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pHe- and glutathione-stepwise-responsive polypeptide nanogel for smart and efficient drug delivery

  • Biomaterials
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Abstract

Smart drug delivery system of core–shell-type polypeptide nanogel of poly(Z-l-lysine-co-l-cystine) (PLL-LC) has been synthesized, which showed high drug loading content (DLC 16.5%) of DOX and pHe–glutathione (GSH) stepwise responsive disassembly. Modifying the shell of the nanogel by 2,3-dimethylmaleic anhydride (DMA) makes it quickly respond to the weak acidic tumor microenvironment (pHe 6.8–6.5), inducing the surface charge reversal and promoting the nanogel efficient uptake by cancer cells. Next, the nanogel can release encapsulated DOX in cytoplasm in the presence of high level of GSH therein via reduction and disassembly of the nanogel, resulting in highly selective cytotoxicity. MTT studies reveal the good biocompatibility of the nanogel before charge reversal and an efficient toxicity to cell under pHe microenvironment. In vitro experiments confirm the smart stepwise degradability of the nanogel and efficient therapy ability to cancer cell, indicating the nanogel is a potential drug delivery system.

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References

  1. Ge Z, Liu S (2013) Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance. Chem Soc Rev 42:7289–7325

    Article  Google Scholar 

  2. Yu X, Zhang B, Wang T, Zhang J, Mu S, Liu C, Zhang N (2016) Two-stage pH-sensitive doxorubicin hydrochloride loaded core–shell nanoparticles with dual drug-loading strategies for the potential anti-tumor treatment. RSC Adv 6:104049–104066

    Article  Google Scholar 

  3. Han SS, Li ZY, Zhu JY, Han K, Zeng ZY, Hong W, Li WX, Jia HZ, Liu Y, Zhuo RX, Zhang XZ (2015) Dual-pH sensitive charge-reversal polypeptide micelles for tumor-triggered targeting uptake and nuclear drug delivery. Small 11:2543–2554

    Article  Google Scholar 

  4. Ding J, Shi F, Xiao C, Lin L, Chen L, He C, Zhuang X, Chen X (2011) One-step preparation of reduction-responsive poly(ethylene glycol)-poly(amino acid)s nanogels as efficient intracellular drug delivery platforms. Polymer Chem 2:2857–2864

    Article  Google Scholar 

  5. Chen J, Ding J, Xu W, Sun T, Xiao H, Zhuang X, Chen X (2017) Receptor and microenvironment dual-recognizable nanogel for targeted chemotherapy of highly metastatic malignancy. Nano Lett 17:4526–4533

    Article  Google Scholar 

  6. Maeda H (2015) Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv Drug Deliv Rev 91:3–6

    Article  Google Scholar 

  7. Li S, Zhang T, Xu W, Ding J, Yin F, Xu J, Sun W, Wang H, Sun M, Cai Z, Hua Y (2018) Sarcoma-targeting peptide-decorated polypeptide nanogel intracellularly delivers shikonin for upregulated osteosarcoma necroptosis and diminished pulmonary metastasis. Theranostics 8:1361–1375

    Article  Google Scholar 

  8. Kanapathipillai M, Brock A, Ingber DE (2014) Nanoparticle targeting of anti-cancer drugs that alter intracellular signaling or influence the tumor microenvironment. Adv Drug Deliv Rev 79–80:107–118

    Article  Google Scholar 

  9. Feng L, Dong Z, Tao D, Zhang Y, Liu Z (2017) The acidic tumor microenvironment: a target for smart cancer nano-theranostics. Natl Sci Rev 5:269–286

    Article  Google Scholar 

  10. Dong C, Liu Z, Zhang L, Guo W, Li X, Liu J, Wang H, Chang J (2015) pHe-induced charge-reversible NIR fluorescence nanoprobe for tumor-specific imaging. ACS Appl Mater Interfaces 7:7566–7575

    Article  Google Scholar 

  11. Du JZ, Du XJ, Mao CQ, Wang J (2011) Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. J Am Chem Soc 133:17560–17563

    Article  Google Scholar 

  12. Sun CY, Shen S, Xu CF, Li HJ, Liu Y, Cao ZT, Yang XZ, Xia JX, Wang J (2015) Tumor acidity-sensitive polymeric vector for active targeted siRNA delivery. J Am Chem Soc 137:15217–15224

    Article  Google Scholar 

  13. Li J, Yu X, Wang Y, Yuan Y, Xiao H, Cheng D, Shuai X (2014) A reduction and pH dual-sensitive polymeric vector for long-circulating and tumor-targeted siRNA delivery. Adv Mater 26:8217–8224

    Article  Google Scholar 

  14. Pacardo DB, Ligler FS, Gu Z (2015) Programmable nanomedicine: synergistic and sequential drug delivery systems. Nanoscale 7:3381–3391

    Article  Google Scholar 

  15. Xing T, Mao C, Lai B, Yan L (2012) Synthesis of disulfide-cross-linked polypeptide nanogel conjugated with a near-infrared fluorescence probe for direct imaging of reduction-induced drug release. ACS Appl Mater Interfaces 4:5662–5672

    Article  Google Scholar 

  16. Ding J, Shi F, Li D, Chen L, Zhuang X, Chen X (2013) Enhanced endocytosis of acid-sensitive doxorubicin derivatives with intelligent nanogel for improved security and efficacy. Biomater Sci 1:633–646

    Article  Google Scholar 

  17. Chen J, Ding J, Wang Y, Cheng J, Ji S, Zhuang X, Chen X (2017) Sequentially responsive shell-stacked nanoparticles for deep penetration into solid tumors. Adv Mater. https://doi.org/10.1002/adma.201701170

    Google Scholar 

  18. Guo H, Xu W, Chen J, Yan L, Ding J, Hou Y, Chen X (2017) Positively charged polypeptide nanogel enhances mucoadhesion and penetrability of 10-hydroxycamptothecin in orthotopic bladder carcinoma. J Control Release 259:136–148

    Article  Google Scholar 

  19. Huang K, Shi B, Xu W, Ding J, Yang Y, Liu H, Zhuang X, Chen X (2015) Reduction-responsive polypeptide nanogel delivers antitumor drug for improved efficacy and safety. Acta Biomater 27:179–193

    Article  Google Scholar 

  20. Shi F, Ding J, Xiao C, Zhuang X, He C, Chen L, Chen X (2012) Intracellular microenvironment responsive PEGylated polypeptide nanogels with ionizable cores for efficient doxorubicin loading and triggered release. J Mater Chem 22:14168–14179

    Article  Google Scholar 

  21. Tang S, Meng Q, Sun H, Su J, Yin Q, Zhang Z, Yu H, Chen L, Gu W, Li Y (2017) Dual pH-sensitive micelles with charge-switch for controlling cellular uptake and drug release to treat metastatic breast cancer. Biomaterials 114:44–53

    Article  Google Scholar 

  22. Chen F, Zhang J, Wang L, Wang Y, Chen M (2015) Tumor pH(e)-triggered charge-reversal and redox-responsive nanoparticles for docetaxel delivery in hepatocellular carcinoma treatment. Nanoscale 7:15763–15779

    Article  Google Scholar 

  23. Li Y, Maciel D, Rodrigues J, Shi X, Tomas H (2015) Biodegradable polymer nanogels for drug/nucleic acid delivery. Chem Rev 115:8564–8608

    Article  Google Scholar 

  24. Gravel C, Lapierre D, Labelle J, Keillor JW (2007) Acyl transfer from carboxylate, carbonate, and thiocarbonate esters to enzymatic and nonenzymatic thiolates. Can J Chem 85:164–174

    Article  Google Scholar 

  25. Sulistio A, Widjaya A, Blencowe A, Zhang X, Qiao G (2011) Star polymers composed entirely of amino acid building blocks: a route towards stereospecific, biodegradable and hierarchically functionalized stars. Chem Commun 47:1151–1153

    Article  Google Scholar 

  26. Jing T, Fu L, Liu L, Yan L (2016) A reduction-responsive polypeptide nanogel encapsulating NIR photosensitizer for imaging guided photodynamic therapy. Polym Chem 7:951–957

    Article  Google Scholar 

  27. Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev 47:113–131

    Article  Google Scholar 

  28. Zhai D, Xu W, Zhang L, Chang YT (2014) The role of “disaggregation” in optical probe development. Chem Soc Rev 43:2402–2411

    Article  Google Scholar 

  29. Yang F, Teves SS, Kemp CJ, Henikoff S (2014) Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 1845:84–89

    Google Scholar 

  30. Nemoto S, Xiang J, Huang S, Lin A (1998) Induction of apoptosis by SB202190 through inhibition of p38β mitogen-activated protein kinase. J Bio Chem 273:16415–16420

    Article  Google Scholar 

Download references

Acknowledgements

This work is supported by the National Natural Science Foundation of China (No. 51673180 and 51373162).

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Authors and Affiliations

  1. Hefei National Research Center for Physical Sciences at the Microscale, Department of Chemical Physics, CAS Key Laboratory of Soft Matter Chemistry, iCHEM, University of Science and Technology of China, Jinzhai Road 96#, Hefei, 230026, Anhui, People’s Republic of China

    Titao Jing, Tuanwei Li, Zheng Ruan & Lifeng Yan

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  1. Titao Jing
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  2. Tuanwei Li
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  4. Lifeng Yan
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Correspondence to Lifeng Yan.

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Jing, T., Li, T., Ruan, Z. et al. pHe- and glutathione-stepwise-responsive polypeptide nanogel for smart and efficient drug delivery. J Mater Sci 53, 14933–14943 (2018). https://doi.org/10.1007/s10853-018-2689-2

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  • DOI: https://doi.org/10.1007/s10853-018-2689-2

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