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Hydrolytically degradable shells on thermoresponsive microgels


Thermoresponsive microgels consisting of poly(N-isopropylacrylamide) cores and poly(N-isopropylmethacrylamide) shells cross-linked with the hydrolytically degradable cross-linker N,O-dimethacryloyl hydroxylamine were synthesized. Their swelling and erosion properties were characterized using a variety of analytical tools including dynamic light scattering, asymmetrical flow field-flow fractionation–multiangle light scattering, and atomic force microscopy. Shell addition leads to particle densification due to the added polymer and the mechanical, compressive force applied by the shell. Upon hydrolytic degradation of the shell cross-links, mechanical and chemical changes occur throughout the core and shell, leading to softer and more porous shells that permit greater core swelling. Such changes, which are triggered on exposure to physiologic conditions, are of potential utility within the realm of triggered drug delivery.

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Scheme 1
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Sodium dodecyl sulfate


Ammonium persulfate


Dynamic light scattering


Asymmetrical flow field-flow fractionation


Multiangle light scattering


Atomic force microscopy


Lower critical solution temperature


  1. 1.

    Couvreur P, Vauthier C (2006) Nanotechnology: intelligent design to treat complex disease. Pharm Res 23(7):1417–1450. doi:10.1007/s11095-006-0284-8

    Article  CAS  Google Scholar 

  2. 2.

    Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2(12):751–760. doi:10.1038/nnano.2007.387

    Article  CAS  Google Scholar 

  3. 3.

    Goldberg M, Gomez-Orellana I (2003) Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov 2(4):289–295. doi:10.1038/Nrd1067

    Article  CAS  Google Scholar 

  4. 4.

    Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4(2):145–160. doi:10.1038/Nrd1632

    Article  CAS  Google Scholar 

  5. 5.

    Yoon HJ, Jang WD (2010) Polymeric supramolecular systems for drug delivery. J Mater Chem 20(2):211–222. doi:10.1039/b910948j

    Article  CAS  Google Scholar 

  6. 6.

    Ghosh P, Han G, De M, Kim CK, Rotello VM (2008) Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 60(11):1307–1315. doi:10.1016/j.addr.2008.03.016

    Article  CAS  Google Scholar 

  7. 7.

    Nayak S, Lyon LA (2005) Soft nanotechnology with soft nanoparticles. Angew Chem Int Ed 44(47):7686–7708. doi:10.1002/anie.200501321

    Article  CAS  Google Scholar 

  8. 8.

    Oh JK, Drumright R, Siegwart DJ, Matyjaszewski K (2008) The development of microgels/nanogels for drug delivery applications. Prog Polym Sci 33(4):448–477. doi:10.1016/j.progpolymsci.2008.01.002

    Article  CAS  Google Scholar 

  9. 9.

    Kabanov AV, Vinogradov SV (2009) Nanogels as pharmaceutical carriers: finite networks of infinite capabilities. Angew Chem Int Ed 48(30):5418–5429. doi:10.1002/anie.200900441

    Article  CAS  Google Scholar 

  10. 10.

    Raemdonck K, Demeester J, De Smedt S (2009) Advanced nanogel engineering for drug delivery. Soft Matter 5(4):707–715. doi:10.1039/b811923f

    Article  CAS  Google Scholar 

  11. 11.

    Bysell H, Mansson R, Hansson P, Malmsten M (2011) Microgels and microcapsules in peptide and protein drug delivery. Adv Drug Deliv Rev 63(13):1172–1185. doi:10.1016/j.addr.2011.08.005

    Article  CAS  Google Scholar 

  12. 12.

    Park K, Shalaby WSW, Park H (1993) Biodegradable hydrogels for drug delivery. Technomic, Lancaster

    Google Scholar 

  13. 13.

    Klinger D, Landfester K (2011) Photo-sensitive PMMA microgels: light-triggered swelling and degradation. Soft Matter 7(4):1426–1440. doi:10.1039/c0sm00638f

    Article  CAS  Google Scholar 

  14. 14.

    Klinger D, Landfester K (2011) Polymeric photoresist nanoparticles: light-induced degradation of hydrophobic polymers in aqueous dispersion. Macromol Rapid Commun 32(24):1979–1985. doi:10.1002/marc.201100493

    Article  CAS  Google Scholar 

  15. 15.

    Klinger D, Landfester K (2011) Dual stimuli-responsive poly(2-hydroxyethyl methacrylate-co-methacrylic acid) microgels based on photo-cleavable cross-linkers: pH-dependent swelling and light-induced degradation. Macromolecules 44(24):9758–9772. doi:10.1021/ma201706r

    Article  CAS  Google Scholar 

  16. 16.

    Nayak S, Gan DJ, Serpe MJ, Lyon LA (2005) Hollow thermoresponsive microgels. Small 1(4):416–421. doi:10.1002/smll.200400089

    Article  CAS  Google Scholar 

  17. 17.

    Smith MH, Herman ES, Lyon LA (2011) Network deconstruction reveals network structure in responsive microgels. J Phys Chem B 115(14):3761–3764. doi:10.1021/jp111634k

    Article  CAS  Google Scholar 

  18. 18.

    Gaulding JC, Smith MH, Hyatt JS, Fernandez-Nieves A, Lyon LA (2012) Reversible inter- and intra-microgel cross-linking using disulfides. Macromolecules 45:39–45. doi:10.1021/ma202282p

    Article  CAS  Google Scholar 

  19. 19.

    Shantha KL, Ravichandran P, Rao KP (1995) Azo polymeric hydrogels for colon targeted drug delivery. Biomaterials 16(17):1313–1318

    Article  CAS  Google Scholar 

  20. 20.

    Ulbrich K, Strohalm J, Kopecek J (1982) Polymers containing enzymatically degradable bonds. VI. Hydrophilic gels cleavable by chymotrypsin. Biomaterials 3(3):150–154

    Article  CAS  Google Scholar 

  21. 21.

    Murthy N, Thng YX, Schuck S, Xu MC, Frechet JMJ (2002) A novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers. J Am Chem Soc 124(42):12398–12399. doi:10.1021/ja026925r

    Article  CAS  Google Scholar 

  22. 22.

    Murthy N, Xu MC, Schuck S, Kunisawa J, Shastri N, Frechet JMJ (2003) A macromolecular delivery vehicle for protein-based vaccines: acid-degradable protein-loaded microgels. Proc Natl Acad Sci U S A 100(9):4995–5000. doi:10.1073/pnas.0930644100

    Article  CAS  Google Scholar 

  23. 23.

    Metz N, Theato P (2009) Synthesis and characterization of base labile poly(N-isopropylacrylamide) networks utilizing a reactive cross-linker. Macromolecules 42(1):37–39. doi:10.1021/ma802279v

    Article  CAS  Google Scholar 

  24. 24.

    Ulbrich K, Subr V, Seymour LW, Duncan R (1993) Novel biodegradable hydrogels prepared using the divinylic crosslinking agent N, O-dimethacryloylhydroxylamine. 1. Synthesis and characterization of rates of gel degradation, and rate of release of model-drugs, in vitro and in vivo. J Control Release 24(1):181–190

    Article  CAS  Google Scholar 

  25. 25.

    Horak D, Chaykivskyy O (2002) Poly(2-hydroxyethyl methacrylate-co-N, O-dimethacryloylhydroxylamine) particles by dispersion polymerization. J Polym Sci A Polym Chem 40(10):1625–1632. doi:10.1002/pola.10238

    Article  CAS  Google Scholar 

  26. 26.

    Yin WS, Akala EO, Taylor RE (2002) Design of naltrexone-loaded hydrolyzable crosslinked nanoparticles. Int J Pharm 244(1–2):9–19

    Article  CAS  Google Scholar 

  27. 27.

    Pradny M, Michalek J, Lesny P, Hejcl A, Vacik J, Slouf M, Sykova E (2006) Macroporous hydrogels based on 2-hydroxyethyl methacrylate. Part 5: hydrolytically degradable materials. J Mat Sci-Mat Med 17(12):1357–1364. doi:10.1007/s10856-006-0611-y

    Article  CAS  Google Scholar 

  28. 28.

    Caruso F (2001) Nanoengineering of particle surfaces. Adv Mater 13(1):11–22

    Article  CAS  Google Scholar 

  29. 29.

    Schartl W (2010) Current directions in core–shell nanoparticle design. Nanoscale 2(6):829–843. doi:10.1039/c0nr00028k

    Article  CAS  Google Scholar 

  30. 30.

    Cayre OJ, Chagneux N, Biggs S (2011) Stimulus responsive core-shell nanoparticles: synthesis and applications of polymer based aqueous systems. Soft Matter 7(6):2211–2234. doi:10.1039/c0sm01072c

    Article  CAS  Google Scholar 

  31. 31.

    Jones CD, Lyon LA (2000) Synthesis and characterization of multiresponsive core–shell microgels. Macromolecules 33(22):8301–8306. doi:10.1021/ma001398m

    Article  CAS  Google Scholar 

  32. 32.

    Blackburn WH, Dickerson EB, Smith MH, McDonald JF, Lyon LA (2009) Peptide-functionalized nanogels for targeted siRNA delivery. Bioconjug Chem 20(5):960–968. doi:10.1021/bc800547c

    Article  CAS  Google Scholar 

  33. 33.

    Nayak S, Lyon LA (2004) Ligand-functionalized core/shell microgels with permselective shells. Angew Chem Int Ed 43(48):6706–6709. doi:10.1002/anie.200461090

    Article  CAS  Google Scholar 

  34. 34.

    Hendrickson GR, Lyon LA (2010) Microgel translocation through pores under confinement. Angew Chem Int Ed 49(12):2193–2197. doi:10.1002/anie.200906606

    Article  CAS  Google Scholar 

  35. 35.

    Smith MH, South AB, Gaulding JC, Lyon LA (2010) Monitoring the erosion of hydrolytically-degradable nanogels via multiangle light scattering coupled to asymmetrical flow field-flow fractionation. Anal Chem 82(2):523–530. doi:10.1021/ac901725m

    Article  CAS  Google Scholar 

  36. 36.

    South AB, Lyon LA (2010) Direct observation of microgel erosion via in-liquid atomic force microscopy. Chem Mater 22(10):3300–3306. doi:10.1021/cm100702p

    Article  CAS  Google Scholar 

  37. 37.

    Blackburn WH, Lyon LA (2008) Size-controlled synthesis of monodisperse core/shell nanogels. Colloid Polym Sci 286(5):563–569. doi:10.1007/s00396-007-1805-7

    Article  CAS  Google Scholar 

  38. 38.

    Berndt I, Richtering W (2003) Doubly temperature sensitive core–shell microgels. Macromolecules 36(23):8780–8785. doi:10.1021/Ma034771+

    Article  CAS  Google Scholar 

  39. 39.

    Lapeyre V, Ancla C, Catargi B, Ravaine V (2008) Glucose-responsive microgels with a core-shell structure. J Colloid Interface Sci 327(2):316–323. doi:10.1016/j.jcis.2008.08.039

    Article  CAS  Google Scholar 

  40. 40.

    Jones CD, Lyon LA (2003) Shell-restricted swelling and core compression in poly(N-isopropylacrylamide) core–shell microgels. Macromolecules 36(6):1988–1993. doi:10.1021/Ma021079q

    Article  CAS  Google Scholar 

  41. 41.

    Berndt I, Pedersen JS, Lindner P, Richtering W (2006) Influence of shell thickness and cross-link density on the structure of temperature-sensitive poly-N-isopropylacrylamide–poly-N-isopropylmethacrylamide core–shell microgels investigated by small-angle neutron scattering. Langmuir 22(1):459–468. doi:10.1021/la052463u

    Article  CAS  Google Scholar 

  42. 42.

    Berndt I, Popescu C, Wortmann FJ, Richtering W (2006) Mechanics versus thermodynamics: swelling in multiple-temperature-sensitive core–shell microgels. Angew Chem Int Ed 45(7):1081–1085. doi:10.1002/anie.200502893

    Article  CAS  Google Scholar 

  43. 43.

    Gan DJ, Lyon LA (2001) Tunable swelling kinetics in core-shell hydrogel nanoparticles. J Am Chem Soc 123(31):7511–7517. doi:10.1021/ja010609f

    Article  CAS  Google Scholar 

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This work was partially supported by the National Institutes of Health (1 R01 GM088291-01). Additional funding for J.C.G. was provided by the National Institutes of Health training grant: GTBioMAT Graduate Training for Rationally Designed, Integrative Biomaterials (T32 EB 006343), by the U.S. Department of Education GAANN awards; the Georgia Tech Center for Drug Design, Development, and Delivery; and the Georgia Tech TI:GER program.

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Correspondence to L. Andrew Lyon.

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Gaulding, J.C., South, A.B. & Lyon, L.A. Hydrolytically degradable shells on thermoresponsive microgels. Colloid Polym Sci 291, 99–107 (2013).

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  • Microgels
  • Core/shell
  • Themoresponsive
  • Degradable