Skip to main content
SpringerLink
Log in

Dual pH-responsive “charge-reversal like” gold nanoparticles to enhance tumor retention for chemo-radiotherapy

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

Abstract

The strategy of pH-responsive aggregation in tumor micro-environment (TME) provides an intriguing platform for enhancing tumor retention and exerting therapeutic effects sufficiently. In this work, we have designed an intelligent dual pH-responsive self-aggregating nano gold system (Au@PAH-Pt/DMMA) for the combined chemo-radiotherapy, in which a “charge-reversal like” strategy was utilized to realize irreversible stable aggregation and pH-specific release of cisplatin prodrug in TME. Responsive aggregation increases the cellular uptake of Au@PAH-Pt/DMMA by 55%–60%, and the cellular uptake of Pt after X-ray irradiation can be further enhanced by 80%. Additionally, responsive aggregation greatly slows down the rate of efflux from tumor in vivo. This system not only promotes B16 cell apoptosis as a chemotherapeutic agent (30.4%), it also enhances the effect of chemo-radiotheray (CRT) by promoting apoptosis as a radiosensitizer (55.3%). The colony formation assay results were fitted to cell survival curve of B16 cells and the sensitization enhancement ratio (SER) was calculated to be 1.29, which shows a good radiosensitizing ability. When exposed to X-ray, this nanoplatform reached the ideal therapeutic effect, and the tumor inhibition rate of Au@PAH-Pt/DMMA reached 91.6% with low drug administration frequency and dose of X-ray. Overall, the dual pH-responsive nanoparticles Au@PAH-Pt/DMMA could effectively enhance tumor therapeutic efficiency by combined chemo-radiotherapy, which provides a potential method for clinical transformation of cancer treatment.

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. Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin.2019, 69, 7–34.

    Google Scholar 

  2. Schürmann, R.; Vogel, S.; Ebel, K.; Bald, I. The physico-chemical basis of DNA radiosensitization: Implications for cancer radiation therapy. Chem.-Eur. J.2018, 24, 10271–10279.

    Google Scholar 

  3. Liu, Y.; Chen, W. Q.; Zhang, P. C.; Jin, X. D.; Liu, X. G.; Li, P.; Li, F. F.; Zhang, H. P.; Zou, G. Z.; Li, Q. Dynamically-enhanced retention of gold nanoclusters in HeLa cells following X-rays exposure: A cell cycle phase-dependent targeting approach. Radiother. Oncol.2016, 119, 544–551.

    Google Scholar 

  4. Liu, Y.; Zhang, P. C.; Li, F. F.; Jin, X. D.; Li, J.; Chen, W. Q.; Li, Q. Metal-based NanoEnhancers for future radiotherapy: Radiosensitizing and synergistic effects on tumor cells. Theranostics2018, 8, 1824–1849.

    CAS  Google Scholar 

  5. Kim, K.; Oh, K. S.; Park, D. Y.; Lee, J. Y.; Lee, B. S.; Kim, I. S.; Kim, K.; Kwon, I. C.; Kim, S. Y; Yuk, S. H. Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting. J. Control. Release2016, 228, 141–149.

    CAS  Google Scholar 

  6. Yi, X.; Chen, L.; Chen, J.; Maiti, D.; Chai, Z. F.; Liu, Z.; Yang, K. Biomimetic copper sulfide for chemo-radiotherapy: Enhanced uptake and reduced efflux of nanoparticles for tumor cells under ionizing radiation. Adv. Funct. Mater.2018, 28, 1705161.

    Google Scholar 

  7. Wang, C. H.; Li, X. H.; Wang, Y.; Liu, Z.; Fu, L.; Hu, L. K. Enhancement of radiation effect and increase of apoptosis in lung cancer cells by thio-glucose-bound gold nanoparticles at megavoltage radiation energies. J. Nanopart. Res.2013, 15, 1642.

    Google Scholar 

  8. Wang, S.; Huang, P.; Chen, X. Y. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization. Adv. Mater.2016, 28, 7340–7364.

    CAS  Google Scholar 

  9. Fernandes, G. F. D. S.; Fernandes, B. C.; Valente, V.; Dos Santos, J. L. Recent advances in the discovery of small molecules targeting glioblastoma. Eur. J. Med. Chem.2019, 164, 8–26.

    CAS  Google Scholar 

  10. Sun, Q. H.; Zhou, Z. X.; Qiu, N. S.; Shen, Y. Q. Rational design of cancer nanomedicine: Nanoproperty integration and synchronization. Adv. Mater.2017, 29, 1606628.

    Google Scholar 

  11. Hu, Q. Y.; Chen, Q.; Gu, Z. Advances in transformable drug delivery systems. Biomaterials2018, 178, 546–558.

    CAS  Google Scholar 

  12. Zhang, Y. M.; Huang, F.; Ren, C. H.; Liu, J. J.; Yang, L. J.; Chen, S. Z.; Chang, J. L.; Yang, C. H.; Wang, W. W.; Zhang, C. N. et al. Enhanced radiosensitization by gold nanoparticles with acid-triggered aggregation in cancer radiotherapy. Adv. Sci.2019, 6, 1801806.

    Google Scholar 

  13. Zhang, Y. M.; Chang, J. L.; Huang, F.; Yang, L. J.; Ren, C. H.; Ma, L.; Zhang, W. X.; Dong, H.; Liu, J. J.; Liu, J. F. Acid-triggered in situ aggregation of gold nanoparticles for multimodal tumor imaging and photothermal therapy. ACS Biomater. Sci. Eng.2019, 5, 1589–1601.

    CAS  Google Scholar 

  14. Gao, X. H.; Yue, Q.; Liu, Z. N.; Ke, M. J.; Zhou, X. Y.; Li, S. H.; Zhang, J. P.; Zhang, R.; Chen, L.; Mao, Y. et al. Guiding brain-tumor surgery via blood-brain-barrier-permeable gold nanoprobes with acid-triggered MRI/SERRS signals. Adv. Mater.2017, 29, 1603917.

    Google Scholar 

  15. Wang, X. Y.; Chang, Z.; Nie, X.; Li, Y. Y.; Hu, Z. P.; Ma, J. L.; Wang, W.; Song, T.; Zhou, P.; Wang, H. Q. et al. A conveniently synthesized Pt (IV) conjugated alginate nanoparticle with ligand self-shielded property for targeting treatment of hepatic carcinoma. Nanomed.: Nanotechnol., Biol. Med.2019, 15, 153–163.

    CAS  Google Scholar 

  16. Du, J. Z.; Li, H. J.; Wang, J. Tumor-acidity-cleavable maleic acid amide (TACMAA): A powerful tool for designing smart nanoparticles to overcome delivery barriers in cancer nanomedicine. Acc. Chem. Res.2018, 51, 2848–2856.

    CAS  Google Scholar 

  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. Biomaterials2016, 85, 152–167.

    CAS  Google Scholar 

  18. Yang, S. Y.; Yao, D. F.; Wang, Y. S.; Yang, W. T.; Zhang, B. B.; Wang, D. B. Enzyme-triggered self-assembly of gold nanoparticles for enhanced retention effects and photothermal therapy of prostate cancer. Chem. Commun.2018, 54, 9841–9844.

    CAS  Google Scholar 

  19. Ruan, S. B.; Hu, C.; Tang, X.; Cun, X. L.; Xiao, W.; Shi, K. R.; He, Q.; Gao, H. L. Increased gold nanoparticle retention in brain tumors by in situ enzyme-induced aggregation. ACS Nano2016, 10, 10086–10098.

    CAS  Google Scholar 

  20. Liu, X. S.; Chen, Y. J.; Li, H.; Huang, N.; Jin, Q.; Ren, K. F.; Ji, J. Enhanced retention and cellular uptake of nanoparticles in tumors by controlling their aggregation behavior. ACS Nano2013, 7, 6244–6257.

    CAS  Google Scholar 

  21. Wu, W.; Zhang, Q. J.; Wang, J. T.; Chen, M.; Li, S.; Lin, Z. F.; Li, J. S. Tumor-targeted aggregation of pH-sensitive nanocarriers for enhanced retention and rapid intracellular drug release. Polym. Chem.2014, 5, 5668–5679.

    CAS  Google Scholar 

  22. Hainfeld, J. F.; Lin, L.; Slatkin, D. N.; Avraham Dilmanian, F.; Vadas, T. M.; Smilowitz, H. M. Gold nanoparticle hyperthermia reduces radiotherapy dose. Nanomed.: Nanotechnol., Biol. Med.2014, 10, 1609–1617.

    CAS  Google Scholar 

  23. Liu, W. J.; Zhang, D.; Li, L. L.; Qiao, Z. Y.; Zhang, J. C.; Zhao, Y. X.; Qi, G. B.; Wan, D.; Pan, J.; Wang, H. In situ construction and characterization of chlorin-based supramolecular aggregates in tumor cells. ACS Appl. Mater. Interfaces2016, 8, 22875–22883.

    CAS  Google Scholar 

  24. Cheng, M. B.; Zhang, Y. H.; Zhang, X. L.; Wang, W.; Yuan, Z. One-pot synthesis of acid-induced in situ aggregating theranostic gold nanoparticles with enhanced retention in tumor cells. Biomater. Sci.2019, 7, 2009–2022.

    CAS  Google Scholar 

  25. Zhou, Q.; Shao, S. Q.; Wang, J. Q.; Xu, C. H.; Xiang, J. J.; Piao, Y.; Zhou, Z. X.; Yu, Q. S.; Tang, J. B.; Liu, X. R. et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol.2019, 14, 799–809.

    CAS  Google Scholar 

  26. Pei, M. L.; Jia, X.; Li, G. P.; Liu, P. Versatile polymeric microspheres with tumor microenvironment bioreducible degradation, pH-activated surface charge reversal, pH-triggered “off-on” fluorescence and drug release as theranostic nanoplatforms. Mol. Pharmaceutics2019, 16, 227–237.

    CAS  Google Scholar 

  27. Miao, Y. L.; Qiu, Y. D.; Yang, W. J.; Guo, Y. Q.; Hou, H. W.; Liu, Z. Y.; Zhao, X. B. Charge reversible and biodegradable nanocarriers showing dual pH-/reduction-sensitive disintegration for rapid site-specific drug delivery. Colloids Surf. B: Biointerfaces2018, 169, 313–320.

    CAS  Google Scholar 

  28. Zhao, X. B.; Wei, Z. H.; Zhao, Z. P.; Miao, Y. L.; Qiu, Y. D.; Yang, W. J.; Jia, X.; Liu, Z. Y.; Hou, H. W. Design and development of graphene oxide nanoparticle/chitosan hybrids showing pH-sensitive surface charge-reversible ability for efficient intracellular doxorubicin delivery. ACS Appl. Mater. Interfaces2018, 10, 6608–6617.

    CAS  Google Scholar 

  29. Feng, T.; Ai, X. Z.; An, G. H.; Yang, P. P.; Zhao, Y. L. Charge-convertible carbon dots for imaging-guided drug delivery with enhanced in vivo cancer therapeutic efficiency. ACS Nano2016, 10, 4410–4420.

    CAS  Google Scholar 

  30. Du, J. Z.; Sun, T. M.; Song, W. J.; Wu, J.; Wang, J. A tumor-acidity-activated charge-conversional nanogel as an intelligent vehicle for promoted tumoral-cell uptake and drug delivery. Angew. Chem., Int. Ed.2010, 49, 3621–3626.

    CAS  Google Scholar 

  31. Han, K.; Zhang, W. Y.; Zhang, J.; Lei, Q.; Wang, S. B.; Liu, J. W.; Zhang, X. Z.; Han, H. Y. Acidity-triggered tumor-targeted chimeric peptide for enhanced intra-nuclear photodynamic therapy. Adv. Funct. Mater.2016, 26, 4351–4361.

    CAS  Google Scholar 

  32. Zhao, C. Y.; Shao, L. H.; Lu, J. Q.; Deng, X. W.; Wu, Y. Tumor acidityinduced sheddable polyethylenimine-poly(trimethylene carbonate)/DNA/ polyethylene glycol-2,3-dimethylmaleicanhydride ternary complex for efficient and safe gene delivery. ACS Appl. Mater. Interfaces2016, 8, 6400–6410.

    CAS  Google Scholar 

  33. Yu, B.; Liu, T.; Du, Y. X.; Luo, Z. D.; Zheng, W. J.; Chen, T. F. X-ray-responsive selenium nanoparticles for enhanced cancer chemo-radiotherapy. Colloids Surf. B: Biointerfaces2016, 139, 180–189.

    CAS  Google Scholar 

  34. Frens, G. Controlled nucleation for the regulation of the particle size in monodisperse gold suspensions. Nat. Phys. Sci.1973, 241, 20–22.

    CAS  Google Scholar 

  35. Zhang, C. W.; Zhao, X. Z.; Guo, S. H.; Lin, T. S.; Guo, H. Q. Highly effective photothermal chemotherapy with pH-responsive polymer-coated drug-loaded melanin-like nanoparticles. Int. J. Nanomedicine2017, 12, 1827–1840.

    CAS  Google Scholar 

  36. Kang, S.; Kim, Y.; Song, Y.; Choi, J. U.; Park, E.; Choi, W.; Park, J.; Lee, Y. Comparison of pH-sensitive degradability of maleic acid amide derivatives. Bioorg. Med. Chem. Lett.2014, 24, 2364–2367.

    CAS  Google Scholar 

  37. Han, L.; Zhao, J.; Zhang, X.; Cao, W. P.; Hu, X. X.; Zou, G. Z.; Duan, X. L.; Liang, X. J. Enhanced siRNA delivery and silencing gold-chitosan nanosystem with surface charge-reversal polymer assembly and good biocompatibility. ACS Nano2012, 6, 7340–7351.

    CAS  Google Scholar 

  38. Bao, Z. R.; He, M. Y.; Quan, H.; Jiang, D. Z.; Zheng, Y.H.; Qin, W. J.; Zhou, Y. F.; Ren, F.; Guo, M. X.; Jiang, C. Z. FePt nanoparticles: A novel nanoprobe for enhanced HeLa cells sensitivity to chemoradiotherapy. RSC Adv.2016, 6, 35124–35134.

    CAS  Google Scholar 

  39. Kim, J. A.; Åberg, C.; Salvati, A.; Dawson, K. A. Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. Nat. Nanotechnol.2012, 7, 62–68.

    CAS  Google Scholar 

  40. Pucci, M.; Bravatà, V.; Forte, G. I.; Cammarata, F. P.; Messa, C.; Gilardi, M. C.; Minafra, L. Caveolin-1, breast cancer and ionizing radiation. Cancer Genomics Proteomics2015, 12, 143–152.

    CAS  Google Scholar 

  41. Franken, N. A. P.; Rodermond, H. M.; Stap, J.; Haveman, J.; Van Bree, C. Clonogenic assay of cells in vitro. Nat. Protoc.2006, 1, 2315–2319.

    CAS  Google Scholar 

  42. Werthmöller, N.; Frey, B.; Rückert, M.; Lotter, M.; Fietkau, R.; Gaipl, U. S. Combination of ionising radiation with hyperthermia increases the immunogenic potential of B16-F10 melanoma cells in vitro and in vivo. Int. J. Hyperthermia2016, 32, 23–30.

    Google Scholar 

  43. Sun, M. M.; Peng, D.; Hao, H. J.; Hu, J.; Wang, D. L.; Wang, K.; Liu, J.; Guo, X. M.; Wei, Y.; Gao, W. P. Thermally triggered in situ assembly of gold nanoparticles for cancer multimodal imaging and photothermal therapy. ACS Appl. Mater. Interfaces2017, 9, 10453–10460.

    CAS  Google Scholar 

  44. Xing, R. R.; Liu, K.; Jiao, T. F.; Zhang, N.; Ma, K.; Zhang, R. Y.; Zou, Q. L.; Ma, G. H.; Yan, X. H. An injectable self-assembling collagen-gold hybrid hydrogel for combinatorial antitumor photothermal/photodynamic therapy. Adv. Mater.2016, 28, 3669–3676.

    CAS  Google Scholar 

  45. Maiti, D.; Chao, Y.; Dong, Z. L.; Yi, X.; He, J. L.; Liu, Z.; Yang, K. Development of a thermosensitive protein conjugated nanogel for enhanced radio-chemotherapy of cancer. Nanoscale2018, 10, 13976–13985.

    CAS  Google Scholar 

  46. Goldberg, E. P.; Hadba, A. R.; Almond, B. A.; Marotta, J. S. Intratumoral cancer chemotherapy and immunotherapy: Opportunities for nonsystemic preoperative drug delivery. J. Pharm. Pharmacol.2002, 54, 159–180.

    CAS  Google Scholar 

  47. Fakhari, A.; Subramony, J. A. Engineered in-situ depot-forming hydrogels for intratumoral drug delivery. J. Control. Release2015, 220, 465–475.

    CAS  Google Scholar 

  48. Liu, Y.; Zhu, Y. Y.; Wei, G.; Lu, W. Y. Effect of carrageenan on poloxamerbased in situ gel for vaginal use: Improved in vitro and in vivo sustainedrelease properties. Eur. J. Pharm. Sci.2009, 37, 306–312.

    CAS  Google Scholar 

  49. Kojarunchitt, T.; Baldursdottir, S.; Dong, Y. D.; Boyd, B. J.; Rades, T.; Hook, S. Modified thermoresponsive Poloxamer 407 and chitosan sol-gels as potential sustained-release vaccine delivery systems. Eur. J. Pharm. Biopharm.2015, 89, 74–81.

    CAS  Google Scholar 

  50. Cafaggi, S.; Leardi, R.; Parodi, B.; Caviglioli, G.; Russo, E.; Bignardi, G. Preparation and evaluation of a chitosan salt-poloxamer 407 based matrix for buccal drug delivery. J. Control. Release2005, 102, 159–169.

    CAS  Google Scholar 

  51. Thambi, T.; Li, Y.; Lee, D. S. Injectable hydrogels for sustained release of therapeutic agents. J. Control. Release2017, 267, 57–66.

    CAS  Google Scholar 

  52. Liu, M.; Ma, S. M.; Liu, M. B.; Hou, Y. F.; Liang, B.; Su, X.; Liu, X. D. Synergistic killing of lung cancer cells by cisplatin and radiation via autophagy and apoptosis. Oncol. Lett.2014, 7, 1903–1910.

    CAS  Google Scholar 

  53. Neshastehriz, A.; Khateri, M.; Ghaznavi, H.; Shakeri-Zadeh, A. Investigating the therapeutic effects of alginate nanogel co-loaded with gold nanoparticles and cisplatin on U87-MG human glioblastoma cells. Anticancer Agents Med. Chem.2018, 18, 882–890.

    CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Nos. 51433004, 51773096, and 21604095); Natural Science Foundation of Tianjin (Nos. 17JCZDJC33500 and 18JCQNJC14500); Program for Innovative Research Team in Peking Union Medical College, CAMS Initiative for Innovative Medicine (No. 2017-I2M-3-022); Specific Program for High-Tech Leader & Team of Tianjin Government, Tianjin innovation and promotion plan key innovation team of immunoreactive biomaterials. We would like to thank Qiang Wu for FTIR spectroscopy and the guidance, Zhiqing Qiao and Lei Chen for ICP-OES, Yujun Yan and Jie Gu for radiotherapy experiments, Yajuan Wan and Rui Wang for flow cytometry, and Mengyue Pei for in vitro experiments.

Author information

Author notes

  1. Xiaolei Zhang and Chuangnian Zhang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China

    Xiaolei Zhang, Mingbo Cheng, Yahui Zhang, Wei Wang & Zhi Yuan

  2. Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, China

    Chuangnian Zhang

Authors
  1. Xiaolei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chuangnian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingbo Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yahui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi Yuan.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Zhang, C., Cheng, M. et al. Dual pH-responsive “charge-reversal like” gold nanoparticles to enhance tumor retention for chemo-radiotherapy. Nano Res. 12, 2815–2826 (2019). https://doi.org/10.1007/s12274-019-2518-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-019-2518-1

Keywords

Search

Navigation