Polymer Bulletin

, Volume 76, Issue 4, pp 1775–1792 | Cite as

Acid/light dual-responsive biodegradable polymeric nanocarriers for efficient intracellular drug delivery

  • Yuanyuan ZhangEmail author
  • Xiang Cao
  • Tian Liang
  • Zhiwei Tong
Original Paper


A novel amphiphilic acid/light dual-cleavable diblock copolymer poly(ε-caprolactone)-acetal-nitrobenzyl ester-poly(ethylene glycol) (PCL-PEG) was prepared via the ring-opening polymerization of ε-caprolactone using 5-propargylether-2-nitrobenzyl alcohol as the initiator and subsequent “click” coupling reaction with azide-terminated poly(ethylene glycol) containing acetal group. Both light-cleavable o-nitrobenzyl methyl ester (ONB) and acid-labile acetal were used as the linkages in between the hydrophilic and hydrophobic polymer blocks. In aqueous solution, the copolymer self-assembled into the spherical polymeric nanoparticles, which were stable under physiological conditions and retained the anticancer drug doxorubicin (DOX) inside. Triggered by acid or UV irradiation, the DOX release rate was significantly enhanced, due to the correspondent degradation of acetal or ONB linkages under the stimulus. In addition, confocal laser scanning microscopy studies further demonstrated the DOX-loaded nanodrug could be efficiently taken up by HeLa cells and exhibited the enhanced DOX release into the cytoplasm upon UV irradiation. Furthermore, in vitro cytotoxicity study verified UV irradiation could improve the antitumor efficacy of the nanodrug against HeLa cells. Thus, this work provides a new method of the design of dual-responsive biodegradable polymers for drug delivery.


Block copolymer Acid/light dual response Polymeric nanoparticles Drug delivery 



This work was financially supported by the Natural Science Foundation of Jiangsu Province, China (BK20171263), China Postdoctoral Science Foundation (2018M630548), Postgraduate Research & Practice Innovation Program of Jiangsu Province, China (KYCX18_2603) and the Lianyungang Industry Prospect and Common Key Technologies Program (No. CG1602).


  1. 1.
    Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 7:771–782CrossRefGoogle Scholar
  2. 2.
    Dawidczyk CM, Kim C, Park JH, Russell LM, Lee KH, Pomper MG, Searson PC (2014) State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J Control Release 187:133–144CrossRefGoogle Scholar
  3. 3.
    Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7:653CrossRefGoogle Scholar
  4. 4.
    Davis ME, Chen Z, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discovery 7:771CrossRefGoogle Scholar
  5. 5.
    Meng F, Cheng R, Deng C, Zhong Z (2012) Intracellular drug release nanosystems. Mater Today 15:436–442CrossRefGoogle Scholar
  6. 6.
    Cheng R, Meng F, Deng C, Zhong Z (2015) Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 10:656–670CrossRefGoogle Scholar
  7. 7.
    Rapoport N (2007) Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Prog Polym Sci 32:962–990CrossRefGoogle Scholar
  8. 8.
    Blum AP, Kammeyer JK, Rush AM, Callmann CE, Hahn ME, Gianneschi NC (2015) Stimuli-Responsive nanomaterials for biomedical applications. J Am Chem Soc 137:2140–2154CrossRefGoogle Scholar
  9. 9.
    Kanamala M, Wilson WR, Yang M, Palmer BD, Wu Z (2016) Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review. Biomaterials 85:152–167CrossRefGoogle Scholar
  10. 10.
    Ma X, Shi X, Bai S, Gao Y-E, Hou M, Han M-Y, Xu Z (2018) Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery. J Mater Sci 53:892–907CrossRefGoogle Scholar
  11. 11.
    Meng F, Hennink WE, Zhong Z (2009) Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 30:2180–2198CrossRefGoogle Scholar
  12. 12.
    Roy D, Brooks WLA, Sumerlin BS (2013) New directions in thermoresponsive polymers. Chem Soc Rev 42:7214–7243CrossRefGoogle Scholar
  13. 13.
    Liu G, Liu W, Dong C-M (2013) UV- and NIR-responsive polymeric nanomedicines for on-demand drug delivery. Polym Chem 4:3431–3443CrossRefGoogle Scholar
  14. 14.
    Zhang Y, Qu Q, Li M, Zhao Y (2015) Intracellular reduction-responsive sheddable copolymer micelles for targeted anticancer drug delivery. Asian J Org Chem 4:226–232CrossRefGoogle Scholar
  15. 15.
    Zhu Y, Zhang J, Meng F, Deng C, Cheng R, Feijen J, Zhong Z (2016) cRGD-functionalized reduction-sensitive shell-sheddable biodegradable micelles mediate enhanced doxorubicin delivery to human glioma xenografts in vivo. J Control Release 233:29–38CrossRefGoogle Scholar
  16. 16.
    Chen M, Gao C, Lu S, Chen Y, Liu M (2016) Dual redox-triggered shell-sheddable micelles self-assembled from mPEGylated starch conjugates for rapid drug release. RSC Adv 6:9164–9174CrossRefGoogle Scholar
  17. 17.
    Zhang Y, Teh C, Li M, Ang CY, Tan SY, Qu Q, Korzh V, Zhao Y (2016) Acid-responsive polymeric doxorubicin prodrug nanoparticles encapsulating a near-infrared dye for combined photothermal-chemotherapy. Chem Mater 28:7039–7050CrossRefGoogle Scholar
  18. 18.
    Ga M, Sk C, Henry LJK, Natesan S, Kandasamy R (2017) Atrial natriuretic peptide-conjugated chitosan-hydrazone-mPEG copolymer nanoparticles as pH-responsive carriers for intracellular delivery of prednisone. Carbohydr Polym 157:1677–1686CrossRefGoogle Scholar
  19. 19.
    Wang H, He J, Zhang M, Tao Y, Li F, Tam KC, Ni P (2013) Biocompatible and acid-cleavable poly(ε-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(ε-caprolactone) triblock copolymers: synthesis, characterization and pH-triggered doxorubicin delivery. J Mater Chem B 1(48):6596–6607CrossRefGoogle Scholar
  20. 20.
    Wang L, Liu G, Wang X, Hu J, Zhang G, Liu S (2015) Acid-disintegratable polymersomes of pH-responsive amphiphilic diblock copolymers for intracellular drug delivery. Macromolecules 48:7262–7272CrossRefGoogle Scholar
  21. 21.
    Satoh K, Poelma JE, Campos LM, Stahl B, Hawker CJ (2012) A facile synthesis of clickable and acid-cleavable PEO for acid-degradable block copolymers. Polym Chem 3:1890–1898CrossRefGoogle Scholar
  22. 22.
    Qiu L, Zhu M, Gong K, Peng H, Ge L, Zhao L, Chen J (2017) pH-triggered degradable polymeric micelles for targeted anti-tumor drug delivery. Mater Sci Eng, C 78:912–922CrossRefGoogle Scholar
  23. 23.
    Hu L, Zhang P, Wang X, Cheng X, Qin J, Tang R (2017) pH-sensitive carboxymethyl chitosan hydrogels via acid-labile ortho ester linkage for potential biomedical applications. Carbohydr Polym 178:166–179CrossRefGoogle Scholar
  24. 24.
    Zhao Y (2012) Light-responsive block copolymer micelles. Macromolecules 45:3647–3657CrossRefGoogle Scholar
  25. 25.
    Xiao P, Zhang J, Zhao J, Stenzel MH (2017) Light-induced release of molecules from polymers. Prog Polym Sci 74:1–33CrossRefGoogle Scholar
  26. 26.
    Jiang J, Tong X, Zhao Y (2005) A new design for light-breakable polymer micelles. J Am Chem Soc 127:8290–8291CrossRefGoogle Scholar
  27. 27.
    Zhang Y, Ang CY, Li M, Tan SY, Qu Q, Luo Z, Zhao Y (2015) Polymer-coated hollow mesoporous silica nanoparticles for triple-responsive drug delivery. ACS Appl Mater Interfaces 7:18179–18187CrossRefGoogle Scholar
  28. 28.
    Gupta MK, Balikov DA, Lee Y, Ko E, Yu C, Chun YW, Sawyer DB, Kim WS, Sung H-J (2017) Gradient release of cardiac morphogens by photo-responsive polymer micelles for gradient-mediated variation of embryoid body differentiation. J Mater Chem B 5:5206–5217CrossRefGoogle Scholar
  29. 29.
    Fan W, Tong X, Yan Q, Fu S, Zhao Y (2014) Photodegradable and size-tunable single-chain nanoparticles prepared from a single main-chain coumarin-containing polymer precursor. Chem Commun 50:13492–13494CrossRefGoogle Scholar
  30. 30.
    Jin Q, Cai T, Han H, Wang H, Wang Y, Ji J (2014) Light and pH dual-degradable triblock copolymer micelles for controlled intracellular drug release. Macromol Rapid Commun 35:1372–1378CrossRefGoogle Scholar
  31. 31.
    Yang L, Lei M, Zhao M, Yang H, Zhang H, Li Y, Zhang K, Lei Z (2017) Synthesis of the light/pH responsive polymer for immobilization of α-amylase. Mater Sci Eng C 71:75–83CrossRefGoogle Scholar
  32. 32.
    Veccharelli KM, Tong VK, Young JL, Yang J, Gianneschi NC (2016) Dual responsive polymeric nanoparticles prepared by direct functionalization of polylactic acid-based polymers via graft-from ring opening metathesis polymerization. Chem Commun 52:567–570CrossRefGoogle Scholar
  33. 33.
    Meng L, Huang W, Wang D, Huang X, Zhu X, Yan D (2013) Chitosan-based nanocarriers with pH and light dual response for anticancer drug delivery. Biomacromolecules 14:2601–2610CrossRefGoogle Scholar
  34. 34.
    John JV, Uthaman S, Augustine R, Manickavasagam Lekshmi K, Park I-K, Kim I (2017) Biomimetic pH/redox dual stimuli-responsive zwitterionic polymer block poly(l-histidine) micelles for intracellular delivery of doxorubicin into tumor cells. J Polym Sci Part A Polym Chem 55:2061–2070CrossRefGoogle Scholar
  35. 35.
    Cheng R, Meng F, Deng C, Klok H-A, Zhong Z (2013) Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34:3647–3657CrossRefGoogle Scholar
  36. 36.
    He X, Liang F, Wang F, Zou L, Wang J, Tang C, Zhao K, Wei D (2018) Targeted delivery and thermo/pH-controlled release of doxorubicin by novel nanocapsules. J Mater Sci 53:2326–2336CrossRefGoogle Scholar
  37. 37.
    Petrova S, Jager E, Konefal R, Jager A, Venturini CG, Spevacek J, Pavlova E, Stepanek P (2014) Novel poly(ethylene oxide monomethyl ether)-b-poly(ε-caprolactone) diblock copolymers containing a pH-acid labile ketal group as a block linkage. Polym Chem 5:3884–3893CrossRefGoogle Scholar
  38. 38.
    Sun H, Guo B, Cheng R, Meng F, Liu H, Zhong Z (2009) Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin. Biomaterials 30:6358–6366CrossRefGoogle Scholar
  39. 39.
    Binder WH, Sachsenhofer R (2008) ‘Click’ chemistry in polymer and material science: an update. Macromol Rapid Commun 29:952–981CrossRefGoogle Scholar
  40. 40.
    Golas PL, Matyjaszewski K (2010) Marrying click chemistry with polymerization: expanding the scope of polymeric materials. Chem Soc Rev 39:1338–1354CrossRefGoogle Scholar
  41. 41.
    Schumers J-M, Gohy J-F, Fustin C-A (2010) A versatile strategy for the synthesis of block copolymers bearing a photocleavable junction. Polym Chem 1(2):161–163CrossRefGoogle Scholar
  42. 42.
    Yuan Y-Y, Wang Y-C, Du J-Z, Wang J (2008) Synthesis of amphiphilic ABC 3-miktoarm star terpolymer by combination of ring-opening polymerization and “click” chemistry. Macromolecules 41:8620–8625CrossRefGoogle Scholar
  43. 43.
    Cabane E, Malinova V, Meier W (2010) Synthesis of photocleavable amphiphilic block copolymers: toward the design of photosensitive nanocarriers. Macromol Chem Phys 211:1847–1856CrossRefGoogle Scholar
  44. 44.
    Bochet CG (2002) Photolabile protecting groups and linkers. J Chem Soc Perkin Trans 1(2):125–142Google Scholar
  45. 45.
    Hrubý M, Koňák Č, Ulbrich K (2005) Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J Control Release 103:137–148CrossRefGoogle Scholar
  46. 46.
    Wang D, Su Y, Jin C, Zhu B, Pang Y, Zhu L, Liu J, Tu C, Yan D, Zhu X (2011) Supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases for drug delivery. Biomacromolecules 12:1370–1379CrossRefGoogle Scholar
  47. 47.
    Gewirtz D (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of Function Control Technology for Advanced Materials, School of Chemical EngineeringHuaihai Institute of TechnologyLianyungangPeople’s Republic of China

Personalised recommendations