Biopolymers, Bio-related Polymer Materials

Rational design of stimuli-cleavable polyrotaxanes for therapeutic applications

Abstract

Polyrotaxanes (PRXs), comprising many cyclic molecules threaded onto a linear polymer chain capped with bulky stopper molecules, have attracted considerable attention in the design of biomaterials. If cleavable linkages are included between the axle polymer terminals and bulky stopper molecules, PRXs acquire a stimuli-responsive dissociation ability. Such stimuli-cleavable PRXs can dissociate into their constituent molecules in response to various chemical and physical stimuli, such as the reductive intracellular environment and the acidic lysosomal environment. In this focus review, the basic principle of stimuli-cleavable PRX design and characteristics of stimuli-cleavable PRXs as drug delivery carriers are described. Additionally, recent progress in the use of β-cyclodextrin-threaded stimuli-cleavable PRXs as a therapeutic agent for treating Niemann–Pick-type C (NPC) disease, a family of lysosomal storage disorders characterized by lysosomal accumulation of cholesterol, is described. The lysosomal release of threaded β-cyclodextrins from PRXs leads to the formation of an inclusion complex with the cholesterols that accumulate in NPC disease, promoting extracellular excretion of cholesterols. Interestingly, these stimuli-cleavable PRXs improve impaired autophagic functions in NPC disease in addition to reducing cholesterol. Therefore, stimuli-cleavable PRXs are promising candidates for the treatment of intractable metabolic disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. 1

    Van Noorden, R. & Castelvecchi, D. World’s tiniest machines win chemistry Nobel. Nature 538, 152–153 (2016).

    CAS  Article  Google Scholar 

  2. 2

    Atkinson, I. M. & Lindoy, L. F. in Self Assembly in Supramolecular Systems (ed. Stoddart, J. F.) (The Royal Society of Chemistry, Cambridge, UK, 2000)

  3. 3

    Bissell, R. A., Córdova, E., Kaifer, A. E. & Stoddart, J. F. A chemically and electrochemically switchable molecular shuttle. Nature 369, 133–137 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Harada, A., Takashima, Y. & Yamaguchi, H. Cyclodextrin-based supramolecular polymers. Chem. Soc. Rev. 38, 875–882 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Harada, A., Hashidzume, A., Yamaguchi, H. & Takashima, Y. Polymeric rotaxanes. Chem. Rev. 109, 5974–6023 (2009).

    CAS  Article  Google Scholar 

  6. 6

    Wenz, G., Han, B.-H. & Müller, A. Cyclodextrin rotaxanes and polyrotaxanes. Chem. Rev. 106, 782–817 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Huang, F. & Gibson, H. W. Polypseudorotaxanes and polyrotaxanes. Prog. Polym. Sci. 30, 982–1018 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Harada, A., Li, J. & Kamachi, M. The molecular necklace: a rotaxane containing many threaded α-cyclodextrins. Nature 356, 325–327 (1992).

    CAS  Article  Google Scholar 

  9. 9

    Yamada, S., Sanada, Y., Tamura, A., Yui, N. & Sakurai, K. Chain architecture and flexibility of α-cyclodextrin/PEG polyrotaxanes in dilute solutions. Polym. J. 47, 464–467 (2015).

    CAS  Article  Google Scholar 

  10. 10

    Ito, K. Novel cross-linking concept of polymer network: synthesis, structure, and properties of slide-ring gels with freely movable junctions. Polym. J. 39, 489–499 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Imran, A. B., Esaki, K., Gotoh, H., Seki, T., Ito, K., Sakai, Y. & Takeoka, Y. Extremely stretchable thermosensitive hydrogels by introducing slide-ring polyrotaxane cross-linkers and ionic groups into the polymer network. Nat. Commun. 5, 5124 (2014).

    Article  Google Scholar 

  12. 12

    Yui, N. & Ooya, T. Molecular mobility of interlocked structures exploiting new functions of advanced biomaterials. Chem. Eur. J. 12, 6730–6737 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Tamura, A. & Yui, N. Threaded macromolecules as a versatile framework for biomaterials. Chem. Commun. 50, 13433–13446 (2014).

    CAS  Article  Google Scholar 

  14. 14

    Seo, J.-H., Kakinoki, S., Yamaoka, T. & Yui, N. Directing stem cell differentiation by changing the molecular mobility of supramolecular surfaces. Adv. Healthcare Mater. 4, 215–222 (2015).

    CAS  Article  Google Scholar 

  15. 15

    Watanabe, J., Ooya, T. & Yui, N. Preparation and characterization of a polyrotaxane with non-enzymatically hydrolyzable stoppers. Chem. Lett. 27, 1031–1032 (1998).

    Article  Google Scholar 

  16. 16

    Ooya, T., Choi, H. S., Yamashita, A., Yui, N., Sugaya, Y., Kano, A., Maruyama, A., Akita, H., Kogure, K. & Harashima, H. Biocleavable polyrotaxane–plasmid DNA polyplex for enhanced gene delivery. J. Am. Chem. Soc. 128, 3852–3853 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Nishida, K., Tamura, A. & Yui, N. Acid-labile polyrotaxane exerting endolysosomal pH-sensitive supramolecular dissociation for therapeutic applications. Polym. Chem. 6, 4040–4047 (2014).

    Article  Google Scholar 

  18. 18

    Seo, J.-H., Fushimi, M., Matsui, N., Takagaki, T., Tagami, J. & Yui, N. UV-cleavable polyrotaxane cross-linker for modulating mechanical strength of photocurable resin plastics. ACS Macro 4, 1154–1157 (2015).

    CAS  Article  Google Scholar 

  19. 19

    Tamura, A. & Yui, N. Cellular internalization and gene silencing of siRNA polyplexes by cytocleavable cationic polyrotaxanes with tailored rigid backbones. Biomaterials 34, 2480–2491 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Tamura, A., Ikeda, G., Seo, J.-H., Tsuchiya, K., Yajima, H., Sasaki, Y., Akiyoshi, K. & Yui, N. Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells. Sci. Rep. 3, 2252 (2013).

    Article  Google Scholar 

  21. 21

    Liu, B., Turley, S. D., Burns, D. K., Miller, A. M., Repa, J. J. & Dietschy, J. M. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse. Proc. Natl Acad. Sci. USA 106, 2377–2382 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Yao, J., Ho, D., Calingasan, N. Y., Pipalia, N. H., Lin, M. T. & Beal, M. F. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209, 2501–2513 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Nociari, M. M., Lehmann, G. L., Perez Bay, A. E., Radu, R. A., Jiang, Z., Goicochea, S., Schreiner, R., Warren, J. D., Shan, J., Adam de Beaumais, S., Ménand, M., Sollogoub, M., Maxfield, F. R. & Rodriguez-Boulan, E. Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium. Proc. Natl Acad. Sci. USA 111, E1402–E1408 (2014).

    CAS  Article  Google Scholar 

  24. 24

    Zimmer, S., Grebe, A., Bakke, S. S., Bode, N., Halvorsen, B., Ulas, T., Skjelland, M., De Nardo, D., Labzin, L. I., Kerksiek, A., Hempel, C., Heneka, M. T., Hawxhurst, V., Fitzgerald, M. L., Trebicka, J., Björkhem, I., Gustafsson, J. Å., Westerterp, M., Tall, A. R., Wright, S. D., Espevik, T., Schultze, J. L., Nickenig, G., Lütjohann, D. & Latz, E. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci. Transl. Med. 8, 333ra50 (2016).

    Article  Google Scholar 

  25. 25

    Kilsdonk, E. P., Yancey, P. G., Stoudt, G. W., Bangerter, F. W., Johnson, W. J., Phillips, M. C. & Rothblat, G. H. Cellular cholesterol efflux mediated by cyclodextrins. J. Biol. Chem. 270, 17250–17256 (1995).

    CAS  Article  Google Scholar 

  26. 26

    Motoyama, K., Toyodome, H., Onodera, R., Irie, T., Hirayama, F., Uekama, K. & Arima, H. Involvement of lipid rafts of rabbit red blood cells in morphological changes induced by methylated β-cyclodextrins. Biol. Pharm. Bull. 32, 700–705 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Tanaka, Y., Ishitsuka, Y., Yamada, Y., Kondo, Y., Takeo, T., Nakagata, N., Higashi, T., Motoyama, K., Arima, H., Matsuo, M., Higaki, K., Ohno, K. & Irie, T. Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models. Mol. Genet. Metab. Rep. 1, 19–30 (2014).

    CAS  Article  Google Scholar 

  28. 28

    Chien, Y. H., Shieh, Y. D., Yang, C. Y., Lee, N. C. & Hwu, W. L. Lung toxicity of hydroxypropyl-β-cyclodextrin infusion. Mol. Genet. Metab. 109, 231–232 (2013).

    CAS  Article  Google Scholar 

  29. 29

    Crumling, M. A., Liu, L., Thomas, P. V., Benson, J., Kanicki, A., Kabara, L., Hälsey, K., Dolan, D. & Duncan, R. K. Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin. PLoS ONE 7, e53280 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Tamura, A. & Yui, N. Lysosomal-specific cholesterol reduction by biocleavable polyrotaxanes for ameliorating Niemann–Pick type C disease. Sci. Rep. 4, 4356 (2014).

    Article  Google Scholar 

  31. 31

    Fujita, H., Ooya, T., Kurisawa, M., Mori, H., Terano, M. & Yui, N. Thermally switchable polyrotaxane as a model of stimuli-responsive supramolecules for nano-scale devices. Macromol. Rapid Commun. 17, 509–515 (1996).

    CAS  Article  Google Scholar 

  32. 32

    Tamura, A., Nishida, K. & Yui, N. Lysosomal pH-inducible supramolecular dissociation of polyrotaxanes possessing acid-labile N-triphenylmethyl end groups and their therapeutic potential for Niemann–Pick type C disease. Sci. Technol. Adv. Mater. 17, 361–374 (2016).

    CAS  Article  Google Scholar 

  33. 33

    Vanier, M. T. Niemann–Pick disease type C. Orphanet J. Rare Dis. 5, 16 (2010).

    Article  Google Scholar 

  34. 34

    Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M. A., Pavan, W. J., Krizman, D. B., Nagle, J., Polymeropoulos, M. H., Sturley, S. L., Ioannou, Y. A., Higgins, M. E., Comly, M., Cooney, A., Brown, A., Kaneski, C. R., Blanchette-Mackie, E. J., Dwyer, N. K., Neufeld, E. B., Chang, T. Y., Liscum, L., Strauss, J. F. III, Ohno, K., Zeigler, M., Carmi, R., Sokol, J., Markie, D., O’Neill, R. R., van Diggelen, O. P., Elleder, M., Patterson, M. C., Brady, R. O., Vanier, M. T., Pentchev, P. G. & Tagle, D. A. Niemann pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228–231 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Naureckiene, S., Sleat, D. E., Lackland, H., Fensom, A., Vanier, M. T., Wattiaux, R., Jadot, M. & Lobel, P. Identification of HE1 as the second gene of Niemann–Pick C disease. Science 290, 2298–2301 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Davidson, C. D., Ali, N. F., Micsenyi, M. C., Stephney, G., Renault, S., Dobrenis, K., Ory, D. S., Vanier, M. T. & Walkley, S. U. Chronic cyclodextrin treatment of murine Niemann–Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS ONE 4, e6951 (2009).

    Article  Google Scholar 

  37. 37

    Vite, C. H., Bagel, J. H., Swain, G. P., Prociuk, M., Sikora, T. U., Stein, V. M., O’Donnell, P., Ruane, T., Ward, S., Crooks, A., Li, S., Mauldin, E., Stellar, S., De Meulder, M., Kao, M. L., Ory, D. S., Davidson, C., Vanier, M. T. & Walkley, S. U. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann–Pick type C1 disease. Sci. Transl. Med. 7, 276ra26 (2015).

    CAS  Article  Google Scholar 

  38. 38

    Matsuo, M., Togawa, M., Hirabaru, K., Mochinaga, S., Narita, A., Adachi, M., Egashira, M., Irie, T. & Ohno, K. Effects of cyclodextrin in two patients with Niemann–Pick Type C disease. Mol. Genet. Metab. 108, 76–81 (2013).

    CAS  Article  Google Scholar 

  39. 39

    Tamura, A. & Yui, N. β-Cyclodextrin-threaded biocleavable polyrotaxanes ameliorate impaired autophagic flux in Niemann–Pick type C disease. J. Biol. Chem. 290, 9442–9454 (2015).

    CAS  Article  Google Scholar 

  40. 40

    Peake, K. B. & Vance, J. E. Defective cholesterol trafficking in Niemann–Pick C-deficient cells. FEBS Lett. 584, 2731–2739 (2010).

    CAS  Article  Google Scholar 

  41. 41

    Ramirez, C. M., Liu, B., Aqul, A., Taylor, A. M., Repa, J. J., Turley, S. D. & Dietschy, J. M. Quantitative role of LAL, NPC2, and NPC1 in lysosomal cholesterol processing defined by genetic and pharmacological manipulations. J. Lipid Res. 52, 688–698 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Shintani, T. & Klionsky, D. J. Autophagy in health and disease: a double-edged sword. Science 306, 990–995 (2004).

    CAS  Article  Google Scholar 

  44. 44

    Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H. & Mizushima, N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E. & Tanaka, K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).

    CAS  Article  Google Scholar 

  47. 47

    Lieberman, A. P., Puertollano, R., Raben, N., Slaugenhaupt, S., Walkley, S. U. & Ballabio, A. Autophagy in lysosomal storage disorders. Autophagy 8, 719–730 (2012).

    CAS  Article  Google Scholar 

  48. 48

    Liao, G., Yao, Y., Liu, J., Yu, Z., Cheung, S., Xie, A., Liang, X. & Bi, X. Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1−/− mouse brain. Am. J. Pathol. 171, 962–975 (2007).

    CAS  Article  Google Scholar 

  49. 49

    Elrick, M. J., Yu, T., Chung, C. & Lieberman, A. P. Impaired proteolysis underlies autophagic dysfunction in Niemann–Pick type C disease. Hum. Mol. Genet 15, 4876–4887 (2012).

    Article  Google Scholar 

  50. 50

    Sarkar, S., Carroll, B., Buganim, Y., Maetzel, D., Ng, A. H., Cassady, J. P., Cohen, M. A., Chakraborty, S., Wang, H., Spooner, E., Ploegh, H., Gsponer, J., Korolchuk, V. I. & Jaenisch, R. Impaired autophagy in the lipid-storage disorder Niemann–Pick type C1 disease. Cell Rep. 5, 1302–1315 (2013).

    CAS  Article  Google Scholar 

  51. 51

    Mizushima, N., Yoshimorim, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    CAS  Article  Google Scholar 

  52. 52

    Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H. & Johansen, T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).

    Article  Google Scholar 

  53. 53

    Kimura, S., Noda, T. & Yoshimori, T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3, 452–460 (2007).

    CAS  Article  Google Scholar 

  54. 54

    Fraldi, A., Annunziata, F., Lombardi, A., Kaiser, H. J., Medina, D. L., Spampanato, C., Fedele, A. O., Polishchuk, R., Sorrentino, N. C., Simons, K. & Ballabio, A. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 29, 3607–3620 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Itakura, E., Kishi-Itakura, C. & Mizushima, N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012).

    CAS  Article  Google Scholar 

  56. 56

    Furuta, N., Fujita, N., Noda, T., Yoshimori, T. & Amano, A. Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol. Biol. Cell. 21, 1001–1010 (2010).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was financially supported by a Grant-in-Aid for Young Scientists (A) from the Japan Society for the Promotion of Science (JSPS) (No 16H05910, to AT); Grant-in-Aid for Young Scientists (B) from JSPS (No 26750155, to AT); Azuma Medical & Dental Research Grant (to AT).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Atsushi Tamura.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tamura, A., Yui, N. Rational design of stimuli-cleavable polyrotaxanes for therapeutic applications. Polym J 49, 527–534 (2017). https://doi.org/10.1038/pj.2017.17

Download citation

Further reading

Search

Quick links