delivery vehicle for cancer therapy. ACS Nano. 2014; 8(7):6633-43. DOI: 10.1021/nn502058j. View

Okholm A, Kjems J . DNA nanovehicles and the biological barriers. Adv Drug Deliv Rev. 2016; 106(Pt A):183-191. DOI: 10.1016/j.addr.2016.05.024. View

10.

Janib S, Moses A, MacKay J . Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev. 2010; 62(11):1052-1063. PMC: 3769170. DOI: 10.1016/j.addr.2010.08.004. View

11.

Gottesman M . Mechanisms of cancer drug resistance. Annu Rev Med. 2002; 53:615-27. DOI: 10.1146/annurev.med.53.082901.103929. View

12.

Kvaerno L, Kumar R, Dahl B, Olsen C, Wengel J . Synthesis of abasic locked nucleic acid and two seco-LNA derivatives and evaluation of their hybridization properties compared with their more flexible DNA counterparts. J Org Chem. 2000; 65(17):5167-76. DOI: 10.1021/jo000275x. View

13.

Meier M, Bider M, Malashkevich V, Spiess M, Burkhard P . Crystal structure of the carbohydrate recognition domain of the H1 subunit of the asialoglycoprotein receptor. J Mol Biol. 2000; 300(4):857-65. DOI: 10.1006/jmbi.2000.3853. View

14.

Geary R, Norris D, Yu R, Bennett C . Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015; 87:46-51. DOI: 10.1016/j.addr.2015.01.008. View

15.

Ji C, Gao Q, Dong X, Yin W, Gu Z, Gan Z . A Size-Reducible Nanodrug with an Aggregation-Enhanced Photodynamic Effect for Deep Chemo-Photodynamic Therapy. Angew Chem Int Ed Engl. 2018; 57(35):11384-11388. DOI: 10.1002/anie.201807602. View

16.

Johannsen M, Crispino L, Wamberg M, Kalra N, Wengel J . Amino acids attached to 2'-amino-LNA: synthesis and excellent duplex stability. Org Biomol Chem. 2010; 9(1):243-52. DOI: 10.1039/c0ob00532k. View

17.

Bramsen J, Laursen M, Nielsen A, Hansen T, Bus C, Langkjaer N . A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity. Nucleic Acids Res. 2009; 37(9):2867-81. PMC: 2685080. DOI: 10.1093/nar/gkp106. View

18.

Sun T, Zhang Y, Pang B, Hyun D, Yang M, Xia Y . Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed Engl. 2014; 53(46):12320-64. DOI: 10.1002/anie.201403036. View

19.

Bramsen J, Kjems J . Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering. Front Genet. 2012; 3:154. PMC: 3422727. DOI: 10.3389/fgene.2012.00154. View

20.

Jiang D, England C, Cai W . DNA nanomaterials for preclinical imaging and drug delivery. J Control Release. 2016; 239:27-38. PMC: 5037045. DOI: 10.1016/j.jconrel.2016.08.013. View