Abstract
The success of gene therapy depends largely on the development of new efficient gene delivery vehicles. The emerging class of molecules for this application is macrocycles that feature persistent shape, thus ensuring higher level of supramolecular organization of the DNA complexes. The review focuses on recently developed calixarenes and close analogues as gene delivery vectors, their chemistry, ability to compact nucleic acids, transfection ability in vitro and cytotoxicity. Their fixed conformation with the possibility of multiple functional groups at the upper and lower rims allows preparation of cone-shaped macromolecules capable of programmed hierarchical assembly in the presence of DNA. It is shown that specially designed calixarenes, particularly those having amphiphilic structure with clustered DNA binding units, can form small virus-sized DNA nanoparticles with well-defined architecture, high transfection efficiency and low toxicity. The field is still largely underexplored so that there is a lot of room for further improvement of the molecular design of calixarenes. Moreover, their evaluation in vivo on animals will be an important step towards their validation for gene therapy.
Similar content being viewed by others
References
Mintzer, M.A., Simanek, E.E.: Nonviral vectors for gene delivery. Chem. Rev. 109, 259 (2009)
Ginn, S.L., Alexander, I.E., Edelstein, M.L., Abedi, M.R., Wixon, J.: Gene therapy clinical trials worldwide to 2012—an update. J. Gene Med. 15, 65–77 (2013)
Dominska, M., Dykxhoorn, D.M.: Breaking down the barriers: siRNA delivery and endosome escape. J. Cell Sci. 123, 1183–1189 (2010)
Nishikawa, M., Huang, L.: Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum. Gene Ther. 12, 861–870 (2001)
Whitehead, K.A., Langer, R., Anderson, D.G.: Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009)
Thomas, C.E., Ehrhardt, A., Kay, M.A.: Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4, 346–358 (2003)
Wasungu, L., Hoekstra, D.: Cationic lipids, lipoplexes and intracellular delivery of genes. J. Control. Release 116, 255 (2006)
Martin, B., Sainlos, M., Aissaoui, A., Oudrhiri, N., Hauchecorne, M., Vigneron, J.P., Lehn, J.M., Lehn, P.: The design of cationic lipids for gene delivery. Curr. Pharm. Des. 11, 375–394 (2005)
Hirko, A., Tang, F., Hughes, J.A.: Cationic lipid vectors for plasmid DNA delivery. Curr. Med. Chem. 10, 1185 (2003)
De Smedt, S.C., Demeester, J., Hennink, W.E.: Cationic polymer based gene delivery systems. Pharm. Res. 17, 113–126 (2000)
Mao, S., Sun, W., Kissel, T.: Chitosan-based formulations for delivery of DNA and siRNA. Adv. Drug Deliv. Rev. 62, 12–27 (2010)
Pack, D.W., Hoffman, A.S., Pun, S., Stayton, P.S.: Design and development of polymers for gene delivery. Nat. Rev. Drug Discov. 4, 581–593 (2005)
Safinya, C.R.: Structures of lipid–DNA complexes: supramolecular assembly and gene delivery. Curr. Opin. Struct. Biol. 11, 440 (2001)
Koltover, I., Salditt, T., Radler, J.O., Safinya, C.R.: An inverted hexagonal phase of cationic liposome–DNA complexes related to DNA release and delivery. Science 281, 78–81 (1998)
Wightman, L., Kircheis, R., Rössler, V., Garotta, S., Ruzicka, R., Kursa, M., Wagner, E.: Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo. J. Gene Med. 3, 362–372 (2001)
Goula, D., Remy, J.S., Erbacher, P., Wasowicz, M., Levi, G., Abdallah, B., Demeneix, B.A.: Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system. Gene Ther. 5, 712–717 (1998)
Lavigne, M.D., Górecki, D.C.: Emerging vectors and targeting methods for nonviral gene therapy. Expert Opin. Emerg. Drugs 11, 541–557 (2006)
Mastrobattista, E., van der Aa, M.A.E.M., Hennink, W.E., Crommelin, D.J.A.: Artificial viruses: a nanotechnological approach to gene delivery. Nat. Rev. Drug Discov. 5, 115–121 (2006)
Kogure, K., Akita, H., Yamada, Y., Harashima, H.: Multifunctional envelope-type nano device (MEND) as a non-viral gene delivery system. Adv. Drug Deliv. Rev. 60, 559–571 (2008)
Kostarelos, K., Miller, A.D.: Synthetic, self-assembly ABCD nanoparticles; a structural paradigm for viable synthetic non-viral vectors. Chem. Soc. Rev. 34, 970–994 (2005)
Ghosh, P.S., Kim, C.K., Han, G., Forbes, N.S., Rotello, V.M.: Efficient gene delivery vectors by tuning the surface charge density of amino acid-functionalized gold nanoparticles. ACS Nano 2, 2213–2218 (2008)
Green, J.J., Zhou, B.Y., Mitalipova, M.M., Beard, C., Langer, R., Jaenisch, R., Anderson, D.G.: Nanoparticles for gene transfer to human embryonic stem cell colonies. Nano Lett. 8, 3126–3130 (2008)
Elemans, J.A.A.W., Rowan, A.E., Nolte, R.J.M.: Mastering molecular matter. Supramolecular architectures by hierarchical self-assembly. J. Mater. Chem. 13, 2661–2670 (2003)
Klymchenko, A.S., Furukawa, S., Müllen, K., Van Der Auweraer, M., De Feyter, S.: Supramolecular hydrophobic–hydrophilic nanopatterns at electrified interfaces. Nano Lett. 7, 791–795 (2007)
Guillot-Nieckowski, M., Eisler, S., Diederich, F.: Dendritic vectors for gene transfection. N. J. Chem. 31, 1111–1127 (2007)
Lee, C.C., MacKay, J.A., Fréchet, J.M.J., Szoka, F.C.: Designing dendrimers for biological applications. Nat. Biotechnol. 23, 1517–1526 (2005)
Reddy Panyala, N., Peña-Méndez, E.M., Havel, J.: Gold and nano-gold in medicine: overview, toxicology and perspectives. J. Appl. Biomed. 7, 75–91 (2009)
Liu, J., Stace-Naughton, A., Brinker, C.J.: Silica nanoparticle supported lipid bilayers for gene delivery. Chem. Commun. 34, 5100–5102 (2009)
Dong, L., Xu, H., Liu, Y.B., Lu, B., Xu, D.M., Li, B.H., Gao, J., Wu, M., Yao, S.D., Zhao, J., Guo, Y.J.: M-PEIs nanogels: potential nonviral vector for systemic plasmid delivery to tumor cells. Cancer Gene Ther. 16, 561–566 (2009)
Hamidi, M., Azadi, A., Rafiei, P.: Hydrogel nanoparticles in drug delivery. Adv. Drug Deliv. Rev. 60, 1638–1649 (2008)
Pantarotto, D., Singh, R., McCarthy, D., Erhardt, M., Briand, J.P., Prato, M., Kostarelos, K., Bianco, A.: Functionalized carbon nanotubes for plasmid DNA gene delivery. Angew. Chem. Int. Ed. 43, 5242–5246 (2004)
Gao, L., Nie, L., Wang, T., Qin, Y., Guo, Z., Yang, D., Yan, X.: Carbon nanotube delivery of the GFP gene into mammalian cells. ChemBioChem 7, 239–242 (2006)
Tran, P.A., Zhang, L., Webster, T.J.: Carbon nanofibers and carbon nanotubes in regenerative medicine. Adv. Drug Deliv. Rev. 61, 1097–1114 (2009)
Ortiz Mellet, C., Benito, J.M., Garcia Fernandez, J.M.: Preorganized, macromolecular, gene-delivery systems. Chem. Eur. J. 16, 6728–6742 (2010)
Aoyama, Y.: Macrocyclic glycoclusters: from amphiphiles through nanoparticles to glycoviruses. Chem. Eur. J. 10, 588–593 (2004)
Aoyama, Y., Kanamori, T., Nakai, T., Sasaki, T., Horiuchi, S., Sando, S., Niidome, T.: Artificial viruses and their application to gene delivery. Size-controlled gene coating with glycocluster nanoparticles. J. Am. Chem. Soc. 125, 3455–3457 (2003)
Hayashida, O., Mizuki, K., Akagi, K., Matsuo, A., Kanamori, T., Nakai, T., Sando, S., Aoyama, Y.: Macrocyclic glycoclusters. Self-aggregation and phosphate-induced agglutination behaviors of calix[4]resorcarene-based quadruple-chain amphiphiles with a huge oligosaccharide pool. J. Am. Chem. Soc. 125, 594–601 (2003)
Nakai, T., Kanamori, T., Sando, S., Aoyama, Y.: Remarkably size-regulated cell invasion by artificial viruses. Saccharide-dependent self-aggregation of glycoviruses and its consequences in glycoviral gene delivery. J. Am. Chem. Soc. 125, 8465–8475 (2003)
Sansone, F., Dudič, M., Donofrio, G., Rivetti, C., Baldini, L., Casnati, A., Cellai, S., Ungaro, R.: DNA condensation and cell transfection properties of guanidinium calixarenes: dependence on macrocycle lipophilicity, size, and conformation. J. Am. Chem. Soc. 128, 14528–14536 (2006)
Dudic, M., Colombo, A., Sansone, F., Casnati, A., Donofrio, G., Ungaro, R.: A general synthesis of water soluble upper rim calix[n]arene guanidinium derivatives which bind to plasmid DNA. Tetrahedron 60, 11613–11618 (2004)
Isobe, H., Nakanishi, W., Tomita, N., Jinno, S., Okayama, H., Nakamura, E.: Gene delivery by aminofullerenes: structural requirements for efficient transfection. Chem. Asian J. 1, 167–175 (2006)
Klumpp, C., Lacerda, L., Chaloin, O., Ros, T.D., Kostarelos, K., Prato, M., Bianco, A.: Multifunctionalised cationic fullerene adducts for gene transfer: design, synthesis and DNA complexation. Chem. Commun. 3762–3764 (2007)
Sigwalt, D., Holler, M., Iehl, J., Nierengarten, J.F., Nothisen, M., Morin, E., Remy, J.S.: Gene delivery with polycationic fullerene hexakis-adducts. Chem. Commun. 47, 4640–4642 (2011)
Sitharaman, B., Zakharian, T.Y., Saraf, A., Ashcroft, P.M.J., Pan, S., Pham, Q.P., Mikos, A.G., Wilson, L.J., Engler, D.A.: Water-soluble fullerene (C60) derivatives as nonviral gene-delivery vectors. Mol. Pharm. 5, 567–578 (2008)
Srinivasachari, S., Fichter, K.M., Reineke, T.M.: Polycationic β-cyclodextrin “click clusters”: monodisperse and versatile scaffolds for nucleic acid delivery. J. Am. Chem. Soc. 130, 4618–4627 (2008)
Ortega-Caballero, F., Mellet, C.O., Le Gourriérec, L., Guilloteau, N., Di Giorgio, C., Vierling, P., Defaye, J., García Fernéndez, J.M.: Tailoring β-cyclodextrin for DNA complexation and delivery by homogeneous functionalization at the secondary face. Org. Lett. 10, 5143–5146 (2008)
Yang, C., Li, H., Goh, S.H., Li, J.: Cationic star polymers consisting of α-cyclodextrin core and oligoethylenimine arms as nonviral gene delivery vectors. Biomaterials 28, 3245–3254 (2007)
Díaz-Moscoso, A., Gourriérec, L.L., Gómez-García, M., Benito, J.M., Balbuena, P., Ortega-Caballero, F., Guilloteau, N., Giorgio, C.D., Vierling, P., Defaye, J., Mellet, C.O., Fernández, J.M.G.: Polycationic amphiphilic cyclodextrins for gene delivery: synthesis and effect of structural modifications on plasmid DNA complex stability, cytotoxicity, and gene expression. Chem. Eur. J. 15, 12871–12888 (2009)
Nierengarten, I., Nothisen, M., Sigwalt, D., Biellmann, T., Holler, M., Remy, J.S., Nierengarten, J.F.: Polycationic pillar[5]arene derivatives: interaction with DNA and biological applications. Chem. Eur. J. 19, 17552–17558 (2013)
Asfari, Z., Boehmer, V., Harowfield, J., Vicens, J. (eds.): Calixarenes. Kluwer Academic Publishers, Dordrecht (2001)
Kim, J.S., Quang, D.T.: Calixarene-derived fluorescent probes. Chem. Rev. 107, 3780–3799 (2007)
Metivier, R., Leray, I., Valeur, B.: Lead and mercury sensing by calixarene-based fluoroionophores bearing two or four dansyl fluorophores. Chem. Eur. J. 10, 4480–4490 (2004)
Yakovenko, A.V., Boyko, V.I., Kalchenko, V.I., Baldini, L., Casnati, A., Sansone, F., Ungaro, R.: N-linked peptidocalix[4]arene bisureas as enantioselective receptors for amino acid derivatives. J. Org. Chem. 72, 3223 (2007)
Brody, M.S., Schalley, C.A., Rudkevich, D.M., Rebek Jr., J.: Synthesis and characterization of a unimolecular capsule. Angew. Chem. Int. Ed. 38, 1640–1644 (1999)
Becherer, M.S., Schade, B., Bottcher, C., Hirsch, A.: Supramolecular assembly of self-labeled amphicalixarenes. Chem. Eur. J. 15, 1637–1648 (2009)
Arimori, S., Nagasaki, T., Shinkai, S.: Self-assembly of tetracationic amphiphiles bearing a calix[4]arene core. Correlation between the core structure and the aggregation properties. J. Chem. Soc. Perkin Trans. 2, 679–683 (1995)
Houmadi, S., Coquiere, D., Legrand, L., Faute, M.C., Goldmam, M., Reinaud, O., Remita, S.: Architecture-controlled “SMART” calix[6]arene self-assemblies in aqueous solution. Langmuir 23, 4849–4855 (2007)
Tanaka, Y., Miyachi, M., Kobuke, Y.: Selective vesicle formation from calixarenes by self-assembly. Angew. Chem. Int. Ed. 38, 504–506 (1999)
Coleman, A.W., Perret, F., Moussa, A., Dupin, M., Guo, Y., Perron, H.: Calix[n]arenes as protein sensors. Top. Curr. Chem. 277, 31 (2007)
De Fatima, A., Fernandes, S.A., Sabino, A.A.: Calixarenes as new platforms for drug design. Curr. Drug Disc. Tech. 6, 151 (2009)
Rodik, R.V., Boyko, V.I., Kalchenko, V.I.: Calixarenes in bio-medical researches. Curr. Med. Chem. 16, 1630 (2009)
Vovk, A.I., Kalchenko, V.I., Cherenok, S.A., Kukhar, V.P., Muzychka, O.V., Lozynsky, M.O.: Calix[4]arene methylenebisphosphonic acids as calf intestine alkaline phosphatase inhibitors. Org. Biomol. Chem. 2, 3162 (2004)
Aoyama, Y.: Glycovirus. Trends Glycosci. Glycotechnol. 17, 39–47 (2005)
Fujimoto, T., Shimizu, C., Hayashida, O., Aoyama, Y.: Solution-to-surface molecular-delivery system using a macrocyclic sugar cluster. Sugar-directed adsorption of guests in water on polar solid surfaces. J. Am. Chem. Soc. 119, 6676–6677 (1997)
Nault, L., Cumbo, A., Pretôt, R.F., Sciotti, M.A., Shahgaldian, P.: Cell transfection using layer-by-layer (LbL) coated calixarene-based solid lipid nanoparticles (SLNs). Chem. Commun. 46, 5581–5583 (2010)
Shahgaldian, P., Sciotti, M.A., Pieles, U.: Amino-substituted amphiphilic calixarenes: self-assembly and interactions with DNA. Langmuir 24, 8522–8526 (2008)
Lalor, R., DiGesso, J.L., Mueller, A., Matthews, S.E.: Efficient gene transfection with functionalised multicalixarenes. Chem. Commun. 2007(46), 4907–4909 (2007)
Hu, W., Blecking, C., Kralj, M., Šuman, L., Piantanida, I., Schrader, T.: Dimeric calixarenes: a new family of major-groove binders. Chem. Eur. J. 18, 3589–3597 (2012)
Bagnacani, V., Sansone, F., Donofrio, G., Baldini, L., Casnati, A., Ungaro, R.: Macrocyclic nonviral vectors: high cell transfection efficiency and low toxicity in a lower rim guanidinium calix[4]arene. Org. Lett. 10, 3953–3956 (2008)
Felgner, J.H., Kumar, R., Sridhar, C.N., Wheeler, C.J., Tsai, Y.J., Border, R., Ramsey, P., Martin, M., Felgner, P.L.: Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J. Biol. Chem. 269, 2550 (1994)
Farhood, H., Serbina, N., Huang, L.: The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim. Biophys. Acta 1235, 289 (1995)
Bagnacani, V., Franceschi, V., Fantuzzi, L., Casnati, A., Donofrio, G., Sansone, F., Ungaro, R.: Lower rim guanidinocalix[4]arenes: macrocyclic nonviral vectors for cell transfection. Bioconjug. Chem. 23, 993–1002 (2012)
Bagnacani, V., Franceschi, V., Bassi, M., Lomazzi, M., Donofrio, G., Sansone, F., Casnati, A., Ungaro, R.: Arginine clustering on calix[4]arene macrocycles for improved cell penetration and DNA delivery. Nat. Commun. 4, 1721 (2013)
Shi, Y., Schneider, H.J.: Interactions between aminocalixarenes and nucleotides or nucleic acids. J. Chem. Soc. Perkin Trans. 2, 1797–1803 (1999)
Mchedlov-Petrossyan, N.O., Vilkova, L.N., Vodolazkaya, N.A., Yakubovskaya, A.G., Rodik, R.V., Boyko, V.I., Kalchenko, V.I.: The nature of aqueous solutions of a cationic calix[4]arene: a comparative study of dye-calixarene and dye-surfactant interactions. Sensors 6, 962–977 (2006)
Rodik, R.V., Klymchenko, A.S., Jain, N., Miroshnichenko, S.I., Richert, L., Kalchenko, V.I., Mély, Y.: Virus-sized DNA nanoparticles for gene delivery based on micelles of cationic calixarenes. Chem. Eur. J. 17, 5526–5538 (2011)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rodik, R.V., Klymchenko, A.S., Mely, Y. et al. Calixarenes and related macrocycles as gene delivery vehicles. J Incl Phenom Macrocycl Chem 80, 189–200 (2014). https://doi.org/10.1007/s10847-014-0412-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10847-014-0412-8