The design of efficient and safe gene delivery vehicles remains a major challenge for the application of gene therapy. Of the many reported gene delivery systems, metal complexes with high affinity for nucleic acids are emerging as an attractive option. We have discovered that certain metallohelices-optically pure, self-assembling triple-stranded arrays of fully encapsulated Fe-act as nonviral DNA delivery vectors capable of mediating efficient gene transfection. They induce formation of globular DNA particles which protect the DNA from degradation by various restriction endonucleases, are of suitable size and electrostatic potential for efficient membrane transport and are successfully processed by cells. The activity is highly structure-dependent-compact and shorter metallohelix enantiomers are far less efficient than less compact and longer enantiomers.

Czech Academy of Sciences Institute of Biophysics Brno CZ 61265 Czech Republic

Department of Chemistry University of Warwick Coventry CV4 7AL UK

Zobrazit více v PubMed

Dunbar C.E., High K.A., Joung J.K., Kohn D.B., Ozawa K., Sadelain M.. Gene therapy comes of age. Science. 2018; 359:eaan4672. PubMed

Mulligan R.C. The basic science of gene therapy. Science. 1993; 260:926–932. PubMed

Yang Y., Nunes F.A., Berencsi K., Gönczöl E., Engelhardt J.F., Wilson J.M.. Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat. Genet. 1994; 7:362–369. PubMed

Ledford H. Gene therapy sees early success against progressive blindness: treatments for inherited eye diseases show promise in clinical trials, but worries linger over how long the beneficial effects will last. Nature. 2015; 526:487–489. PubMed

Pahle J., Walther W.. Vectors and strategies for nonviral cancer gene therapy. Exp. Opin. Biol. Ther. 2016; 16:443–461. PubMed

Ibraheem D., Elaissari A., Fessi H.. Gene therapy and DNA delivery systems. Int. J. Pharm. 2014; 459:70–83. PubMed

Mintzer M.A., Simanek E.E.. Nonviral vectors for gene delivery. Chem. Rev. 2009; 109:259–302. PubMed

Thomas T.J., Tajmir-Riahi H.A., Thomas T.. Polyamine-DNA interactions and development of gene delivery vehicles. Amino Acids. 2016; 48:2423–2431. PubMed

Soliman M., Allen S., Davies M.C., Alexander C.. Responsive polyelectrolyte complexes for triggered release of nucleic acid therapeutics. Chem. Commun. 2010; 46:5421–5433. PubMed

Green J.J., Langer R., Anderson D.G.. A combinatorial polymer library approach yields insight into nonviral gene delivery. Acc. Chem. Res. 2008; 41:749–759. PubMed PMC

Gabrielson N.P., Lu H., Yin L., Li D., Wang F., Cheng J.. Reactive and bioactive cationic α-helical polypeptide template for nonviral gene delivery. Angew. Chem. Int. Ed. 2012; 51:1143–1147. PubMed PMC

Zhi D., Zhang S., Cui S., Zhao Y., Wang Y., Zhao D.. The headgroup evolution of cationic lipids for gene delivery. Bioconjug. Chem. 2013; 24:487–519. PubMed

Lai W.-F. Cyclodextrins in non-viral gene delivery. Biomaterials. 2014; 35:401–411. PubMed PMC

Yang J., Zhang Q., Chang H., Cheng Y.. Surface-engineered dendrimers in gene delivery. Chem. Rev. 2015; 115:5274–5300. PubMed

Kotterman M.A., Chalberg T.W., Schaffer D.V.. Viral vectors for gene therapy: translational and clinical outlook. Annu. Rev. Biomed. Eng. 2015; 17:63–89. PubMed

Thomas C.E., Ehrhardt A., Kay M.A.. Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 2003; 4:346–358. PubMed

Yin H., Kanasty R.L., Eltoukhy A.A., Vegas A.J., Dorkin J.R., Anderson D.G.. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 2014; 15:541–555. PubMed

Li G.-Y., Guan R.-L., Ji L.-N., Chao H.. DNA condensation induced by metal complexes. Coord. Chem. Rev. 2014; 281:100–113.

Bhat S.S., Kumbhar A.S., Kumbhar A.A., Khan A., Lönnecke P., Hey-Hawkins E.. Ruthenium(II) polypyridyl complexes as carriers for DNA delivery. Chem. Commun. 2011; 47:11068–11070. PubMed

Bhat S.S., Kumbhar A.S., Kumbhar A.A., Khan A.. Efficient DNA condensation induced by ruthenium(II) complexes of a bipyridine-functionalized molecular clip ligand. Chem. Eur. J. 2012; 18:16383–16392. PubMed

Yu B., Chen Y., Ouyang C., Huang H., Ji L., Chao H.. A luminescent tetranuclear ruthenium(II) complex as a tracking non-viral gene vector. Chem. Commun. 2013; 49:810–812. PubMed

Bhat S.S., Revankar V.K., Khan A., Pinjari R.V., Necas M.. Luminescent ruthenium(II) polypyridyl complexes as nonviral carriers for DNA delivery. Chem. Asian J. 2017; 12:254–264. PubMed

Yu B., Ouyang C., Qiu K., Zhao J., Ji L., Chao H.. Lipophilic tetranuclear ruthenium(II) complexes as two-photon luminescent tracking non-viral gene vectors. Chem. Eur. J. 2015; 21:3691–3700. PubMed

Rouwei J., Jun Y., Si H., Xianggao M., Changlin L.. Cobalt(II)-polybenzimidazole complexes as a nonviral gene carrier: effects of charges and benzimidazolyl groups. Curr. Drug Deliv. 2013; 10:122–133. PubMed

Liu L., Zhang H., Meng X., Yin J., Li D., Liu C.. Dinuclear metal(II) complexes of polybenzimidazole ligands as carriers for DNA delivery. Biomaterials. 2010; 31:1380–1391. PubMed

Huang X., Dong X., Li X., Meng X., Zhang D., Liu C.. Metal–polybenzimidazole complexes as a nonviral gene carrier: effects of the DNA affinity on gene delivery. J. Inorg. Biochem. 2013; 129:102–111. PubMed

Yin J., Meng X., Zhang S., Zhang D., Wang L., Liu C.. The effect of a nuclear localization sequence on transfection efficacy of genes delivered by cobalt(II)–polybenzimidazole complexes. Biomaterials. 2012; 33:7884–7894. PubMed

Liu L., Zhang H., Meng X., Yin J., Li D., Liu C.. Dinuclear metal(II) complexes of polybenzimidazole ligands as carriers for DNA delivery. Biomaterials. 2010; 31:1380–1391. PubMed

Bao F.-F., Xu X.-X., Zhou W., Pang C.-Y., Li Z., Gu Z.-G.. Enantioselective DNA condensation induced by heptameric lanthanum helical supramolecular enantiomers. J. Inorg. Biochem. 2014; 138:73–80. PubMed

Zhang D., Wang J., Xu D.. Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems. J. Control Release. 2016; 229:130–139. PubMed

Malina J., Hannon M.J., Brabec V.. Iron(II) supramolecular helicates condense plasmid DNA and inhibit vital DNA-related enzymatic activities. Chem. Eur. J. 2015; 21:11189–11195. PubMed

Crlikova H., Malina J., Novohradsky V., Kostrhunova H., Vasdev R.A.S., Crowley J.D., Kasparkova J., Brabec V.. Antiproliferative activity and associated DNA interactions of [Co2L3]6+ cylinders derived from bis(bidentate) 2-pyridyl-1,2,3-triazole ligands. Organometallics. 2020; 39:1448–1455.

Hrabina O., Malina J., Kostrhunova H., Novohradsky V., Pracharova J., Rogers N., Simpson D.H., Scott P., Brabec V.. Optically pure metallohelices that accumulate in cell nuclei, condense/aggregate DNA, and inhibit activities of DNA processing enzymes. Inorg. Chem. 2020; 59:3304–3311. PubMed

Howson S.E., Bolhuis A., Brabec V., Clarkson G.J., Malina J., Rodger A., Scott P.. Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity. Nature Chem. 2012; 4:31–36. PubMed

Faulkner A.D., Kaner R.A., AbdallahQasem M.A., Clarkson G., Fox D.J., Gurnani P., Howson S.E., Phillips R.M., Roper D.I., Simpson D.H.et al. .. Asymmetric triplex metallohelices with high and selective activity against cancer cells. Nat. Chem. 2014; 6:797–803. PubMed

Kaner R.A., Allison S.J., Faulkner A.D., Phillips R.M., Roper D.I., Shepherd S.L., Simpson D.H., Waterfield N.R., Scott P.. Anticancer metallohelices: nanomolar potency and high selectivity. Chem. Sci. 2016; 7:951–958. PubMed PMC

Simpson D.H., Hapeshi A., Rogers N.J., Brabec V., Clarkson G.J., Fox D.J., Hrabina O., Kay G.L., King A.K., Malina J.et al. .. Metallohelices that kill Gram-negative pathogens using intracellular antimicrobial peptide pathways. Chem. Sci. 2019; 10:9708–9720. PubMed PMC

Song H., Rogers N.J., Brabec V., Clarkson G.J., Coverdale J.P.C., Kostrhunova H., Phillips R.M., Postings M., Shepherd S.L., Scott P.. Triazole-based, optically-pure metallosupramolecules; highly potent and selective anticancer compounds. Chem. Commun. 2020; 56:6392–6395. PubMed

Wilson R.W., Bloomfield V.A.. Counterion-induced condensation of deoxyribonucleic acid. A light-scattering study. Biochemistry. 1979; 18:2192–2196. PubMed

Hibino K., Yoshikawa Y., Murata S., Saito T., Zinchenko A.A., Yoshikawa K.. Na+ more strongly inhibits DNA compaction by spermidine (3+) than k+. Chem. Phys. Lett. 2006; 426:405–409.

Pratihar S., Suseela Y.V., Govindaraju T.. Threading intercalator-induced nanocondensates and role of endogenous metal ions in decondensation for DNA delivery. ACS Appl. Bio Mater. 2020; 3:6979–6991. PubMed

Malina J., Kostrhunova H., Scott P., Brabec V.. FeII metallohelices stabilize DNA G-quadruplexes and downregulate the expression of G-quadruplex-regulated oncogenes. Chem. Eur. J. 2021; 27:11682–11692. PubMed

Hansma H.G., Golan R., Hsieh W., Lollo C.P., Mullen-Ley P., Kwoh D.. DNA condensation for gene therapy as monitored by atomic force microscopy. Nucleic Acids Res. 1998; 26:2481–2487. PubMed PMC

Pjura P.E., Grzeskowiak K., Dickerson R.E.. Binding of hoechst 33258 to the minor groove of B-DNA. J. Mol. Biol. 1987; 197:257–271. PubMed

Burres N.S., Frigo A., Rasmussen R.R., McAlpine J.B.. A colorimetric microassay for the detection of agents that interact with DNA. J. Nat. Prod. 1992; 55:1582–1587. PubMed

Riddick T.M. Control of colloid stability through zeta potential : with a closing chapter on its relationship to cardiovascular disease. 1968; 1:Wynnewood, Pa: Published for Zeta-Meter, Inc., by Livingston Pub. Co.