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Self-targeting visualizable hyaluronate nanogel for synchronized intracellular release of doxorubicin and cisplatin in combating multidrug-resistant breast cancer

Abstract

Multidrug-resistance (MDR) featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic. Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR. However, the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites. In the present study, a type of self-targeting hyaluronate (HA) nanogels (CDDPHANG/DOX) to reverse drug resistance through the synchronized pharmacokinetics, intratumoral distribution, and intracellular release of topoisomerase II inhibitor doxorubicin (DOX) and DNA-crosslinking agent cisplatin (CDDP) is developed. With prolonged circulation time and enhanced intratumoral accumulation in vivo, CDDPHANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity. Besides, fluorescence imaging of DOX combined with the micro-computed tomography (micro-CT) imaging of CDDP facilitates the visualization of this combination tumor chemotherapy. With visualizable synchronized drug delivery, the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.

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References

  1. [1]

    Robey, R. W.; Pluchino, K. M.; Hall, M. D.; Fojo, A. T.; Bates, S. E.; Gottesman, M. M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 2018, 18, 452–464.

    CAS  Google Scholar 

  2. [2]

    Liu, J.; Wei, T.; Zhao, J.; Huang, Y. Y.; Deng, H.; Kumar, A.; Wang, C. X.; Liang, Z. C.; Ma, X. W.; Liang, X. J. Multifunctional aptamerbased nanoparticles for targeted drug delivery to circumvent cancer resistance. Biomaterials 2016, 91, 44–56.

    CAS  Google Scholar 

  3. [3]

    Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2016, 17, 20–37.

    Google Scholar 

  4. [4]

    Cong, Y. W.; Xiao, H. H.; Xiong, H. J.; Wang, Z. G.; Ding, J. X.; Li, C.; Chen, X. S.; Liang, X. J.; Zhou, D. F.; Huang, Y. B. Dual drug backboned shattering polymeric theranostic nanomedicine for synergistic eradication of patient-derived lung cancer. Adv. Mater. 2018, 30, 1706220.

    Google Scholar 

  5. [5]

    Hu, Q. Y.; Sun, W. J.; Wang, C.; Gu, Z. Recent advances of cocktail chemotherapy by combination drug delivery systems. Adv. Drug Deliv. Rev. 2016, 98, 19–34.

    CAS  Google Scholar 

  6. [6]

    Palmer, A. C.; Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 2017, 171, 1678–1691.e13.

    CAS  Google Scholar 

  7. [7]

    Yang, Y. Y.; Adebali, O.; Wu, G.; Selby, C. P.; Chiou, Y. Y.; Rashid, N.; Hu, J. C.; Hogenesch, J. B.; Sancar, A. Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues. Proc. Natl. Acad. Sci. USA 2018, 115, E4777–E4785.

    CAS  Google Scholar 

  8. [8]

    Lee, S. M.; O’Halloran, T. V.; Nguyen, S. B. T. Polymer-caged nanobins for synergistic cisplatin-doxorubicin combination chemotherapy. J. Am. Chem. Soc. 2010, 132, 17130–17138.

    CAS  Google Scholar 

  9. [9]

    Zhang, Y.; Wang, F.; Li, M. Q.; Yu, Z. Q.; Qi, R. G.; Ding, J. X.; Zhang, Z. Y.; Chen, X. S. Self-stabilized hyaluronate nanogel for intracellular codelivery of doxorubicin and cisplatin to osteosarcoma. Adv. Sci. 2018, 5, 1700821.

    Google Scholar 

  10. [10]

    Gazzano, E.; Rolando, B.; Chegaev, K.; Salaroglio, I. C.; Kopecka, J.; Pedrini, I.; Saponara, S.; Sorge, M.; Buondonno, I.; Stella, B. et al. Folate-targeted liposomal nitrooxy-doxorubicin: An effective tool against P-glycoprotein-positive and folate receptor-positive tumors. J. Control. Release 2018, 270, 37–52.

    CAS  Google Scholar 

  11. [11]

    Hu, C. M. J.; Zhang, L. F. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem. Pharmacol. 2012, 83, 1104–1111.

    CAS  Google Scholar 

  12. [12]

    Sivak, L.; Subr, V.; Tomala, J.; Rihova, B.; Strohalm, J.; Etrych, T.; Kovar, M. Overcoming multidrug resistance via simultaneous delivery of cytostatic drug and P-glycoprotein inhibitor to cancer cells by HPMA copolymer conjugate. Biomaterials 2017, 115, 65–80.

    CAS  Google Scholar 

  13. [13]

    Cohen, K.; Emmanuel, R.; Kisin-Finfer, E.; Shabat, D.; Peer, D. Modulation of drug resistance in ovarian adenocarcinoma using chemotherapy entrapped in hyaluronan-grafted nanoparticle clusters. ACS Nano 2014, 8, 2183–2195.

    CAS  Google Scholar 

  14. [14]

    Hamaguchi, K.; Godwin, A. K.; Yakushiji, M.; O’Dwyer, P. J.; Ozols, R. F.; Hamilton, T. C. Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. Cancer Res. 1993, 53, 5225–5232.

    CAS  Google Scholar 

  15. [15]

    Yang, X.; Pagé, M. P-glycoprotein expression in ovarian cancer cell line following treatment with cisplatin. Oncol. Res. 1995, 7, 619–624.

    CAS  Google Scholar 

  16. [16]

    Ye, M. Z.; Han, Y. X.; Tang, J. B.; Piao, Y.; Liu, X. R.; Zhou, Z. X.; Gao, J. Q.; Rao, J. H.; Shen, Y. Q. A Tumor-specific cascade amplification drug release nanoparticle for overcoming multidrug resistance in cancers. Adv. Mater. 2017, 29, 1702342.

    Google Scholar 

  17. [17]

    Kim, H.; Jeong, H.; Han, S.; Beack, S.; Hwang, B. W.; Shin, M.; Oh, S. S.; Hahn, S. K. Hyaluronate and its derivatives for customized biomedical applications. Biomaterials 2017, 123, 155–171.

    CAS  Google Scholar 

  18. [18]

    Li, M. Q.; Tang, Z. H.; Zhang, D. W.; Sun, H.; Liu, H. Y.; Zhang, Y.; Zhang, Y. Y.; Chen, X. S. Doxorubicin-loaded polysaccharide nanoparticles suppress the growth of murine colorectal carcinoma and inhibit the metastasis of murine mammary carcinoma in rodent models. Biomaterials 2015, 51, 161–172.

    CAS  Google Scholar 

  19. [19]

    Qhattal, H. S. S.; Hye, T.; Alali, A.; Liu, X. L. Hyaluronan polymer length, grafting density, and surface poly(ethylene glycol) coating influence in vivo circulation and tumor targeting of hyaluronangrafted liposomes. ACS Nano 2014, 8, 5423–5440.

    CAS  Google Scholar 

  20. [20]

    Matzke-Ogi, A.; Jannasch, K.; Shatirishvili, M.; Fuchs, B.; Chiblak, S.; Morton, J.; Tawk, B.; Lindner, T.; Sansom, O.; Alves, F. et al. Inhibition of tumor growth and metastasis in pancreatic cancer models by interference with CD44v6 signaling. Gastroenterology 2016, 150, 513–525.e10.

    Google Scholar 

  21. [21]

    Wickens, J. M.; Alsaab, H. O.; Kesharwani, P.; Bhise, K.; Amin, M. C. I. M.; Tekade, R. K.; Gupta, U.; Iyer, A. K. Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy. Drug Discov. Today 2017, 22, 665–680.

    CAS  Google Scholar 

  22. [22]

    Zhang, Y.; Wang, F.; Li, M. Q.; Yu, Z. Q.; Qi, R. G.; Ding, J. X.; Zhang, Z. Y.; Chen, X. S. Self-stabilized hyaluronate nanogel for intracellular codelivery of doxorubicin and cisplatin to osteosarcoma. Adv. Sci. 2018, 5, 1700821.

    Google Scholar 

  23. [23]

    Feng, X. R.; Ding, J. X.; Gref, R.; Chen, X. S. Poly(ß-cyclodextrin)- mediated polylactide-cholesterol stereocomplex micelles for controlled drug delivery. Chin. J. Polym. Sci. 2017, 35, 693–699.

    CAS  Google Scholar 

  24. [24]

    Padhye, P.; Alam, A.; Ghorai, S.; Chattopadhyay, S.; Poddar, P. Doxorubicin-conjugated ß-NaYF4:Gd3+/Tb3+ multifunctional, phosphor nanorods: A multi-modal, luminescent, magnetic probe for simultaneous optical and magnetic resonance imaging and an excellent pH-triggered anti-cancer drug delivery nanovehicle. Nanoscale 2015, 7, 19501–19518.

    CAS  Google Scholar 

  25. [25]

    Li, M. Q.; Tang, Z. H.; Lin, J.; Zhang, Y.; Lv, S. X.; Song, W. T.; Huang, Y. B.; Chen, X. S. Synergistic antitumor effects of doxorubicinloaded carboxymethyl cellulose nanoparticle in combination with endostar for effective treatment of non-small-cell lung cancer. Adv. Health care. Mater. 2014, 3, 1877–1888.

    CAS  Google Scholar 

  26. [26]

    Pramod, P. S.; Shah, R.; Jayakannan, M. Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells. Nanoscale 2015, 7, 6636–6652.

    CAS  Google 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 shell-stacked nanoparticles for deep penetration into solid tumors. Adv. Mater. 2017, 29, 1701170.

    Google Scholar 

  28. [28]

    Wang, F.; Wang, Y. C.; Dou, S.; Xiong, M. H.; Sun, T. M.; Wang, J. Doxorubicin-tethered responsive gold nanoparticles facilitate intracellular drug delivery for overcoming multidrug resistance in cancer cells. ACS Nano 2011, 5, 3679–3692.

    CAS  Google Scholar 

  29. [29]

    Kievit, F. M.; Wang, F. Y.; Fang, C.; Mok, H.; Wang, K.; Silber, J. R.; Ellenbogen, R. G.; Zhang, M. Q. Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. J. Control. Release 2011, 152, 76–83.

    CAS  Google Scholar 

  30. [30]

    Li, S. Z.; Zhao, Q.; Wang, B.; Yuan, S.; Wang, X. Y.; Li, K. Quercetin reversed MDR in breast cancer cells through down-regulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation. Phytother. Res. 2018, 32, 1530–1536.

    CAS  Google Scholar 

  31. [31]

    Ishikawa, T.; Ali-Osman, F. Glutathione-associated cisdiamminedichloroplatinum( II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathioneplatinum complex and its biological significance. J. Biol. Chem. 1993, 268, 20116–20125.

    CAS  Google Scholar 

  32. [32]

    Kartalou, M.; Essigmann, J. M. Mechanisms of resistance to cisplatin. Mutat. Res. 2001, 478, 23–43.

    CAS  Google Scholar 

  33. [33]

    Huang, D.; Chen, Y. S.; Rupenthal, I. D. Hyaluronic acid coated albumin nanoparticles for targeted peptide delivery to the retina. Mol. Pharmaceutics 2017, 14, 533–545.

    CAS  Google Scholar 

  34. [34]

    Lv, Y. Q.; Xu, C. R.; Zhao, X. M.; Lin, C. S.; Yang, X.; Xin, X. F.; Zhang, L.; Qin, C.; Han, X. P.; Yang, L. et al. Nanoplatform assembled from a CD44-targeted prodrug and smart liposomes for dual targeting of tumor microenvironment and cancer cells. ACS Nano 2018, 12, 1519–1536.

    CAS  Google Scholar 

  35. [35]

    Gu, X. Y.; Ding, J. X.; Zhang, Z. Y.; Li, Q.; Zhuang, X. L.; Chen, X. S. Polymeric nanocarriers for drug delivery in osteosarcoma treatment. Curr. Pharm. Des. 2015, 21, 5187–5197.

    CAS  Google Scholar 

  36. [36]

    Kastl, L.; Sasse, D.; Wulf, V.; Hartmann, R.; Mircheski, J.; Ranke, C.; Carregal-Romero, S.; Martínez-López, J. A.; Fernández-Chacón, R.; Parak, W. J. et al. Multiple internalization pathways of polyelectrolyte multilayer capsules into mammalian cells. ACS Nano 2013, 7, 6605–6618.

    CAS  Google Scholar 

  37. [37]

    Mulcahy, L. A.; Pink, R. C.; Carter, D. R. F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 2014, 3, 24641.

    Google Scholar 

  38. [38]

    Zhou, K. J.; Wang, Y. G.; Huang, X. N.; Luby-Phelps, K.; Sumer, B. D.; Gao, J. M. Tunable, ultrasensitive pH-responsive nanoparticles targeting specific endocytic organelles in living cells. Angew. Chem., Int. Ed. 2011, 50, 6109–6114.

    CAS  Google Scholar 

  39. [39]

    Chen, J. J.; Ding, J. X.; Xu, W. G.; Sun, T. M.; Xiao, H. H.; Zhuang, X. L.; Chen, X. S. Receptor and microenvironment dual-recognizable nanogel for targeted chemotherapy of highly metastatic malignancy. Nano Lett. 2017, 17, 4526–4533.

    CAS  Google Scholar 

  40. [40]

    Elzoghby, A. O.; Mostafa, S. K.; Helmy, M. W.; El Demellawy, M. A.; Sheweita, S. A. Superiority of aromatase inhibitor and cyclooxygenase-2 inhibitor combined delivery: Hyaluronate-targeted versus PEGylated protamine nanocapsules for breast cancer therapy. Int. J. Pharm. 2017, 529, 178–192.

    CAS  Google Scholar 

  41. [41]

    Wilhelm, S.; Tavares, A. J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H. F.; Chan, W. C. W. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 2016, 1, 16014.

    CAS  Google Scholar 

  42. [42]

    Schiller, J. H.; Harrington, D.; Belani, C. P.; Langer, C.; Sandler, A.; Krook, J.; Zhu, J. M.; Johnson, D. H. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 2002, 346, 92–98.

    CAS  Google Scholar 

  43. [43]

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

    CAS  Google Scholar 

  44. [44]

    Sun, D. K.; Ding, J. X.; Xiao, C. S.; Chen, J. J.; Zhuang, X. L.; Chen, X. S. Preclinical evaluation of antitumor activity of acidsensitive PEGylated doxorubicin. ACS Appl. Mater. Interfaces 2014, 6, 21202–21214.

    CAS  Google Scholar 

  45. [45]

    Ding, J. X.; Xu, W. G.; Zhang, Y.; Sun, D. K.; Xiao, C. S.; Liu, D. H.; Zhu, X. J.; Chen, X. S. Self-reinforced endocytoses of smart polypeptide nanogels for “on-demand” drug delivery. J. Control. Release 2013, 172, 444–455.

    CAS  Google Scholar 

  46. [46]

    Xiao, H. H.; Yan, L. S.; Dempsey, E. M.; Song, W. T.; Qi, R. G.; Li, W. L.; Huang, Y. B.; Jing, X. B.; Zhou, D. F.; Ding, J. X. et al. Recent progress in polymer-based platinum drug delivery systems. Prog. Polym. Sci. 2018, 87, 70–106.

    CAS  Google Scholar 

  47. [47]

    Xu, W. G.; Ding, J. X.; Xiao, C. S.; Li, L. Y.; Zhuang, X. L.; Chen, X. S. Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic. Biomaterials 2015, 54, 72–86.

    CAS  Google Scholar 

  48. [48]

    Banzato, A.; Bobisse, S.; Rondina, M.; Renier, D.; Bettella, F.; Esposito, G.; Quintieri, L.; Meléndez-Alafort, L.; Mazzi, U.; Zanovello, P. et al. A paclitaxel-hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity. Clin. Cancer Res. 2008, 14, 3598–3606.

    CAS  Google Scholar 

  49. [49]

    Sales Gil, R.; Vagnarelli, P. Ki-67: More hidden behind a ‘classic proliferation marker’. Trends Biochem. Sci. 2018, 43, 747–748.

    CAS  Google Scholar 

  50. [50]

    Elser, M.; Borsig, L.; Hassa, P. O.; Erener, S.; Messner, S.; Valovka, T.; Keller, S.; Gassmann, M.; Hottiger, M. O. Poly(ADP-ribose) polymerase 1 promotes tumor cell survival by coactivating hypoxiainducible factor-1-dependent gene expression. Mol. Cancer Res. 2008, 6, 282–290.

    CAS  Google Scholar 

  51. [51]

    Martin-Oliva, D.; Aguilar-Quesada, R.; O’Valle, F.; Muñoz-Gámez, J. A.; Martínez-Romero, R.; García del Moral, R.; Ruiz de Almodóvar, J. M.; Villuendas, R.; Piris, M. A.; Oliver, F. J. Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res. 2006, 66, 5744–5756.

    CAS  Google Scholar 

  52. [52]

    Ritman, E. L. Molecular imaging in small animals—roles for micro-CT. J. Cell. Biochem. 2002, 87, 116–124.

    Google Scholar 

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Correspondence to Yu Shrike Zhang, Jianxun Ding or Zhiqiang Yu.

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Ma, W., Chen, Q., Xu, W. et al. Self-targeting visualizable hyaluronate nanogel for synchronized intracellular release of doxorubicin and cisplatin in combating multidrug-resistant breast cancer. Nano Res. 14, 846–857 (2021). https://doi.org/10.1007/s12274-020-3124-y

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Keywords

  • hyaluronate nanogel
  • self-targetability
  • intracellular drug codelivery
  • multimodal imaging
  • reversal of multidrug resistance