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Nano Research 2024, 17(6): 5409-5423 https://doi.org/10.1007/s12274-024-6435-6
Research Article | Issue | Published: 26 January 2024

ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

Show Author's Information Ding Wang1,  Qi Jiang1,  Ruoyu Shen1,  Lijun Peng1,  Wentao Zhou1,  Tingting Meng1,  Fuqiang Hu1,2,  Jianwei Wang3,  Hong Yuan1,2( )
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China
Jinhua Institute of Zhejiang University, Jinhua 321299, China
The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, China
Keywords:
nanotechnology, combination treatment, targeted delivery, intestinal barrier, reactive oxygen species (ROS)-responsive, inflammatory bowel disease (IBD)
Topics:
Controlled drug deliveryDrug deliveryTargeted drug delivery
Cite this article:
Wang D, Jiang Q, Shen R, et al. ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation. Nano Research, 2024, 17(6): 5409-5423. https://doi.org/10.1007/s12274-024-6435-6
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Abstract Full text Electronic supplementary material About this article

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage. Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease (IBD). Oral administration is the most common route for intestinal diseases. In this study, a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment, which can interrupt the pathological process of IBD, resulting in the significantly improved efficacy of existing treatments. Based on the specific pH values and high reactive oxygen species (ROS) levels in inflammatory sites of IBD, an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed, and confirmed in vitro and in vivo. The anti-inflammatory drug dexamethasone acetate (Dex) and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions (TJs). The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis. In brief, a drug delivery system and a therapeutic strategy for IBD are successfully developed.


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Electronic supplementary material
About this article

ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

Show Author's information Ding Wang1, Qi Jiang1, Ruoyu Shen1, Lijun Peng1, Wentao Zhou1, Tingting Meng1, Fuqiang Hu1,2, Jianwei Wang3, Hong Yuan1,2( )
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China
Jinhua Institute of Zhejiang University, Jinhua 321299, China
The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, China

Abstract

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage. Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease (IBD). Oral administration is the most common route for intestinal diseases. In this study, a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment, which can interrupt the pathological process of IBD, resulting in the significantly improved efficacy of existing treatments. Based on the specific pH values and high reactive oxygen species (ROS) levels in inflammatory sites of IBD, an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed, and confirmed in vitro and in vivo. The anti-inflammatory drug dexamethasone acetate (Dex) and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions (TJs). The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis. In brief, a drug delivery system and a therapeutic strategy for IBD are successfully developed.

Keywords: nanotechnology, combination treatment, targeted delivery, intestinal barrier, reactive oxygen species (ROS)-responsive, inflammatory bowel disease (IBD)

References(64)

[1]

Bernstein, C. N.; Fried, M.; Krabshuis, J. H.; Cohen, H.; Eliakim, R.; Fedail, S.; Gearry, R.; Goh, K. L.; Hamid, S.; Khan, A. G. et al. World gastroenterology organization practice guidelines for the diagnosis and management of IBD in 2010. Inflamm. Bowel Dis. 2010, 16, 112–124.
DOI Google Scholar
[2]

Thompson, A. I.; Lees, C. W. Genetics of ulcerative colitis. Inflamm. Bowel Dis. 2011, 17, 831–848.
DOI Google Scholar
[3]

Xavier, R. J.; Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448, 427–434.
DOI Google Scholar
[4]

Mohan, H. M.; Coffey, J. C. Potential roles of the mesentery in Crohn’s disease. Semin. Colon Rectal Surg. 2020, 31, 100743.
DOI Google Scholar
[5]

Gajendran, M.; Loganathan, P.; Catinella, A. P.; Hashash, J. G. A comprehensive review and update on Crohn’s disease. Dis. Mon. 2018, 64, 20–57.
DOI Google Scholar
[6]

Ek, W. E.; D'Amato, M.; Halfvarson, J. The history of genetics in inflammatory bowel disease. Ann. Gastroenterol. 2014, 27, 294–303.
Google Scholar
[7]

Khan, I.; Ullah, N.; Zha, L.; Bai, Y. R.; Khan, A.; Zhao, T.; Che, T. J.; Zhang, C. J. Alteration of gut microbiota in inflammatory bowel disease (IBD): Cause or consequence. IBD treatment targeting the gut microbiome. Pathogens 2019, 8, 126.
Google Scholar
[8]

Thompson-Chagoyán, O. C.; Maldonado, J.; Gil, A. Aetiology of inflammatory bowel disease (IBD): Role of intestinal microbiota and gut-associated lymphoid tissue immune response. Clin. Nutr. 2005, 24, 339–352.
DOI Google Scholar
[9]

de Souza, H. S. P.; Fiocchi, C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 13–27.
DOI Google Scholar
[10]

Kmieć, Z.; Cyman, M.; Ślebioda, T. J. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv. Med. Sci. 2017, 62, 1–16.
DOI Google Scholar
[11]

Chelakkot, C.; Ghim, J.; Ryu, S. H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp. Mol. Med. 2018, 50, 1–9.
DOI Google Scholar
[12]

Salim, S. Y.; Söderholm, J. D. Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm. Bowel Dis. 2011, 17, 362–381.
DOI Google Scholar
[13]

Hering, N. A.; Fromm, M.; Schulzke, J. D. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J. Physiol. 2012, 590, 1035–1044.
DOI Google Scholar
[14]

Atreya, R.; Neurath, M. F. Molecular pathways controlling barrier function in IBD. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 67–68.
DOI Google Scholar
[15]

Zallot, C.; Peyrin-Biroulet, L. Deep remission in inflammatory bowel disease: Looking beyond symptoms. Curr. Gastroenterol. Rep. 2013, 15, 315.
DOI Google Scholar
[16]

Raghu Subramanian, C.; Triadafilopoulos, G. Care of inflammatory bowel disease patients in remission. Gastroenterol. Rep. 2016, 4, 261–271.
DOI Google Scholar
[17]

Jeong, D. Y.; Kim, S.; Son, M. J.; Son, C. Y.; Kim, J. Y.; Kronbichler, A.; Lee, K. H.; Shin, J. I. Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review. Autoimmun. Rev. 2019, 18, 439–454.
DOI Google Scholar
[18]

Nielsen, O. H.; Munck, L. K. Drug insight: Aminosalicylates for the treatment of IBD. Nat. Clin. Pract. Gastroenterol. Hepatol. 2007, 4, 160–170.
DOI Google Scholar
[19]

Hartwig, O.; Boushehri, M. A. S.; Shalaby, K. S.; Loretz, B.; Lamprecht, A.; Lehr, C. M. Drug delivery to the inflamed intestinal mucosa-targeting technologies and human cell culture models for better therapies of IBD. Adv. Drug Deliv. Rev. 2021, 175, 113828.
DOI Google Scholar
[20]

Yang, C. H.; Merlin, D. Nanoparticle-mediated drug delivery systems for the treatment of IBD: Current perspectives. Int. J. Nanomed. 2019, 14, 8875–8889.
DOI Google Scholar
[21]

Zhang, S. F.; Langer, R.; Traverso, G. Nanoparticulate drug delivery systems targeting inflammation for treatment of inflammatory bowel disease. Nano Today 2017, 16, 82–96.
DOI Google Scholar
[22]

Nedelcu, A.; Mosteanu, O.; Pop, T.; Mocan, T.; Mocan, L. Recent advances in nanoparticle-mediated treatment of inflammatory bowel diseases. Appl. Sci. 2021, 11, 438.
DOI Google Scholar
[23]

Soni, J. M.; Sardoiwala, M. N.; Choudhury, S. R.; Sharma, S. S.; Karmakar, S. Melatonin-loaded chitosan nanoparticles endows nitric oxide synthase 2 mediated anti-inflammatory activity in inflammatory bowel disease model. Mater. Sci. Eng. C 2021, 124, 112038.
DOI Google Scholar
[24]

Neudecker, V.; Haneklaus, M.; Jensen, O.; Khailova, L.; Masterson, J. C.; Tye, H.; Biette, K.; Jedlicka, P.; Brodsky, K. S.; Gerich, M. E. et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J. Exp. Med. 2017, 214, 1737–1752.
DOI Google Scholar
[25]

Fukata, T.; Mizushima, T.; Nishimura, J.; Okuzaki, D.; Wu, X.; Hirose, H.; Yokoyama, Y.; Kubota, Y.; Nagata, K.; Tsujimura, N. et al. The supercarbonate apatite-microRNA complex inhibits dextran sodium sulfate-induced colitis. Mol. Ther. Nucl. Acids 2018, 12, 658–671.
DOI Google Scholar
[26]

Mehandru, S.; Colombel, J. F. The intestinal barrier, an arbitrator turned provocateur in IBD. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 83–84.
DOI Google Scholar
[27]

Lopetuso, L. R.; Petito, V.; Scaldaferri, F.; Gasbarrini, A. Gut microbiota modulation and mucosal immunity: Focus on rifaximin. Mini Rev. Med. Chem. 2015, 16, 179–185.
DOI Google Scholar
[28]

Lee, S. H. Intestinal permeability regulation by tight junction: Implication on inflammatory bowel diseases. Intest. Res. 2015, 13, 11–18.
DOI Google Scholar
[29]

Lapierre, L. A. The molecular structure of the tight junction. Adv. Drug Deliv. Rev. 2000, 41, 255–264.
DOI Google Scholar
[30]

Otani, T.; Furuse, M. Tight junction structure and function revisited. Trends Cell Biol. 2020, 30, 805–817.
DOI Google Scholar
[31]

Citi, S. Intestinal barriers protect against disease. Science 2018, 359, 1097–1098.
DOI Google Scholar
[32]

Nighot, P.; Ma, T. Endocytosis of intestinal tight junction proteins: In time and space. Inflamm. Bowel Dis. 2021, 27, 283–290.
DOI Google Scholar
[33]

Szabó, I.; Kiss, A.; Schaff, Z.; Sobel, G. Claudins as diagnostic and prognostic markers in gynecological cancer. Histol. Histopathol. 2009, 24, 1607–1615.
Google Scholar
[34]

Koch, S.; Nusrat, A. Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann. N. Y. Acad. Sci. 2009, 1165, 220–227.
DOI Google Scholar
[35]

Hering, N. A.; Schulzke, J. D. Therapeutic options to modulate barrier defects in inflammatory bowel disease. Dig. Dis. 2009, 27, 450–454.
DOI Google Scholar
[36]

Capaldo, C. T.; Nusrat, A. Claudin switching: Physiological plasticity of the tight junction. Semin. Cell Dev. Biol. 2015, 42, 22–29.
DOI Google Scholar
[37]

Bücker, R.; Schumann, M.; Amasheh, S.; Schulzke, J. D. Claudins in intestinal function and disease. Curr. Top. Membr. 2010, 65, 195–227.
Google Scholar
[38]

Miner-Williams, W. M.; Moughan, P. J. Intestinal barrier dysfunction: Implications for chronic inflammatory conditions of the bowel. Nutr. Res. Rev. 2016, 29, 40–59.
DOI Google Scholar
[39]

Luettig, J.; Rosenthal, R.; Barmeyer, C.; Schulzke, J. D. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers 2015, 3, e977176.
DOI Google Scholar
[40]

Zhang, Y. G.; Lu, R.; Xia, Y. L.; Zhou, D.; Petrof, E.; Claud, E. C.; Sun, J. Lack of vitamin D receptor leads to hyperfunction of claudin-2 in intestinal inflammatory responses. Inflamm. Bowel Dis. 2019, 25, 97–110.
DOI Google Scholar
[41]

Hu, C. A.; Hou, Y. Q.; Yi, D.; Qiu, Y. S.; Wu, G. Y.; Kong, X. F.; Yin, Y. L. Autophagy and tight junction proteins in the intestine and intestinal diseases. Anim. Nutr. 2015, 1, 123–127.
DOI Google Scholar
[42]

Li, M.; Oshima, T.; Ito, C.; Yamada, M.; Tomita, T.; Fukui, H.; Miwa, H. Glutamine blocks interleukin-13-induced intestinal epithelial barrier dysfunction. Digestion 2021, 102, 170–179.
DOI Google Scholar
[43]

Liu, F.; Wang, Y. X.; Yao, W. J.; Xue, Y. Y.; Zhou, J. Q.; Liu, Z. H. Geniposide attenuates neonatal mouse brain injury after hypoxic-ischemia involving the activation of PI3K/Akt signaling pathway. J. Chem. Neuroanat. 2019, 102, 101687.
DOI Google Scholar
[44]

Li, N.; Neu, J. Glutamine deprivation alters intestinal tight junctions via a PI3-K/Akt mediated pathway in Caco-2 cells. J. Nutr. 2009, 139, 710–714.
DOI Google Scholar
[45]

Suzuki, T.; Yoshinaga, N.; Tanabe, S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J. Biol. Chem. 2011, 286, 31263–31271.
DOI Google Scholar
[46]

Khare, V.; Dammann, K.; Asboth, M.; Krnjic, A.; Jambrich, M.; Gasche, C. Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer. Inflamm. Bowel Dis. 2015, 21, 287–296.
DOI Google Scholar
[47]

Zhou, Y.; Tu, C. T.; Zhao, Y.; Liu, H. C.; Zhang, S. C. Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease. Biochem. Biophys. Res. Commun. 2016, 470, 967–974.
DOI Google Scholar
[48]
Chen, S. P.; Peng, J. H.; Sherchan, P.; Ma, Y. J.; Xiang, S. S.; Yan, F.; Zhao, H.; Jiang, Y.; Wang, N.; Zhang, J. H. et al. TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice. J. Neuroinflammation 2020 , 17, 168.
[49]

Zhou, T.; Xiong, H.; Wang, S. Q.; Zhang, H. L.; Zheng, W. W.; Gou, Z. R.; Fan, C. Y.; Gao, C. Y. An injectable hydrogel dotted with dexamethasone acetate-encapsulated reactive oxygen species-scavenging micelles for combinatorial therapy of osteoarthritis. Mater. Today Nano 2022, 17, 100164.
DOI Google Scholar
[50]

Zhang, Y. M.; Liu, L.; Wang, T. Y.; Mao, C.; Shan, P. F.; Lau, C. S.; Li, Z. Y.; Guo, W. S.; Wang, W. P. Reactive oxygen species-responsive polymeric prodrug nanoparticles for selective and effective treatment of inflammatory diseases. Adv. Healthc. Mater. 2023, 12, 2301394.
DOI Google Scholar
[51]

Liu, J. X.; Jia, B. Y.; Li, Z. B.; Li, W. L. Reactive oxygen species-responsive polymer drug delivery systems. Front. Bioeng. Biotechnol. 2023, 11, 1115603.
DOI Google Scholar
[52]

Tan, C.; Fan, H.; Ding, J. H.; Han, C. Q.; Guan, Y.; Zhu, F.; Wu, H.; Liu, Y. J.; Zhang, W.; Hou, X. H. et al. ROS-responsive nanoparticles for oral delivery of luteolin and targeted therapy of ulcerative colitis by regulating pathological microenvironment. Mater. Today Bio 2022, 14, 100246.
DOI Google Scholar
[53]

Rinaldi, A.; Caraffi, R.; Grazioli, M. V.; Oddone, N.; Giardino, L.; Tosi, G.; Vandelli, M. A.; Calzà, L.; Ruozi, B.; Duskey, J. T. Applications of the ROS-responsive thioketal linker for the production of smart nanomedicines. Polymers 2022, 14, 687.
DOI Google Scholar
[54]

Hensley, K.; Benaksas, E. J.; Bolli, R.; Comp, P.; Grammas, P.; Hamdheydari, L.; Mou, S. Y.; Pye, Q. N.; Stoddard, M. F.; Wallis, G. et al. New perspectives on vitamin E: γ-Tocopherol and carboxyethylhydroxychroman metabolites in biology and medicine. Free Radical Biol. Med. 2004, 36, 1–15.
Google Scholar
[55]

Elmowafy, M.; Alhakamy, N. A.; Shalaby, K.; Alshehri, S.; Ali, H. M.; Mohammed, E. F.; Alruwaili, N. K.; Zafar, A. Hybrid polylactic acid/Eudragit L100 nanoparticles: A promising system for enhancement of bioavailability and pharmacodynamic efficacy of luteolin. J. Drug Deliv. Sci. Technol. 2021, 65, 102727.
DOI Google Scholar
[56]

Dutta, P.; Mukherjee, K.; Saha, A.; Das, A.; Badwaik, H. R.; Giri, T. K. Colonic delivery of surface charge decorated nanocarrier for IBD therapy. J. Drug Deliv. Sci. Technol. 2022, 76, 103754.
DOI Google Scholar
[57]
Chassaing, B.; Aitken, J. D.; Malleshappa, M.; Vijay-Kumar, M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr. Protoc. Immunol., in press, https://doi.org/10.1002/0471142735.im1525s104.
[58]

Lee, Y.; Sugihara, K.; Gillilland III, M. G.; Jon, S.; Kamada, N.; Moon, J. J. Hyaluronic acid-bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis. Nat. Mater. 2020, 19, 118–126.
DOI Google Scholar
[59]

Chen, S. Q.; Wang, C.; Tao, S.; Wang, Y. X.; Hu, F. Q.; Yuan, H. Rational design of redox-responsive and p-gp-inhibitory lipid nanoparticles with high entrapment of paclitaxel for tumor therapy. Adv. Healthc. Mater. 2018, 7, 1800485.
DOI Google Scholar
[60]

Kamimoto, M.; Rung-Ruangkijkrai, T.; Iwanaga, T. Uptake ability of hepatic sinusoidal endothelial cells and enhancement by lipopolysaccharide. Biomed. Res. 2005, 26, 99–107.
DOI Google Scholar
[61]

Srinivasan, B.; Kolli, A. R.; Esch, M. B.; Abaci, H. E.; Shuler, M. L.; Hickman, J. J. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 2015, 20, 107–126.
DOI Google Scholar
[62]

Nazari, H.; Shrestha, J.; Naei, V. Y.; Bazaz, S. R.; Sabbagh, M.; Thiery, J. P.; Warkiani, M. E. Advances in TEER measurements of biological barriers in microphysiological systems. Biosens. Bioelectron. 2023, 234, 115355.
DOI Google Scholar
[63]

Walkiewicz, D.; Werlin, S. L.; Fish, D.; Scanlon, M.; Hanaway, P.; Kugathasan, S. Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease. Inflamm. Bowel Dis. 2008, 14, 669–673.
DOI Google Scholar
[64]

Liu, F.; Lee, S. A.; Riordan, S. M.; Zhang, L.; Zhu, L. X. Global studies of using fecal biomarkers in predicting relapse in inflammatory bowel disease. Front. Med. 2020, 7, 580803.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 05 November 2023
Revised: 18 December 2023
Accepted: 20 December 2023
Published: 26 January 2024
Issue date: June 2024

Copyright

© Tsinghua University Press 2024

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81973267) and the Zhejiang Provincial Natural Science Foundation of China (No. LZ22H060001).

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