Advertisement

Convenient preparation of charge-adaptive chitosan nanomedicines for extended blood circulation and accelerated endosomal escape

  • Yapei Zhang
  • Yingying Li
  • Jinlong Ma
  • Xinyu Wang
  • Zhi Yuan
  • Wei Wang
Research Article
  • 64 Downloads

Abstract

A major impediment in the development of chitosan nanoparticles (CTS NPs) as effective drug delivery vesicles is their rapid clearance from blood and endosome entrapment. To overcome these problems, a convenient and promising template system was developed by decorating poly(methacrylic acid) (PMAA) to the surface of 10-hydroxy camptothecin (HCPT)-loaded CTS NPs (HCPT-CTS/PMAA NPs). The results show that the presence of negatively charged PMAA significantly elongated the blood circulation time of HCPT-CTS NPs from 12 to 24 h, and reduced the blood clearance (Cl) from 30.57 to 6.72 mL/h in vivo. The calculated area under curve (AUC0-24h) and terminal elimination half-life (t1/2) of HCPT-CTS/PMAA NPs were 4.37-fold and 2.48-fold compared with those of HCPT-CTS NPs. Furthermore, the positively charged HCPT-CTS/PMAA NPs triggered by tumor acidic microenvironment (pH 6.5) result in a 453-fold higher cellular uptake than the negatively charged counterparts at pH 7.4. Additionally, HCPT-CTS/PMAA NPs have the ability to escape endosomal entrapment via “proton sponge effect” after incubation with HepG2 cells for 3 h at pH 6.5. Taken together, these findings open up a convenient, low-cost, but effective way to prepare HCPT-CTS/PMAA NPs as a candidate for developing vectors with enhanced long blood circulation and endosomal escape ability in future clinical experiments.

Keywords

chitosan poly(methyl methacrylate) blood circulation charge reverse endosomal escape 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 51433004 and 51773096), Natural Science Foundation of Tianjin (No. 17JCZDJC3 3500), PCSIRT (No. IRT1257). We also appreciate Prof. Deling Kong at Nankai University for help with the cellular experiments and Prof. Qiang Wu at Nankai University for help with the characterization of materials.

Supplementary material

12274_2018_2014_MOESM1_ESM.pdf (1.8 mb)
Convenient preparation of charge-adaptive chitosan nanomedicines for extended blood circulation and accelerated endosomal escape

References

  1. [1]
    Yan, L. S.; Crayton, S. H.; Thawani, J. P.; Amirshaghaghi, A.; Tsourkas, A.; Cheng, Z. L. A pH-responsive drug-delivery platform based on glycol chitosan-coated liposomes. Small 2015, 11, 4870–4874.CrossRefGoogle Scholar
  2. [2]
    Shi, G.-N.; Zhang, C.-N.; Xu, R.; Niu, J.-F.; Song, H.-J.; Zhang, X.-Y.; Wang, W.-W.; Wang, Y.-M.; Li, C.; Wei, X.-Q. et al. Enhanced antitumor immunity by targeting dendritic cells with tumor cell lysate-loaded chitosan nanoparticles vaccine. Biomaterials 2017, 113, 191–202.CrossRefGoogle Scholar
  3. [3]
    Shen, B. B.; Ma, Y.; Yu, S. Y.; Ji, C. H. Smart multifunctional magnetic nanoparticle-based drug delivery system for cancer thermo-chemotherapy and intracellular imaging. ACS Appl. Mater. Interfaces 2016, 8, 24502–24508.CrossRefGoogle Scholar
  4. [4]
    Richard, I.; Thibault, M.; De Crescenzo, G.; Buschmann, M. D.; Lavertu, M. Ionization behavior of chitosan and chitosan-DNA polyplexes indicate that chitosan has a similar capability to induce a proton-sponge effect as PEI. Biomacromolecules 2013, 14, 1732–1740.CrossRefGoogle Scholar
  5. [5]
    Wu, Y. K.; Wu, J.; Cao, J.; Zhang, Y. J.; Xu, Z.; Qin, X. Y.; Wang, W.; Yuan, Z. Facile fabrication of poly(acrylic acid) coated chitosan nanoparticles with improved stability in biological environments. J. Pharmaceutics Biopharmaceutics 2017, 112, 148–154.CrossRefGoogle Scholar
  6. [6]
    Xie, Y.; Qiao, H. Z.; Su, Z. G.; Chen, M. L.; Ping, Q. N.; Sun, M. J. PEGylated carboxymethyl chitosan/calcium phosphate hybrid anionic nanoparticles mediated hTERT siRNA delivery for anticancer therapy. Biomaterials 2014, 35, 7978–7991.CrossRefGoogle Scholar
  7. [7]
    Zhang, L. L.; Liu, Y.; Liu, G.; Xu, D.; Liang, S.; Zhu, X. Y.; Lu, Y. F.; Wang, H. Prolonging the plasma circulation of proteins by nano-encapsulation with phosphorylcholine-based polymer. Nano Res. 2016, 9, 2424–2432.CrossRefGoogle Scholar
  8. [8]
    Sheng, Y.; Liu, C. S.; Yuan, Y.; Tao, X. Y.; Yang, F.; Shan, X. Q.; Zhou, H. J.; Xu, F. Long-circulating polymeric nanoparticles bearing a combinatorial coating of PEG and water-soluble chitosan. Biomaterials 2009, 30, 2340–2348.CrossRefGoogle Scholar
  9. [9]
    Piao, J. G.; Gao, F.; Li, Y. N.; Yu, L.; Liu, D.; Tan, Z. B.; Xiong, Y. J.; Yang, L. H.; You, Y. Z. pH-sensitive zwitterionic coating of gold nanocages improves tumor targeting and photothermal treatment efficacy. Nano Res., in press, DOI: 10.1007/s12274-017-1736-7.Google Scholar
  10. [10]
    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
  11. [11]
    Zhang, K.; Jia, Y. G.; Tsai, I. H.; Strandman, S.; Ren, L.; Hong, L. Z.; Zhang, G. Z.; Guan, Y.; Zhang, Y. J.; Zhu, X. X. “Bitter-sweet” polymeric micelles formed by block copolymers from glucosamine and cholic acid. Biomacromolecules 2017, 18, 778–786.CrossRefGoogle Scholar
  12. [12]
    Wang, S.; Zhang, L.; Dong, C. H.; Su, L.; Wang, H. J.; Chang, J. Smart pH-responsive upconversion nanoparticles for enhanced tumor cellular internalization and near-infrared light-triggered photodynamic therapy. Chem. Commun. 2015, 51, 406–408.CrossRefGoogle Scholar
  13. [13]
    Yang, W.; Zhang, L.; Wang, S. L.; White, A. D.; Jiang, S. Y. Functionalizable and ultra stable nanoparticles coated with zwitterionic poly(carboxybetaine) in undiluted blood serum. Biomaterials 2009, 30, 5617–5621.CrossRefGoogle Scholar
  14. [14]
    Jia, Y. G.; Zhu, X. X. Thermo- and pH-responsive copolymers bearing cholic acid and oligo(ethylene glycol) pendants: Self-assembly and pH-controlled release. ACS Appl. Mater. Interfaces 2015, 7, 24649–24655.CrossRefGoogle Scholar
  15. [15]
    Hu, X. G.; Gao, X. H. Silica-polymer dual layer-encapsulated quantum dots with remarkable stability. ACS Nano 2010, 4, 6080–6086.CrossRefGoogle Scholar
  16. [16]
    Liu, R. Y.; Li, Y.; Zhang, Z. Z.; Zhang, X. Drug carriers based on highly protein-resistant materials for prolonged in vivo circulation time. Regen. Biomater. 2015, 2, 125–133.CrossRefGoogle Scholar
  17. [17]
    Kanamala, M.; Wilson, W. R.; Yang, M. M.; Palmer, B. D.; Wu, Z. M. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review. Biomaterials 2016, 85, 152–167.CrossRefGoogle Scholar
  18. [18]
    Shen, T.; Guan, S. L.; Gan, Z. H.; Zhang, G.; Yu, Q. S. Polymeric micelles with uniform surface properties and tunable size and charge: Positive charges improve tumor accumulation. Biomacromolecules 2016, 17, 1801–1810.CrossRefGoogle Scholar
  19. [19]
    Sun, M. J.; Li, J.; Zhang, C. T.; Xie, Y.; Qiao, H. Z.; Su, Z. G.; Oupický, D.; Ping, Q. N. Arginine-modified nanostructured lipid carriers with charge-reversal and pH-sensitive membranolytic properties for anticancer drug delivery. Adv. Healthc. Mater. 2017, 6, 1600693.CrossRefGoogle Scholar
  20. [20]
    Ding, H.; Portilla-Arias, J.; Patil, R.; Black, K. L.; Ljubimova, J. Y.; Holler, E. The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery. Biomaterials 2011, 32, 5269–5278.CrossRefGoogle Scholar
  21. [21]
    Hühn, D.; Kantner, K.; Geidel, C.; Brandholt, S.; De Cock, I.; Soenen, S. J. H.; Riveragil, P.; Montenegro, J. M.; Braeckmans, K.; Müllen, K. et al. Polymer-coated nanoparticles interacting with proteins and cells: Focusing on the sign of the net charge. ACS Nano 2013, 7, 3253–3263.CrossRefGoogle Scholar
  22. [22]
    Hu, D. D.; Xu, Z. P.; Hu, Z. Y.; Hu, B. H.; Yang, M. Y.; Zhu, L. J. pH-triggered charge-reversal silk sericin-based nanoparticles for enhanced cellular uptake and doxorubicin delivery. ACS Sustainble Chem. Eng. 2017, 5, 1638–1647.CrossRefGoogle Scholar
  23. [23]
    Yan, X.; Yu, Q. S.; Guo, L. Y.; Guo, W. X.; Guan, S. L.; Tang, H.; Lin, S. S.; Gan, Z. H. Positively charged combinatory drug delivery systems against multi-drug-resistant breast cancer: Beyond the drug combination. ACS Appl. Mater. Interfaces 2017, 9, 6804–6815.CrossRefGoogle Scholar
  24. [24]
    Qian, J.; Gao, X. H. Triblock copolymer-encapsulated nanoparticles with outstanding colloidal stability for siRNA delivery. ACS Appl. Mater. Interfaces 2013, 5, 2845–2852.CrossRefGoogle Scholar
  25. [25]
    Hu, Y. C.; Gong, X.; Zhang, J. M.; Chen, F. Q.; Fu, C. M.; Li, P.; Zou, L.; Zhao, G. Activated charge-reversal polymeric nano-system: The promising strategy in drug delivery for cancer therapy. Polymers 2016, 8, 99.CrossRefGoogle Scholar
  26. [26]
    Yuan, Y.Y.; Mao, C. Q.; Du, X. J.; Du, J. Z.; Wang, F.; Wang, J. Surface charge switchable nanoparticles based on zwitterionic polymer for enhanced drug delivery to tumor. Adv. Mater. 2012, 24, 5476-5480.CrossRefGoogle Scholar
  27. [27]
    Chen, J. J.; Ding, J. X.; Wang, Y. C.; Cheng, J. J.; Ji, S. X. Zhuang, X, L. Chen, X. S. Sequentially responsive shellstacked nanoparticles for deep penetration into solid tumors. Adv. Mater. 2017, 29, 1701170.Google Scholar
  28. [28]
    Mo, R.; Sun, Q.; Xue, J. W.; Li, N.; Li, W. Y.; Zhang, C.; Ping, Q, N. Multistage pH-responsive liposomes for mitochondrial-targeted anticancer drug delivery. Adv. Mater. 2012, 24, 3659–3665.CrossRefGoogle Scholar
  29. [29]
    Arnold, A. E.; Czupiel, P.; Shoichet, M. Engineered polymeric nanoparticles to guide the cellular internalization and trafficking of small interfering ribonucleic acids. J. Control. Release 2017, 259, 3–15.CrossRefGoogle Scholar
  30. [30]
    Wang, F. H.; Zhang, W. J.; Shen, Y. Y.; Huang, Q.; Zhou, D. J.; Guo, S. R. Efficient RNA delivery by integrin-targeted glutathione responsive polyethyleneimine capped gold nanorods. Acta Biomater. 2015, 23, 136–146.CrossRefGoogle Scholar
  31. [31]
    Chen, J. L.; Luo, J.; Zhao, Y.; Pu, L. Y.; Lu, X. J.; Gao, R.; Wang, G.; Gu, Z. W. Increase in transgene expression by pluronic L64-mediated endosomal/lysosomal escape through its membrane-disturbing action. ACS Appl. Mater. Interfaces 2015, 7, 7282–7293.CrossRefGoogle Scholar
  32. [32]
    Dobay, M. P.; Schmidt, A.; Mendoza, E.; Bein, T.; Rädler, J. O. Cell type determines the light-induced endosomal escape kinetics of multifunctional mesoporous silica nanoparticles. Nano Lett. 2013, 13, 1047–1052.CrossRefGoogle Scholar
  33. [33]
    Gu, W. Y.; Jia, Z. F.; Truong, N. P.; Prasadam, I.; Xiao, Y.; Monteiro, M. J. Polymer nanocarrier system for endosome escape and timed release of siRNA with complete gene silencing and cell death in cancer cells. Biomacromolecules 2013, 14, 3386–3389.CrossRefGoogle Scholar
  34. [34]
    Gilleron, J.; Querbes, W.; Zeigerer, A.; Borodovsky, A.; Marsico, G.; Schubert, U.; Manygoats, K.; Seifert, S.; Andree, C.; Stöter, M. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 2013, 31, 638–646.CrossRefGoogle Scholar
  35. [35]
    Leroueil, P. R.; Berry, S. A.; Duthie, K.; Han, G.; Rotello, V. M.; McNerny, D. Q.; Baker, J. R.; Orr, B. G.; Holl, M. M. B. Wide varieties of cationic nanoparticles induce defects in supported lipid bilayers. Nano Lett. 2008, 8, 420–424.CrossRefGoogle Scholar
  36. [36]
    Bieber, T.; Meissner, W.; Kostin, S.; Niemann, A.; Elsasser, H. P. Intracellular route and transcriptional competence of polyethylenimine-DNA complexes. J. Control. Release 2002, 82, 441–454.CrossRefGoogle Scholar
  37. [37]
    Wang, C. F.; Lin, Y. X.; Jiang, T.; He, F.; Zhuo, R. X. Polyethylenimine-grafted polycarbonates as biodegradable polycations for gene delivery. Biomaterials 2009, 30, 4824–4832.CrossRefGoogle Scholar
  38. [38]
    Wen, Y. T.; Guo, Z. H.; Du, Z.; Fang, R.; Wu, H. M.; Zeng, X.; Wang, C.; Feng, M.; Pan, S. R. Serum tolerance and endosomal escape capacity of histidine-modified pDNAloaded complexes based on polyamidoamine dendrimer derivatives. Biomaterials 2012, 33, 8111–8121.CrossRefGoogle Scholar
  39. [39]
    Roth, J. A.; Cristiano, R. J. Gene therapy for cancer: What have we done and where are we going? J. Natl. Cancer Inst. 1997, 89, 21–39.CrossRefGoogle Scholar
  40. [40]
    Xu, Q. X.; Wang, C. H.; Pack, D. W. Polymeric carriers for gene delivery: Chitosan and poly(amidoamine) dendrimers. Curr. Pharmaceut. Des. 2010, 16, 2350–2368.CrossRefGoogle Scholar
  41. [41]
    Tian, Q.; Zhang, C. N.; Wang, X. H.; Wang, W.; Huang, W.; Cha, R. T.; Wang, C. H.; Yuan, Z.; Liu, M.; Wan, H. Y. et al. Glycyrrhetinic acid-modified chitosan/poly(ethylene glycol) nanoparticles for liver-targeted delivery. Biomaterials 2010, 31, 4748–4756.CrossRefGoogle Scholar
  42. [42]
    Lee, Y.; Miyata, K.; Oba, M.; Ishii, T.; Fukushima, S.; Han, M. R.; Koyama, H.; Nishiyama, N.; Kataoka, K. Chargeconversion ternary polyplex with endosome disruption moiety: A technique for efficient and safe gene delivery. Angew. Chem., Int. Ed. 2008, 47, 5163–5166.CrossRefGoogle Scholar
  43. [43]
    Chung, M. F.; Liu, H. Y.; Lin, K. J.; Chia, W. T.; Sung, H. W. A pH-responsive carrier system that generates NO bubbles to trigger drug release and reverse P-glycoproteinmediated multidrug resistance. Angew. Chem., Int. Ed. 2015, 54, 9890–9893.CrossRefGoogle Scholar
  44. [44]
    Wang, S. J.; Teng, Z. G.; Huang, P.; Liu, D. B.; Liu, Y.; Tian, Y.; Sun, J.; Li, Y. J.; Ju, H. X.; Chen, X. Y. et al. Reversibly extracellular pH controlled cellular uptake and photothermal therapy by PEGylated mixed-charge gold nanostars. Small 2015, 11, 1801–1810.CrossRefGoogle Scholar
  45. [45]
    Ma, J. L.; Hu, Z. P.; Wang, W.; Wang, X. Y.; Wu, Q.; Yuan, Z. pH-sensitive reversible programmed targeting strategy by the self-assembly/disassembly of gold nanoparticles. ACS Appl. Mater. Interfaces 2017, 9, 16767–16777.CrossRefGoogle Scholar
  46. [46]
    Wang, W. W.; Cheng, D.; Gong, F. M.; Miao, X. M.; Shuai, X. T. Design of multifunctional micelle for tumor-targeted intracellular drug release and fluorescent imaging. Adv. Mater. 2012, 24, 115–120.CrossRefGoogle Scholar
  47. [47]
    Gao, M.; Fan, F.; Li, D. D.; Yu, Y.; Mao, K. R.; Sun, T. M.; Qian, H. S.; Tao, W.; Yang, X. Z. Tumor acidity-activatable TAT targeted nanomedicine for enlarged fluorescence/ magnetic resonance imaging-guided photodynamic therapy. Biomaterials 2017, 133, 165–175.CrossRefGoogle Scholar
  48. [48]
    Wang, L.; Jia, X. H.; Liu, X. H.; Yuan, Z.; Huang, J. X. Synthesis and characterization of a functionalized amphiphilic diblock copolymer: MePEG-b-poly(DL-lactide-co-RS-ß-malic acid). Coll. Polym. Sci. 2006, 285, 273–281.CrossRefGoogle Scholar
  49. [49]
    Roy, A.; Zhao, Y. C.; Yang, Y.; Szeitz, A.; Klassen, T.; Li, S. D. Selective targeting and therapy of metastatic and multidrug resistant tumors using a long circulating podophyllotoxin nanoparticle. Biomaterials 2017, 137, 11–22.CrossRefGoogle Scholar
  50. [50]
    Verma, A.; Stellacci, F. Effect of surface properties on nanoparticle-cell interactions. Small 2010, 6, 12–21.CrossRefGoogle Scholar
  51. [51]
    Zhang, X. J.; Chen, D. W.; Ba, S.; Zhu, J.; Zhang, J.; Hong, W.; Zhao, X. L.; Hu, H. Y.; Qiao, M. X. Poly(L-histidine) based triblock copolymers: pH induced reassembly of copolymer micelles and mechanism underlying endolysosomal escape for intracellular delivery. Biomacromolecules 2014, 15, 4032–4045.CrossRefGoogle Scholar
  52. [52]
    Varkouhi, A. K.; Scholte, M.; Storm, G.; Haisma, H. J. Endosomal escape pathways for delivery of biologicals. J. Control. Release 2011, 151, 220–228.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yapei Zhang
    • 1
  • Yingying Li
    • 1
  • Jinlong Ma
    • 1
  • Xinyu Wang
    • 1
  • Zhi Yuan
    • 1
    • 2
  • Wei Wang
    • 1
  1. 1.Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of ChemistryNankai UniversityTianjinChina
  2. 2.Collaborative Innovation Center of Chemical Science and EngineeringNankai UniversityTianjinChina

Personalised recommendations