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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.


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Ultrasound responsive microcapsules for antibacterial nanodrug delivery

Show Author's information Jilin Fan1,2,3Mingjun Xuan2,3( )Pengkun Zhao2,3Mark Loznik2,3Junlin Chen4Fabian Kiessling4Lifei Zheng1( )Andreas Herrmann2,3( )
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
DWI—Leibniz Institute for Interactive Materials, Forckenbeckstr. 50, 52074 Aachen, Germany
Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
Institute for Experimental Molecular Imaging, University Hospital Aachen, Forckenbeckstr.55, 52074 Aachen, Germany

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.

Keywords: microcapsules, drug release, vancomycin-nanodrug, sonication

References(60)

[1]

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

[2]

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

[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.

[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.

[5]

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

[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.

[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.

[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.

[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.

[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.

[11]

Peyratout, C. S.; Dähne, L. Tailor-made polyelectrolyte microcapsules: From multilayers to smart containers. Angew. Chem., Int. Ed. 2004, 43, 3762–3783.

[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.

[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.

[14]

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

[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.

[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.

[17]

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

[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.

[19]

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

[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.

[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.

[22]

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

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[32]

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

[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.

[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.

[35]

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

[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.

[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.

[38]

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

[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.

[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.

[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.

[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.

[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.

[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, 4215–4221.

[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.

[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.

[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.

[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.

[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.

[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.

[51]

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

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

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Publication history
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Acknowledgements

Publication history

Received: 27 June 2022
Revised: 09 August 2022
Accepted: 15 August 2022
Published: 03 November 2022
Issue date: February 2023

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

A. H. gratefully acknowledges funding from the European Research Council through the Advanced Grant “Suprabiotics” (No. 694610). J. L. F. was supported by a CSC scholarship. M. J. X. thanks the Alexander von Humboldt Foundation for a fellowship and financial support (No. 3.5-CHN-1210658-HFST-P). L. F. Z. 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.

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