Advertisement

Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

  • Xin Xu
  • Weijing Yang
  • Qiujun Liang
  • Yanan Shi
  • Wenxin Zhang
  • Xiao Wang
  • Fenghua Meng
  • Zhiyuan Zhong
  • Lichen Yin
Research Article
  • 27 Downloads

Abstract

Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crosslinked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulation, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (∼ 98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect. Intravenous injection of the co-delivery TKPR-RCP mediated potent and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

Keywords

ulcerative colitis (UC anti-inflammatory therapy polymersomes reversible crosslinking siRNA/drug co-delivery macrophage targeting 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 51573123, 51722305, and 51633005), the Ministry of Science and Technology of China (No. 2016YFA0201200), 111 project, and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Supplementary material

12274_2019_2274_MOESM1_ESM.pdf (1.8 mb)
Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

References

  1. [1]
    Wilson, D. S.; Dalmasso, G.; Wang, L. X.; Sitaraman, S. V.; Merlin, D.; Murthy, N. Orally delivered thioketal-nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines. Nat. Mater. 2010, 9, 923–928.CrossRefGoogle Scholar
  2. [2]
    Vong, L. B.; Tomita, T.; Yoshitomi, T.; Matsui, H.; Nagasaki, Y. An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice. Gastroenterology 2012, 143, 1027–1036.e3.CrossRefGoogle Scholar
  3. [3]
    Cleynen, I.; Boucher, G.; Jostins, L.; Schumm, L. P.; Zeissig, S.; Ahmad, T.; Andersen, V.; Andrews, J. M.; Annese, V.; Brand, S. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: A genetic association study. Lancet 2015, 387, 156–167.CrossRefGoogle Scholar
  4. [4]
    Frede, A.; Neuhaus, B.; Klopfleisch, R.; Walker, C.; Buer, J.; Müller, W.; Epple, M.; Westendorf, A. M. Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo. J. Control. Release 2016, 222, 86–96.CrossRefGoogle Scholar
  5. [5]
    Dernedde, J.; Rausch, A.; Weinhart, M.; Enders, S.; Tauber, R.; Kai, L.; Schirner, M.; Zügel, U.; von Bonin, A.; Haag, R. Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation. Proc. Natl. Acad. Sci. USA 2010, 107, 19679–19684.CrossRefGoogle Scholar
  6. [6]
    Taylor, K. M.; Irving, P. M. Optimization of conventional therapy in patients with IBD. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 646–656.CrossRefGoogle Scholar
  7. [7]
    Neurath, M. F.; Travis, S. P. L. Mucosal healing in inflammatory bowel diseases: A systematic review. Gut 2012, 61, 1619–1635.CrossRefGoogle Scholar
  8. [8]
    Sandborn, W. J.; Gasink, C.; Gao, L. L.; Blank, M. A.; Johanns, J.; Guzzo, C.; Sands, B. E.; Hanauer, S. B.; Targan, S.; Rutgeerts, P. et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N. Engl. J. Med. 2012, 367, 1519–1528.CrossRefGoogle Scholar
  9. [9]
    Peng, Y. M.; Nie, J. P.; Cheng, W.; Liu, G.; Zhu, D. W.; Zhang, L. H.; Liang, C. Y.; Mei, L.; Huang, L. Q.; Zeng, X. W. A multifunctional nanoplatform for cancer chemo-photothermal synergistic therapy and overcoming multidrug resistance. Biomater. Sci. 2018, 6, 1084–1098.CrossRefGoogle Scholar
  10. [10]
    Song, Y.; Kim, Y. R.; Kim, S. M.; Ul Ain, Q.; Jang, K.; Yang, C. S.; Kim, Y. H. RNAi-mediated silencing of TNF-α converting enzyme to downregulate soluble TNF-α production for treatment of acute and chronic colitis. J. Control. Release 2016, 239, 231–241.CrossRefGoogle Scholar
  11. [11]
    Yin, L. C.; Song, Z. Y.; Qu, Q. H.; Kim, K. H.; Zheng, N.; Yao, C.; Chaudhury, I.; Tang, H. Y.; Gabrielson, N. P.; Uckun, F. M. et al. Supramolecular selfassembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation. Angew. Chem., Int. Ed. 2013, 52, 5757–5761.CrossRefGoogle Scholar
  12. [12]
    Rutgeerts, P.; Sandborn, W. J.; Feagan, B. G.; Reinisch, W.; Olson, A.; Johanns, J.; Travers, S.; Rachmilewitz, D.; Hanauer, S. B.; Lichtenstein, G. R. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2005, 353, 2462–2476.CrossRefGoogle Scholar
  13. [13]
    Davis, M. E.; Zuckerman, J. E.; Choi, C. H. J.; Seligson, D.; Tolcher, A.; Alabi, C. A.; Yun, Y.; Heidel, J. D.; Ribas, A. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010, 464, 1067–1070.CrossRefGoogle Scholar
  14. [14]
    Lee, H.; Lytton-Jean, A. K. R.; Chen, Y.; Love, K. T.; Park, A. I.; Karagiannis, E. D.; Sehgal, A.; Querbes, W.; Zurenko, C. S.; Jayaraman, M. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol. 2012, 7, 389–393.CrossRefGoogle Scholar
  15. [15]
    Luo, X.; Wang, W.; Dorkin, J. R.; Veiseh, O.; Chang, P. H.; Abutbul-Ionita, I.; Danino, D.; Langer, R.; Anderson, D. G.; Dong, Y. Poly(glycoamidoamine) brush nanomaterials for systemic siRNA delivery in vivo. Biomater. Sci. 2017, 5, 38–40.CrossRefGoogle Scholar
  16. [16]
    Li, J. G.; Yu, X. S.; Wang, Y.; Yuan, Y. Y.; Xiao, H.; Cheng, D.; Shuai, X. T. A reduction and pH dual-sensitive polymeric vector for long-circulating and tumor-targeted siRNA delivery. Adv. Mater. 2014, 26, 8217–8224.CrossRefGoogle Scholar
  17. [17]
    Kozielski, K. L.; Tzeng, S. Y.; De Mendoza, B. A. H.; Green, J. J. Bioreducible cationic polymer-based nanoparticles for efficient and environmentally triggered cytoplasmic siRNA delivery to primary human brain cancer cells. ACS Nano 2014, 8, 3232–3241.CrossRefGoogle Scholar
  18. [18]
    Forbes, D. C.; Peppas, N. A. Polycationic nanoparticles for siRNA delivery: Comparing ARGET ATRP and UV-initiated formulations. ACS Nano 2014, 8, 2908–2917.CrossRefGoogle Scholar
  19. [19]
    Meyer, M.; Philipp, A.; Oskuee, R.; Schmidt, C.; Wagner, E. Breathing life into polycations: Functionalization with pH-responsive endosomolytic peptides and polyethylene glycol enables siRNA delivery. J. Am. Chem. Soc. 2008, 130, 3272–3273.CrossRefGoogle Scholar
  20. [20]
    Kanasty, R.; Dorkin, J. R.; Vegas, A.; Anderson, D. Delivery materials for siRNA therapeutics. Nat. Mater. 2013, 12, 967–977.CrossRefGoogle Scholar
  21. [21]
    Sun, C. Y.; Shen, S.; Xu, C. F.; Li, H. J.; Liu, Y.; Cao, Z. T.; Yang, X. Z.; Xia, J. X.; Wang, J. Tumor acidity-sensitive polymeric vector for active targeted siRNA delivery. J. Am. Chem. Soc. 2015, 137, 15217–15224.CrossRefGoogle Scholar
  22. [22]
    Yang, X. Z.; Du, J. Z.; Dou, S.; Mao, C. Q.; Long, H. Y.; Wang, J. Sheddable ternary nanoparticles for tumor acidity-targeted siRNA delivery. ACS Nano 2012, 6, 771–781.CrossRefGoogle Scholar
  23. [23]
    Zhang, S. F.; Ermann, J.; Succi, M. D.; Zhou, A.; Hamilton, M. J.; Cao, B.; Korzenik, J. R.; Glickman, J. N.; Vemula, P. K.; Glimcher, L. H. et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci. Transl. Med. 2015, 7, 300ra128.Google Scholar
  24. [24]
    Molodecky, N. A.; Soon, I. S.; Rabi, D. M.; Ghali, W. A.; Ferris, M.; Chernoff, G.; Benchimol, E. I.; Panaccione, R.; Ghosh, S.; Barkema, H. W. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012, 142, 46–54.e42.CrossRefGoogle Scholar
  25. [25]
    Meng, H.; Mai, W. X.; Zhang, H. Y.; Xue, M.; Xia, T.; Lin, S. J.; Wang, X.; Zhao, Y.; Ji, Z. X.; Zink, J. I. et al. Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano 2013, 7, 994–1005.CrossRefGoogle Scholar
  26. [26]
    Chang, Y. C.; Yang, K.; Wei, P.; Huang, S. S.; Pei, Y. X.; Zhao, W.; Pei, Z. C. Cationic vesicles based on amphiphilic pillar[5]arene capped with ferrocenium: A redox-responsive system for drug/siRNA co-delivery. Angew. Chem., Int. Ed. 2014, 53, 13126–13130.CrossRefGoogle Scholar
  27. [27]
    He, C. B.; Lu, K. D.; Liu, D. M.; Lin, W. B. Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled sirnas to enhance therapeutic efficacy in drug-resistant ovarian cancer cells. J. Am. Chem. Soc. 2014, 136, 5181–5184.CrossRefGoogle Scholar
  28. [28]
    Deng, Z. J.; Morton, S. W.; Ben-Akiva, E.; Dreaden, E. C.; Shopsowitz, K. E.; Hammond, P. T. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano 2013, 7, 9571–9584.CrossRefGoogle Scholar
  29. [29]
    Deng, C.; Jiang, Y. J.; Cheng, R.; Meng, F. H.; Zhong, Z. Y. Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: Promises, progress and prospects. Nano Today 2012, 7, 467–480.CrossRefGoogle Scholar
  30. [30]
    Wong, C. K.; Laos, A. J.; Soeriyadi, A. H.; Wiedenmann, J.; Curmi, P. M. G.; Gooding, J. J.; Marquis, C. P.; Stenzel, M. H.; Thordarson, P. Polymersomes prepared from thermoresponsive fluorescent protein-polymer bioconjugates: Capture of and report on drug and protein payloads. Angew. Chem., Int. Ed. 2015, 127, 5407–5412.CrossRefGoogle Scholar
  31. [31]
    Zou, Y.; Zheng, M.; Yang, W. J.; Meng, F. H.; Miyata, K.; Kim, H. J.; Kataoka, K.; Zhong, Z. Y. Virus-mimicking chimaeric polymersomes boost targeted cancer siRNA therapy in vivo. Adv. Mater. 2017, 29, 1703285.CrossRefGoogle Scholar
  32. [32]
    Thambi, T.; Park, J. H.; Lee, D. S. Stimuli-responsive polymersomes for cancer therapy. Biomater. Sci. 2016, 4, 55–69.CrossRefGoogle Scholar
  33. [33]
    Zou, Y.; Fang, Y.; Meng, H.; Meng, F. H.; Deng, C.; Zhang, J.; Zhong, Z. Y. Self-crosslinkable and intracellularly decrosslinkable biodegradable micellar nanoparticles: A robust, simple and multifunctional nanoplatform for high-efficiency targeted cancer chemotherapy. J. Control. Release 2016, 244, 326–335.CrossRefGoogle Scholar
  34. [34]
    Jain, S.; Amiji, M. Tuftsin-modified alginate nanoparticles as a noncondensing macrophage-targeted DNA delivery system. Biomacromolecules 2012, 13, 1074–1085.CrossRefGoogle Scholar
  35. [35]
    Jain, S.; Tran, T. H.; Amiji, M. Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. Biomaterials 2015, 61, 162–177.CrossRefGoogle Scholar
  36. [36]
    Chung, M. F.; Chia, W. T.; Wan, W. L.; Lin, Y. J.; Sung, H. W. Controlled release of an anti-inflammatory drug using an ultrasensitive ROS-responsive gas-generating carrier for localized inflammation inhibition. J. Am. Chem. Soc. 2015, 137, 12462–12465.CrossRefGoogle Scholar
  37. [37]
    Zhang, J.; Tang, C.; Yin, C. H. Galactosylated trimethyl chitosan-cysteine nanoparticles loaded with MAP4K4 siRNA for targeting activated macrophages. Biomaterials 2013, 34, 3667–3677.CrossRefGoogle Scholar
  38. [38]
    Zuo, L. S.; Huang, Z.; Dong, L.; Xu, L. Q.; Zhu, Y. A.; Zeng, K.; Zhang, C. Y.; Chen, J. N.; Zhang, J. F. Targeting delivery of anti-TNF-α oligonucleotide into activated colonic macrophages protects against experimental colitis. Gut 2010, 59, 470–479.CrossRefGoogle Scholar
  39. [39]
    Balakrishnan, B.; Jayakrishnan, A. Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials 2005, 26, 3941–3951.CrossRefGoogle Scholar
  40. [40]
    Deng, Q. R.; Li, X. D.; Zhu, L. P.; He, H.; Chen, D. L.; Chen, Y. B.; Yin, L. C. Serum-resistant, reactive oxygen species (ROS)-potentiated gene delivery in cancer cells mediated by fluorinated, diselenide-crosslinked polyplexes. Biomater. Sci. 2017, 5, 1174–1182.CrossRefGoogle Scholar
  41. [41]
    Papadakis, K. A.; Targan, S. R. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu. Rev. Med. 2000, 51, 289–298.CrossRefGoogle Scholar
  42. [42]
    Crielaard, B. J.; Rijcken, C. J.; Quan, L. D.; Van der Wal, S.; Altintas, I.; Van der Pot, M.; Kruijtzer, J. A. W.; Liskamp, R. M. J.; Schiffelers, R. M.; van Nostrum, C. F. et al. Glucocorticoid-loaded core-cross-linked polymeric micelles with tailorable release kinetics for targeted therapy of rheumatoid arthritis. Angew. Chem., Int. Ed. 2012, 124, 7366–7370.CrossRefGoogle Scholar
  43. [43]
    Tang, H. Y.; Yin, L. C.; Kim, K. H.; Cheng, J. J. Helical poly(arginine) mimics with superior cell-penetrating and molecular transporting properties. Chem. Sci. 2013, 4, 3839–3844.CrossRefGoogle Scholar
  44. [44]
    He, H.; Zheng, N.; Song, Z. Y.; Kim, K. H.; Yao, C.; Zhang, R. J.; Zhang, C. L.; Huang, Y. H.; Uckun, F. M.; Cheng, J. J. et al. Suppression of hepatic inflammation via systemic siRNA delivery by membrane-disruptive and endosomolytic helical polypeptide hybrid nanoparticles. ACS Nano 2016, 10, 1859–1870.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Xin Xu
    • 1
  • Weijing Yang
    • 2
  • Qiujun Liang
    • 1
  • Yanan Shi
    • 2
  • Wenxin Zhang
    • 1
  • Xiao Wang
    • 1
  • Fenghua Meng
    • 2
  • Zhiyuan Zhong
    • 2
  • Lichen Yin
    • 1
  1. 1.Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM), the Collaborative Innovation Center of Suzhou Nano Science and TechnologySoochow UniversitySuzhouChina
  2. 2.Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials ScienceSoochow UniversitySuzhouChina

Personalised recommendations