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SCIENCE CHINA Chemistry, Volume 61, Issue 11: 1447-1459(2018) https://doi.org/10.1007/s11426-018-9269-6

Dual-stimuli-sensitive poly(ortho ester disulfide urethanes)-based nanospheres with rapid intracellular drug release for enhanced chemotherapy

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  • ReceivedFeb 25, 2018
  • AcceptedApr 23, 2018
  • PublishedSep 3, 2018

Abstract

Herein, new poly(ortho ester disulfide urethanes) (POEDU) and poly(ortho ester urethanes) (POEU) were successfully synthesized via polycondensation between active esters of 1,6-hexandiol (HD) and dual-stimuli-sensitive ortho ester disulfide diamine or pH-senstive ortho ester diamine. The corresponding POEDU and POEU nanospheres were easily fabricated using an oil-in-water emulsion technique. In vitro degradation experiments indicated that POEDU nanospheres degraded faster than POEU nanospheres in mildly acidic and reductive environments. Doxorubicin (DOX) as a model antitumor drug was successfully incorporated into these nanospheres to give DOX-loaded nanoparticles (POEDU-DOX and POEU-DOX). In vitro drug release studies showed that release of DOX from dual-stimuli-sensitive POEDU-DOX was accelerated compared with release from the pH-sensitive POEU-DOX under DL-dithiothreitol (DTT) and mildly acidic conditions. In addition, in vitro uptake and cytotoxicity assays revealed that POEDU-DOX exhibited more efficient antitumor effect than POEU-DOX did against both two-dimensional (2D) cells and three-dimensional (3D) multicellular tumor spheroids (MCTS). Finally, in a mice H22 tumor model, POEDU-DOX exhibited preferable antitumor capability. In conclusion, the pH and redox dual-stimuli-sensitive POEDU nanospheres can be superior drug carriers for cancer treatment.


Funded by

the National Natural Science Foundation of China(51503001,51603001)

the Research Foundation for Key Program of Education Department of Anhui Province of China(KJ2016A030)

the Doctor Research Foundation of Anhui University(J10113190075)

and the Academic and Technology Introduction Project of Anhui University(AU02303203)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (51503001, 51603001), the Research Foundation for Key Program of Education Department of Anhui Province of China (KJ2016A030), the Doctor Research Foundation of Anhui University (J10113190075), and the Academic and Technology Introduction Project of Anhui University (AU02303203).


Interest statement

The authors declare that they have no conflict of interest.


Supplement

The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors


References

[1] Minchinton AI, Tannock IF. Nat Rev Cancer, 2006, 6: 583-592 CrossRef PubMed Google Scholar

[2] Zhang Y, Xiao C, Li M, Ding J, He C, Zhuang X, Chen X. Polym Chem, 2014, 5: 2801-2808 CrossRef Google Scholar

[3] Meng F, Cheng R, Deng C, Zhong Z. Mater Today, 2012, 15: 436-442 CrossRef Google Scholar

[4] Gao GH, Im GH, Kim MS, Lee JW, Yang J, Jeon H, Lee JH, Lee DS. Small, 2010, 6: 1201-1204 CrossRef PubMed Google Scholar

[5] Zhuang Y, Wang D, Yin C, Deng H, Sun M, He L, Su Y, Zhu X. Sci China Chem, 2016, 59: 1600-1608 CrossRef Google Scholar

[6] Zhang J, Chen H, Xu L, Gu Y. J Control Release, 2008, 131: 34-40 CrossRef PubMed Google Scholar

[7] Ma N, Li Y, Xu H, Wang Z, Zhang X. J Am Chem Soc, 2010, 132: 442-443 CrossRef PubMed Google Scholar

[8] Liu J, Pang Y, Huang W, Zhu Z, Zhu X, Zhou Y, Yan D. Biomacromolecules, 2011, 12: 2407-2415 CrossRef PubMed Google Scholar

[9] Zhao J, Liu J, Xu S, Zhou J, Han S, Deng L, Zhang J, Liu J, Meng A, Dong A. ACS Appl Mater Interfaces, 2013, 5: 13216-13226 CrossRef PubMed Google Scholar

[10] Azagarsamy MA, Sokkalingam P, Thayumanavan S. J Am Chem Soc, 2009, 131: 14184-14185 CrossRef PubMed Google Scholar

[11] Min KH, Kim JH, Bae SM, Shin H, Kim MS, Park S, Lee H, Park RW, Kim IS, Kim K, Kwon IC, Jeong SY, Lee DS. J Control Release, 2010, 144: 259-266 CrossRef PubMed Google Scholar

[12] Wang L, Zhang H, Qin A, Jin Q, Tang BZ, Ji J. Sci China Chem, 2016, 59: 1609-1615 CrossRef Google Scholar

[13] Prabaharan M, Grailer JJ, Pilla S, Steeber DA, Gong S. Biomaterials, 2009, 30: 5757-5766 CrossRef PubMed Google Scholar

[14] Chen W, Meng F, Cheng R, Zhong Z. J Control Release, 2010, 142: 40-46 CrossRef PubMed Google Scholar

[15] Knorr V, Ogris M, Wagner E. Pharm Res, 2008, 25: 2937-2945 CrossRef PubMed Google Scholar

[16] Du JZ, Du XJ, Mao CQ, Wang J. J Am Chem Soc, 2011, 133: 17560-17563 CrossRef PubMed Google Scholar

[17] Dai J, Lin S, Cheng D, Zou S, Shuai X. Angew Chem Int Ed, 2011, 50: 9404-9408 CrossRef PubMed Google Scholar

[18] Bai L, Wang X, Song F, Wang X, Wang Y. Chem Commun, 2015, 51: 93-96 CrossRef PubMed Google Scholar

[19] Qiao ZY, Zhang R, Du FS, Liang DH, Li ZC. J Control Release, 2011, 152: 57-66 CrossRef PubMed Google Scholar

[20] Chen W, Zhong P, Meng F, Cheng R, Deng C, Feijen J, Zhong Z. J Control Release, 2013, 169: 171-179 CrossRef PubMed Google Scholar

[21] Cai K, Yen J, Yin Q, Liu Y, Song Z, Lezmi S, Zhang Y, Yang X, Helferich WG, Cheng J. Biomater Sci, 2015, 3: 1061-1065 CrossRef PubMed Google Scholar

[22] Zhang Q, He J, Zhang M, Ni P. J Mater Chem B, 2015, 3: 4922-4932 CrossRef Google Scholar

[23] Zhou X, Luo S, Tang R, Wang R, Wang J. Macromol Biosci, 2015, 15: 385-394 CrossRef PubMed Google Scholar

[24] Luo S, Tao Y, Tang R, Wang R, Ji W, Wang C, Zhao Y. J Biomater Sci Polym Ed, 2014, 25: 965-984 CrossRef PubMed Google Scholar

[25] Yan G, Wang J, Qin J, Hu L, Zhang P, Wang X, Tang R. Macromol Biosci, 2017, 17: 1600503 CrossRef PubMed Google Scholar

[26] Tang R, Ji W, Wang C. Polymer, 2011, 52: 921-932 CrossRef PubMed Google Scholar

[27] Wei B, Tao Y, Wang X, Tang R, Wang J, Wang R, Qiu L. ACS Appl Mater Interfaces, 2015, 7: 10436-10445 CrossRef Google Scholar

[28] Fu S, Yang G, Wang J, Wang X, Cheng X, Tang R. Polymer, 2017, 114: 1-14 CrossRef Google Scholar

[29] Zha Q, Wang X, Cheng X, Fu S, Yang G, Yao W, Tang R. Mater Sci Eng-C, 2017, 78: 246-257 CrossRef PubMed Google Scholar

[30] Wang X, Zhen X, Wang J, Zhang J, Wu W, Jiang X. Biomaterials, 2013, 34: 4667-4679 CrossRef PubMed Google Scholar

[31] Liu J, Jiang Z, Zhang S, Saltzman WM. Biomaterials, 2009, 30: 5707-5719 CrossRef PubMed Google Scholar

[32] Vandamme TF, Heller J. J Control Release, 1995, 36: 209-213 CrossRef Google Scholar

[33] Zhang L, Yu M, Wang J, Tang R, Yan G, Yao W, Wang X. Macromol Biosci, 2016, 16: 1175-1187 CrossRef PubMed Google Scholar

[34] Yu M, Zhang L, Wang J, Tang R, Yan G, Cao Z, Wang X. Polymer, 2016, 96: 146-155 CrossRef Google Scholar

[35] Palamoor M, Jablonski MM. Mol Pharm, 2013, 10: 701-708 CrossRef PubMed Google Scholar

[36] Heller J, Barr J, Ng SY, Abdellauoi KS, Gurny R. Adv Drug Deliv Rev, 2002, 54: 1015-1039 CrossRef Google Scholar

[37] Sun H, Guo B, Cheng R, Meng F, Liu H, Zhong Z. Biomaterials, 2009, 30: 6358-6366 CrossRef PubMed Google Scholar

[38] Faisant N, Akiki J, Siepmann F, Benoit JP, Siepmann J. Int J Pharm, 2006, 314: 189-197 CrossRef PubMed Google Scholar

[39] Zhou T, Zhou X, Xing D. Biomaterials, 2014, 35: 4185-4194 CrossRef PubMed Google Scholar

[40] Wu Y, Kuang H, Xie Z, Chen X, Jing X, Huang Y. Polym Chem, 2014, 5: 4488-4498 CrossRef Google Scholar

[41] Pu Y, Chang S, Yuan H, Wang G, He B, Gu Z. Biomaterials, 2013, 34: 3658-3666 CrossRef PubMed Google Scholar

[42] Chen L, Mccrate JM, C-M Lee J, Li H. Nanotechnology, 2011, 22: 105708 CrossRef PubMed ADS Google Scholar

[43] Li YL, Zhu L, Liu Z, Cheng R, Meng F, Cui JH, Ji SJ, Zhong Z. Angew Chem Int Ed, 2009, 48: 9914-9918 CrossRef PubMed Google Scholar

[44] Wang X, Yang C, Zhang Y, Zhen X, Wu W, Jiang X. Biomaterials, 2014, 35: 6439-6453 CrossRef PubMed Google Scholar

[45] Wang X, Tang H, Wang C, Zhang J, Wu W, Jiang X. Theranostics, 2016, 6: 1378-1392 CrossRef PubMed Google Scholar

[46] Erlichman C, Vidgen D. Cancer Res, 1984, 44: 5369–5375. Google Scholar

[47] Bryce NS, Zhang JZ, Whan RM, Yamamoto N, Hambley TW. Chem Commun, 2009, 47: 2673-2675 CrossRef PubMed Google Scholar

[48] Wang B, He X, Zhang Z, Zhao Y, Feng W. Acc Chem Res, 2012, 46: 761-769 CrossRef PubMed Google Scholar

  • Figure 1

    (a) 1H NMR spectra of compound 2 in d-chloroform; (b) 13C NMR spectra of compound 2 in d-chloroform.

  • Scheme 1

    Synthetic routes of compound 2 (a), POEU (b) and POEDU (c). Reaction condition: (i) py-PTSA; (ii) NaOH/H2O/THF; (iii) DCM; (iv) DCM.

  • Figure 2

    1H NMR spectra of POEU (a) and POEDU (b) in d-chloroform.

  • Figure 3

    SEM images of POEU (a) and POEDU nanospheres (b); TEM images of POEU (c) and POEDU nanospheres (d); Scale bar: 200 nm.

  • Figure 4

    Time course of changes in average diameter (a) and count rate (b) of POEU and POEDU nanospheres in PBS buffer (pH 5.0 and 7.4, with or without DTT) (color online).

  • Figure 5

    Cumulative release of DOX from DOX-loaded nanospheres in PBS buffer (pH 5.0 and 7.4, with or without DTT) at 37 °C. (*: p<0.05; **: p<0.01). Data are represented as mean±SD (n=3) (color online).

  • Figure 6

    CLSM images of SH-SY5Y (a) and HepG2 cells (b) incubated with POEU-DOX, POEDU-DOX, or free DOX for 4 h (DOX dosage: 8 μg/mL). Cell nuclei were stained with Hoechst 33258 (blue). Scale bar: 20 μm (color online).

  • Figure 7

    Flow cytometry plots of SH-SY5Y and HepG2 cells treated with free DOX (d), POEU-DOX (b), POEDU-DOX (c), or DMEM medium (a) at 37 °C for 4 h (DOX dosage: 8 μg/mL) (color online).

  • Figure 8

    In vitro biocompatibility assay of blank nanospheres, free DOX, and DOX-loaded nanospheres after incubating with SH-SY5Y (a) and HepG2 cells (b) for 24 h; in vitro biocompatibility assay of blank nanospheres, free DOX, and DOX-loaded nanospheres after incubating with SH-SY5Y (c) and HepG2 cells (d) for 48 h. *: p<0.05; **: p<0.01. Date are represented as mean±SD (n=3) (color online).

  • Figure 9

    (a) CLSM images of HepG2 MCTS incubated with free DOX, POEU-DOX, or POEDU-DOX at various time points; (b) fluorescence intensity of MCTS co-cultured with POEU-DOX, POEDU-DOX, or free DOX at different time points. The scale bar is 100 μm (color online).

  • Figure 10

    (a) Representative images of HepG2 MCTS treated with DMEM medium, blank nanospheres, DOX-loaded nanospheres, or free DOX; (b) MCTS diameter changes after various treatment (*: p<0.05; **: p<0.01). Date are represented as mean±SD (n=3). The scale bar is 100 μm (color online).

  • Figure 11

    Biodistribution of DOX in different organs of H22 tumor-bearing mice at various time points after i.v. injection of DOX (a), POEU-DOX (b), or POEDU-DOX (c). Date are represented as mean±SD (n=3) (color online).

  • Figure 12

    In vivo antitumor activity of DOX-loaded nanospheres in H22 tumor-bearing mice. Changes in tumor volume (a) (*: p<0.05; **: p<0.01); changes in body weights of mice (b) (color online).

  • Figure 13

    Weights of H22 grafted tumors after daily administration for 7 d (a) (*: p<0.05, **: p<0.01); images of H22 grafted tumors at the end time point of each treatment (b); date are represented as mean±SD (n=8) (color online).

  • Table 1   Characterization of two copolymers

    Polymer

    Yield (%)

    Mn (×104)a)

    Mw (×104)a)

    PDIa)

    POEU

    89.6

    1.29

    2.50

    1.92

    POEDU

    87.1

    1.38

    2.22

    1.61

    Calculated based on data from GPC.

  • Table 2   Characterization of two types of nanospheres

    Nanospheres

    Yield (%)

    Size (nm)a)

    PDIa)

    POEU

    91.1

    206.1

    0.114

    POEDU

    93.4

    213.5

    0.109

    Determined by DLS in PBS buffer (0.01 M, pH 7.4).

  • Table 3   Characterization of DOX-loaded nanospheres

    DOX/nanospheres

    Size (nm)a)

    PDIa)

    DLC (%)b)

    DLE (%)c)

    POEU-DOX

    240

    0.115

    13.2±1.5

    66.4±4.7

    POEDU-DOX

    253

    0.104

    13.6± 1.7

    67.8±3.4

    Determined by DLS in PBS buffer (0.01 M, pH 7.4); b) DLC=drug loading content; c) DLE=drug loading efficiency.

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