Skip to main content
SpringerLink
Log in

Ultrasound responsive microcapsules for antibacterial nanodrug delivery

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes, including proteins, nucleic acids, and even cells for biomedical applications. However, utilizing microcapsules to transport small molecular cargoes remains a challenge, because the leakage of drugs before ultrasound irradiation might cause side effects such as the undesired toxicity and the decrease of effective drug concentration at the target site. Herein, we present a novel strategy to tackle these shortcomings by employing nanodrugs which refers to nanoparticles coated with small molecule drugs. We showed that the drug leakage was prevented when encapsulating the nanodrug in microcapsules. Moreover, the fabricated drug delivery system was responsive not only to unfocused high-intensity ultrasound but also to the clinically relevant high-intensity focused ultrasound. Finally, as a proof of concept, we showed that the antibacterial activity of the nanodrug@Microcapsules could be activated by applying ultrasound in situ. These results may provide new insights into the development of ultrasound triggered small molecule drug delivery assisted by metallic nanoparticles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Caruso, F.; Caruso, R. A.; Möhwald, H. Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating. Science 1998, 282, 1111–1114.

    Article  CAS  Google Scholar 

  2. Parak, W. J. Complex colloidal assembly. Science 2011, 334, 1359–1360.

    Article  CAS  Google Scholar 

  3. Ochs, M.; Carregal-Romero, S.; Rejman, J.; Braeckmans, K.; De Smedt, S. C.; Parak, W. J. Light-addressable capsules as caged compound matrix for controlled triggering of cytosolic reactions. Angew. Chem., Int. Ed. 2013, 52, 695–699.

    Article  CAS  Google Scholar 

  4. Yang, Y.; Liu, H. L.; Han, M. J.; Sun, B. B.; Li, J. B. Multilayer microcapsules for FRET analysis and two-photon-activated photodynamic therapy. Angew. Chem., Int. Ed. 2016, 55, 13538–13543.

    Article  CAS  Google Scholar 

  5. He, Q.; Cui, Y.; Li, J. B. Molecular assembly and application of biomimetic microcapsules. Chem. Soc. Rev. 2009, 38, 2292–2303.

    Article  CAS  Google Scholar 

  6. Pavlov, A. M.; De Geest, B. G.; Louage, B.; Lybaert, L.; De Koker, S.; Koudelka, Z.; Sapelkin, A.; Sukhorukov, G. B. Magnetically engineered microcapsules as intracellular anchors for remote control over cellular mobility. Adv. Mater. 2013, 25, 6945–6950.

    Article  CAS  Google Scholar 

  7. Ejima, H.; Richardson, J. J.; Liang, K; Best, J. P.; Van Koeverden, M. P.; Such, G. K.; Cui, J. W.; Caruso, F. One-step assembly of coordination complexes for versatile film and particle engineering. Science 2013, 341, 154–157.

    Article  CAS  Google Scholar 

  8. Kolbe, A.; Del Mercato, L. L.; Abbasi, A. Z.; Gil, P. R.; Gorzini, S. J.; Huibers, W. H. C.; Poolman, B.; Parak, W. J.; Herrmann, A. De novo design of supercharged, unfolded protein polymers, and their assembly into supramolecular aggregates. Macromol. Rapid Commun. 2011, 32, 186–190.

    Article  CAS  Google Scholar 

  9. Skirtach, A. G.; De Geest, B. G.; Mamedov, A.; Antipov, A. A.; Kotov, N. A.; Sukhorukov, G. B. Ultrasound stimulated release and catalysis using polyelectrolyte multilayer capsules. J. Mater. Chem. 2007, 17, 1050–1054.

    Article  CAS  Google Scholar 

  10. Boehnke, N.; Correa, S.; Hao, L. L.; Wang, W. D.; Straehla, J. P.; Bhatia, S. N.; Hammond, P. T. Theranostic layer-by-layer nanoparticles for simultaneous tumor detection and gene silencing. Angew. Chem., Int. Ed. 2020, 59, 2776–2783.

    Article  CAS  Google Scholar 

  11. Peyratout, C. S.; Dähne, L. Tailor-made polyelectrolyte microcapsules: From multilayers to smart containers. Angew. Chem., Int. Ed. 2004, 33, 3762–3783.

    Article  Google Scholar 

  12. Muslimov, A. R.; Timin, A. S.; Petrova, A. V.; Epifanovskaya, O. S.; Shakirova, A. I.; Lepik, K. V.; Gorshkov, A.; Il’inskaja, E. V.; Vasin, A. V.; Afanasyev, B. V. et al. Mesenchymal stem cells engineering: Microcapsules-assisted gene transfection and magnetic cell separation. ACS Biomater. Sci. Eng. 2017, 3, 2314–2324.

    Article  CAS  Google Scholar 

  13. Park, J. H.; Kim, K.; Lee, J.; Choi, J. Y.; Hong, D.; Yang, S. H.; Caruso, F.; Lee, Y.; Choi, I. S. A cytoprotective and degradable metal-polyphenol nanoshell for single-cell encapsulation. Angew. Chem., Int. Ed. 2014, 53, 12420–12425.

    Article  CAS  Google Scholar 

  14. Decher, G. Fuzzy nanoassemblies: Toward layered polymeric multicomposites. Science 1997, 277, 1232–1237.

    Article  CAS  Google Scholar 

  15. Popov, A. L.; Popova, N.; Gould, D. J.; Shcherbakov, A. B.; Sukhorukov, G. B.; Ivanov, V. K. Ceria nanoparticles-decorated microcapsules as a smart drug delivery/protective system: Protection of encapsulated P. pyralis luciferase. ACS Appl. Mater. Interfaces 2018, 10, 14367–14377.

    Article  CAS  Google Scholar 

  16. Fakhrullin, R. F.; Lvov, Y. M. “Face-lifting” and “make-up” for microorganisms: Layer-by-layer polyelectrolyte nanocoating. ACS Nano 2012, 6, 4557–4564.

    Article  CAS  Google Scholar 

  17. Liu, X. Q.; Picart, C. Layer-by-Layer assemblies for cancer treatment and diagnosis. Adv. Mater. 2016, 28, 1295–1301.

    Article  CAS  Google Scholar 

  18. Ariga, K.; Lvov, Y. M.; Kawakami, K.; Ji, Q. M.; Hill, J. P. Layer-by-layer self-assembled shells for drug delivery. Adv. Drug Delivery Rev. 2011, 63, 762–771.

    Article  CAS  Google Scholar 

  19. Zelikin, A. N.; Li, Q.; Caruso, F. Degradable polyelectrolyte capsules filled with oligonucleotide sequences. Angew. Chem., Int. Ed. 2006, 45, 7743–7745.

    Article  CAS  Google Scholar 

  20. Richardson, J. J.; Maina, J. W.; Ejima, H.; Hu, M.; Guo, J. L.; Choy, M. Y.; Gunawan, S. T.; Lybaert, L.; Hagemeyer, C. E.; De Geest, B. G. et al. Versatile loading of diverse cargo into functional polymer capsules. Adv. Sci. 2015, 2, 1400007.

    Article  Google Scholar 

  21. De Koker, S.; De Geest, B. G.; Singh, S. K.; De Rycke, R.; Naessens, T.; Van Kooyk, Y.; Demeester, J.; De Smedt, S. C.; Grooten, J. Polyelectrolyte microcapsules as antigen delivery vehicles to dendritic cells: Uptake, processing, and cross-presentation of encapsulated antigens. Angew. Chem. 2009, 121, 8637–8641.

    Article  Google Scholar 

  22. Song, W. X.; Möhwald, H.; Li, J. B. Movement of polymer microcarriers using a biomolecular motor. Biomaterials 2010, 31, 1287–1292.

    Article  CAS  Google Scholar 

  23. Du, C. L.; Zhao, J.; Fei, J. B.; Cui, Y.; Li, J. B. Assembled microcapsules by doxorubicin and polysaccharide as high effective anticancer drug carriers. Adv. Healthcare Mater. 2013, 2, 1246–1251.

    Article  CAS  Google Scholar 

  24. Ju, Y.; Cui, J. W.; Sun, H. L.; Müllner, M.; Dai, Y. L.; Guo, J. L.; Bertleff-Zieschang, N.; Suma, T.; Richardson, J. J.; Caruso, F. Engineered metal-phenolic capsules show tunable targeted delivery to cancer cells. Biomacromolecules 2016, 17, 2268–2276.

    Article  CAS  Google Scholar 

  25. Zhao, S.; Caruso, F.; Dähne, L.; Decher, G.; De Geest, B. G.; Fan, J. C.; Feliu, N.; Gogotsi, Y.; Hammond, P. T.; Hersam, M. C. et al. The future of layer-by-layer assembly: A tribute to ACS Nano associate editor Helmuth Mohwald. ACS Nano 2019, 13, 6151–6169.

    Article  CAS  Google Scholar 

  26. Zhao, J.; Wang, A. H.; Si, T. Y.; Hong, J. D.; Li, J. B. Gold nanorods based multicompartment mesoporous silica composites as bioagents for highly efficient photothermal therapy. J. Colloid Interface Sci. 2019, 549, 9–15.

    Article  CAS  Google Scholar 

  27. Zieringer, M. A.; Carroll, N. J.; Abbaspourrad, A.; Koehler, S. A.; Weitz, D. A. Microcapsules for enhanced cargo retention and diversity. Small 2015, 11, 2903–2909.

    Article  CAS  Google Scholar 

  28. Wu, Y. Z.; Ihme, S.; Feuring-Buske, M.; Kuan, S. L.; Eisele, K.; Lamla, M.; Wang, Y. R.; Buske, C.; Weil, T. A core-shell albumin copolymer nanotransporter for high capacity loading and two-step release of doxorubicin with enhanced anti-leukemia activity. Adv. Healthcare Mater. 2013, 2, 884–894.

    Article  CAS  Google Scholar 

  29. Hitchcock, J. P.; Tasker, A. L.; Baxter, E. A.; Biggs, S.; Cayre, O. J. Long-term retention of small, volatile molecular species within metallic microcapsules. ACS Appl. Mater. Interfaces 2015, 7, 14808–14815.

    Article  Google Scholar 

  30. Deshmukh, P. K.; Ramani, K. P.; Singh, S. S.; Tekade, A. R.; Chatap, V. K.; Patil, G. B.; Bari, S. B. Stimuli-sensitive layer-by-layer (LbL) self-assembly systems: Targeting and biosensory applications. J. Controlled Release 2013, 166, 294–306.

    Article  CAS  Google Scholar 

  31. De Koker, S.; De Geest, B. G.; Cuvelier, C.; Ferdinande, L.; Deckers, W.; Hennink, W. E.; De Smedt, S. C.; Mertens, N. In vivo cellular uptake, degradation, and biocompatibility of polyelectrolyte microcapsules. Adv. Funct. Mater. 2007, 17, 3754–3763.

    Article  CAS  Google Scholar 

  32. Radt, B.; Smith, T. A.; Caruso, F. Optically addressable nanostructured capsules. Adv. Mater. 2004, 16, 2184–2189.

    Article  CAS  Google Scholar 

  33. Timin, A. S.; Muslimov, A. R.; Lepik, K. V.; Saprykina, N. N.; Sergeev, V. S.; Afanasyev, B. V.; Vilesov, A. D.; Sukhorukov, G. B. Triple-responsive inorganic-organic hybrid microcapsules as a biocompatible smart platform for the delivery of small molecules. J. Mater. Chem. B 2016, 4, 7270–7282.

    Article  CAS  Google Scholar 

  34. Carregal-Romero, S.; Guardia, P.; Yu, X.; Hartmann, R.; Pellegrino, T.; Parak, W. J. Magnetically triggered release of molecular cargo from iron oxide nanoparticle loaded microcapsules. Nanoscale 2015, 7, 570–576.

    Article  CAS  Google Scholar 

  35. Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013, 12, 991–1003.

    Article  CAS  Google Scholar 

  36. De Geest, B. G.; Skirtach, A. G.; Mamedov, A. A.; Antipov, A. A.; Kotov, N. A.; De Smedt, S. C.; Sukhorukov, G. B. Ultrasound-triggered release from multilayered capsules. Small 2007, 3, 804–808.

    Article  CAS  Google Scholar 

  37. Gao, H.; Wen, D. S.; Sukhorukov, G. B. Composite silica nanoparticle/polyelectrolyte microcapsules with reduced permeability and enhanced ultrasound sensitivity. J. Mater. Chem. B 2015, 3, 1888–1897.

    Article  CAS  Google Scholar 

  38. Shchukin, D. G.; Gorin, D. A.; Möhwald, H. Ultrasonically induced opening of polyelectrolyte microcontainers. Langmuir 2006, 22, 7400–7404.

    Article  CAS  Google Scholar 

  39. Anandhakumar, S.; Mahalakshmi, V.; Raichur, A. M. Silver nanoparticles modified nanocapsules for ultrasonically activated drug delivery. Mater. Sci. Eng. C 2012, 32, 2349–2355.

    Article  CAS  Google Scholar 

  40. Kolesnikova, T. A.; Gorin, D. A.; Fernandes, P.; Kessel, S.; Khomutov, G. B.; Fery, A.; Shchukin, D. G.; Möhwald, H. Nanocomposite microcontainers with high ultrasound sensitivity. Adv. Funct. Mater. 2010, 20, 1189–1195.

    Article  CAS  Google Scholar 

  41. Chen, J.; Ratnayaka, S.; Alford, A.; Kozlovskaya, V.; Liu, F.; Xue, B.; Hoyt, K.; Kharlampieva, E. Theranostic multilayer capsules for ultrasound imaging and guided drug delivery. ACS Nano 2017, 11, 3135–3146.

    Article  CAS  Google Scholar 

  42. Alford, A.; Rich, M.; Kozlovskaya, V.; Chen, J.; Sherwood, J.; Bolding, M.; Warram, J.; Bao, Y. P.; Kharlampieva, E. Ultrasound-triggered delivery of anticancer therapeutics from MRI-visible multilayer microcapsules. Adv. Therap. 2018, 1, 1800051.

    Article  Google Scholar 

  43. Lai, H. Z.; Chen, W. Y.; Wu, C. Y.; Chen, Y. C. Potent antibacterial nanoparticles for pathogenic bacteria. ACS Appl. Mater. Interfaces 2015, 7, 2046–2054.

    Article  CAS  Google Scholar 

  44. Haiss, W.; Thanh, N. T. K.; Aveyard, J.; Fernig, D. G. Determination of size and concentration of gold nanoparticles from UV-vis spectra. Anal. Chem. 2007, 79, 4215–1221.

    Article  CAS  Google Scholar 

  45. Wang, A. H.; Yang, Y.; Qi, Y. F.; Qi, W.; Fei, J. B.; Ma, H. C.; Zhao, J.; Cui, W.; Li, J. B. Fabrication of mesoporous silica nanoparticle with well-defined multicompartment structure as efficient drug carrier for cancer therapy in vitro and in vivo. ACS Appl. Mater. Interfaces 2016, 8, 8900–8907.

    Article  CAS  Google Scholar 

  46. Huo, S. D.; Zhao, P. K.; Shi, Z. Y.; Zou, M. C.; Yang, X. T.; Warszawik, E.; Loznik, M.; Göstl, R.; Herrmann, A. Mechanochemical bond scission for the activation of drugs. Nat. Chem. 2021, 13, 131–139.

    Article  CAS  Google Scholar 

  47. Wiegand, I.; Hilpert, K.; Hancock, R. E. W. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc. 2008, 3, 163–175.

    Article  CAS  Google Scholar 

  48. Liang, X. L.; Gao, J.; Jiang, L. D.; Luo, J. W.; Jing, L. J.; Li, X. D.; Jin, Y. S.; Dai, Z. F. Nanohybrid liposomal cerasomes with good physiological stability and rapid temperature responsiveness for high intensity focused ultrasound triggered local chemotherapy of cancer. ACS Nano 2015, 9, 1280–1293.

    Article  CAS  Google Scholar 

  49. Song, F. Y.; Gao, H.; Li, D. Y.; Petrov, A. V.; Petrov, V. V.; Wen, D. S.; Sukhorukov, G. B. Low intensity focused ultrasound responsive microcapsules for non-ablative ultrafast intracellular release of small molecules. J. Mater. Chem. B 2021, 9, 2384–2393.

    Article  CAS  Google Scholar 

  50. Devarakonda, S. B.; Myers, M. R.; Lanier, M.; Dumoulin, C.; Banerjee, R. K. Assessment of gold nanoparticle-mediated-enhanced hyperthermia using MR-guided high-intensity focused ultrasound ablation procedure. Nano Lett. 2017, 17, 2532–2538.

    Article  CAS  Google Scholar 

  51. Kennedy, J. E. High-intensity focused ultrasound in the treatment of solid tumours. Nat. Rev. Cancer 2005, 5, 321–327.

    Article  CAS  Google Scholar 

  52. Zhu, L. L.; Zhao, H. Y.; Zhou, Z. Y.; Xia, Y. H.; Wang, Z. G.; Ran, H. T.; Li, P.; Ren, J. L. Peptide-functionalized phase-transformation nanoparticles for low intensity focused ultrasound-assisted tumor imaging and therapy. Nano Lett. 2018, 18, 1831–1841.

    Article  CAS  Google Scholar 

  53. Said, F. A.; Bousserrhine, N.; Alphonse, V.; Michely, L.; Belbekhouche, S. Antibiotic loading and development of antibacterial capsules by using porous CaCO3 microparticles as starting material. Int. J. Pharm. 2020, 579, 119175.

    Article  Google Scholar 

  54. Gessner, I.; Krakor, E.; Jurewicz, A.; Wulff, V.; Kling, L.; Christiansen, S.; Brodusch, N.; Gauvin, R.; Wortmann, L.; Wolke, M. et al. Hollow silica capsules for amphiphilic transport and sustained delivery of antibiotic and anticancer drugs. RSC Adv. 2018, 8, 24883–24892.

    Article  CAS  Google Scholar 

  55. Tarrat, N.; Benoit, M.; Giraud, M.; Ponchet, A.; Casanove, M. J. The gold/ampicillin interface at the atomic scale. Nanoscale 2015, 7, 14515–14524.

    Article  CAS  Google Scholar 

  56. Feng, Y.; Chen, W. W.; Jia, Y. X.; Tian, Y.; Zhao, Y. Y.; Long, F.; Rui, Y. K.; Jiang, X. Y. N-Heterocyclic molecule-capped gold nanoparticles as effective antibiotics against multi-drug resistant bacteria. Nanoscale 2016, 8, 13223–13227.

    Article  CAS  Google Scholar 

  57. Payne, J. N.; Waghwani, H. K.; Connor, M. G.; Hamilton, W.; Tockstein, S.; Moolani, H.; Chavda, F.; Badwaik, V.; Lawrenz, M. B.; Dakshinamurthy, R. Novel synthesis of kanamycin conjugated gold nanoparticles with potent antibacterial activity. Front. Microbiol. 2016, 7, 607.

    Article  Google Scholar 

  58. Li, X. N.; Robinson, S. M.; Gupta, A.; Saha, K.; Jiang, Z. W.; Moyano, D. F.; Sahar, A.; Riley, M. A.; Rotello, V. M. Functional gold nanoparticles as potent antimicrobial agents against multi-drug-resistant bacteria. ACS Nano 2014, 8, 10682–10686.

    Article  CAS  Google Scholar 

  59. Shaikh, S.; Nazam, N.; Rizvi, S. M. D.; Ahmad, K.; Baig, M. H.; Lee, E. J.; Choi, I. Mechanistic insights into the antimicrobial actions of metallic nanoparticles and their implications for multidrug resistance. Int. J. Mol. Sci. 2019, 20, 2468.

    Article  Google Scholar 

  60. Sanchez, C.; Diab, D. E. H.; Connord, V.; Clerc, P.; Meunier, E.; Pipy, B.; Payré, B.; Tan, R. P.; Gougeon, M.; Carrey, J. et al. Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death. ACS Nano 2014, 8, 1350–1363.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

A. Herrmann gratefully acknowledges funding from the European Research Council through the Advanced Grant “Supaabiotics” (No. 694610). J. Fan was supported by a CSC scholarship. M. Xuan thanks the Alexander von Humboldt Foundation for a fellowship and financial support (No. 3.5-CHN-1210658-HFST-P). L. Zheng acknowledges financial support from Wenzhou Institute, University of Chinese Academy of Sciences (No. WIUCASQD2020015). The authors would like to thank the DWI-Leibniz Institute for Interactive Materials for support of this research. The authors thank Stefan Hauk for his help with the acquisition of SEM images.

Author information

Authors and Affiliations

  1. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China

    Jilin Fan & Lifei Zheng

  2. DWI—Leibniz Institute for Interactive Materials, Forckenbeckstr. 50, 52074, Aachen, Germany

    Jilin Fan, Mingjun Xuan, Pengkun Zhao, Mark Loznik & Andreas Herrmann

  3. Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany

    Jilin Fan, Mingjun Xuan, Pengkun Zhao, Mark Loznik & Andreas Herrmann

  4. Institute for Experimental Molecular Imaging, University Hospital Aachen, Forckenbeckstr.55, 52074, Aachen, Germany

    Junlin Chen & Fabian Kiessling

Authors
  1. Jilin Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingjun Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pengkun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark Loznik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junlin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabian Kiessling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lifei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mingjun Xuan, Lifei Zheng or Andreas Herrmann.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, J., Xuan, M., Zhao, P. et al. Ultrasound responsive microcapsules for antibacterial nanodrug delivery. Nano Res. 16, 2738–2748 (2023). https://doi.org/10.1007/s12274-022-4919-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-022-4919-9

Keywords

Search

Navigation