Co-delivery of Doxorubicin and Afatinib with pH-responsive Polymeric Nanovesicle for Enhanced Lung Cancer Therapy

  • Heng-Ye Gong
  • Yan-Gui Chen
  • Xing-Su Yu
  • Hong Xiao
  • Jin-Peng Xiao
  • Yong Wang
  • Xin-Tao ShuaiEmail author


Drug-resistance and drastic side effects are two major issues of traditional chemotherapy which may result in trail failure even death. Nanoparticle-mediated multidrug combination treatment has been proven to be a feasible strategy to overcome these challenges. In the present study, amphipathic block polymer of methoxyl poly(ethylene glycol)-poly(aspartyl(dibutylethylenediamine)-co-phenylalanine) (mPEG-P(Asp(DBA)-co-Phe)) was synthesized and self-assembled into pH-responsive polymeric vesicle. The vesicle was utilized to co-deliver cancer-associated epidermal growth factor (EGFR) inhibitor of afatinib and DNA-damaging chemotherapeutic doxorubicin hydrochloride (DOX) for enhanced non-small-cell lung cancer (NSCLC) therapy. As evaluated in vitro, the pH-responsive design of nanovesicle resulted in a rapid release of encapsulated drugs into tumor cells and caused enhanced cell apoptosis. In addition, in vivo therapeutic studies were conducted and the results evidenced that the co-delevery of DOX and afatinib using pH-sensitive nanovector was a promising strategy for NSCLC treatment.


Nanovesicle Polymeric vector Combination therapy pH-responsive 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was financially supported by the National Basic Research Program of China (No. 2015CB755500), the Natural Science Foundation of Guangdong Province (No. 2014A030312018), and Science and Technology Planning Project of Guangdong Province (No. 2016A020215088).


  1. 1.
    Bray, F.; Ferlay, J.; Soerjomataram I.; Siegel, R. L.; Torre, L. A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.CrossRefGoogle Scholar
  2. 2.
    Pesch, B. Cigarette smoking and lung cancerjrelative risk estimates for the major histological types from a pooled analysis of case—control studies. Int. J. Cancer. 2012, 131, 1210–1219.CrossRefGoogle Scholar
  3. 3.
    Lara, M. S.; Brunson, A.; Wun, T.; Tomlinson, B.; Qi, L.; Cress, R.; Gandara, D. R.; Kelly, K. Predictors of survival for younger patients less than 50 years of age with non-small cell lung cancer (NSCLC): A California cancer registry analysis. Lung Cancer 2014, 85, 264–269.CrossRefGoogle Scholar
  4. 4.
    Fennell, D. A.; Summers, Y.; Cadranel, J.; Benepal, T.; Christoph, D. C.; Lal, R.; Das, M.; Maxwell, F.; Visseren-Grul, C.; Ferry, D. Cisplatin in the modern era: The backbone of firstline chemotherapy for non-small cell lung cancer. Cancer Treat. Rev. 2016, 44, 42–50.CrossRefGoogle Scholar
  5. 5.
    Schuler, M.; Wu, Y. L.; Hirsh, V.; O’Byrne, K.; Yamamoto, N.; Mok, T.; Popat, S.; Sequist, L. V.; Massey, D.; Zazulina, V.; Yang, J. C. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J. Thorac. Oncol. 2016, 11, 380–390.CrossRefGoogle Scholar
  6. 6.
    Liang, J.; Chen, C.; Zhao, Y.; Wang, C.; Circumventing tumor resistance to chemotherapy by nanotechnology. in Multi-drug resistance in cancer. Humana Press, New York, 2000, p. 467–488.Google Scholar
  7. 7.
    Mok, T.; Wu, Y. L.; Lee, J. S.; Yu, C. J.; Sriuranpong, V.; Sandoval-Tan, J.; Ladrera, G.; Thongprasert, S.; Srimuninnimit, V.; Liao, M.; Zhu, Y.; Zhou, C.; Fuerte, F.; Margono, B.; Wen, W.; Tsai, J.; Truman, M.; Klughammer, B.; Shames, D. S.; Wu, L. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin. Cancer Res. 2015, 21, 3196–3203.CrossRefGoogle Scholar
  8. 8.
    Manegold, C.; Dingemans, A. C.; Gray, J. E.; Nakagawa, K.; Nicolson, M.; Peters, S.; Reck, M.; Wu, Y. L.; Brustugun, O. T.; Crinò, L.; Felip, E.; Fennell, D.; Garrido, P.; Huber, R. M.; Marabelle, A.; Moniuszko, M.; Mornex, F.; Novello, S.; Papotti, M.; Pérol, M.; Smit, E. F.; Syrigos, K.; van Meerbeeck, J. P.; van Zandwijk, N.; Chih-Hsin Yang, J.; Zhou, C.; Vokes, E. The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC. J. Thorac. Oncol. 2017, 12, 194–207.CrossRefGoogle Scholar
  9. 9.
    Liu, Y.; Qiao, L.; Zhang, S.; Wan, G.; Chen, B.; Zhou, P.; Zhang, N.; Wang, Y. Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy. Acta Biomater. 2018, 66, 310–324.CrossRefGoogle Scholar
  10. 10.
    Zhang, T.; Xiong, H.; Dahmani, F. Z.; Sun, L.; Li, Y.; Yao, L.; Zhou, J.; Yao, J. Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles. Nanotechnology 2015, 26, 145101.CrossRefGoogle Scholar
  11. 11.
    Kemp, J. “Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv. Drug Deliv. Rev. 2016, 98, 3–18.CrossRefGoogle Scholar
  12. 12.
    Geschwind, J. H.; Ko, Y. H.; Torbenson, M. S.; Magee, C.; Pedersen, P. L. Novel therapy for liver cancer: Direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res. 2012, 62, 3909–3913.Google Scholar
  13. 13.
    Maione, P. Overcoming resistance to targeted therapies in NSCLC: Current approaches and clinical application. Ther. Adv. Med. Oncol. 205, 7, 273.Google Scholar
  14. 14.
    Lee, M. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 2012, 149, 780–794.CrossRefGoogle Scholar
  15. 15.
    Iyer, A. K.; Singh, A.; Ganta, S.; Amiji, M. M. Role of integrated cancer nanomedicine in overcoming drug resistance. Adv. Drug Deliv. Rev. 2013, 65, 1784–1802.CrossRefGoogle Scholar
  16. 16.
    He, Y.; Su, Z.; Xue, L.; Xu, H.; Zhang, C. Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy. J. Control. Release 2016, 229, 80–92.CrossRefGoogle Scholar
  17. 17.
    Hu, C. J.; Zhang, L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem. Pharmacol. 2012, 83, 1104–1111.CrossRefGoogle Scholar
  18. 18.
    Li, J.; Li, Z.; Chu, D.; Jin, L.; Zhang, X. Fabrication and biocompatibility of core-shell structured magnetic fibrous scaffold. J. Biomed. Nanotechnol. 2019, 15, 500–6.CrossRefGoogle Scholar
  19. 19.
    Li, Z. Synthesis and characterization of pH-responsive copolypeptides vesicles for siRNA and chemotherapeutic drug co-delivery. Macromol. Biosci. 2015, 15, 1497–506.CrossRefGoogle Scholar
  20. 20.
    Xu, X.; Ho, W.; Zhang, X.; Bertrand, N.; Farokhzad, O. Cancer nanomedicine: From targeted delivery to combination therapy. Trends Mol. Med. 2015, 21, 223–232.CrossRefGoogle Scholar
  21. 21.
    Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387–6392.Google Scholar
  22. 22.
    Le, Z. Hydrogen-bonded tannic acid-based anticancer nanoparticle for enhancement of oral chemotherapy. ACS Appl. Mater. Interfaces 2018, 10, 42186–97.CrossRefGoogle Scholar
  23. 23.
    Abdelaziz, H. M.; Gaber, M.; Abd-Elwakil, M. M.; Mabrouk, M. T.; Elgohary, M. M.; Kamel, N. M.; Kabary, D. M.; Freag, M. S.; Samaha, M. W.; Mortada, S. M.; Elkhodairy, K. A.; Fang, J. Y.; Elzoghby, A. O. Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates. J. Control. Release 2017, 269, 374–392.CrossRefGoogle Scholar
  24. 24.
    Kamaly, N.; Yameen, B.; Wu, J.; Farokhzad, O. C. Degradable controlled-release polymers and polymeric nanoparticles: Mechanisms of controlling drug release. Chem. Rev. 2016, 116, 2602–2663.CrossRefGoogle Scholar
  25. 25.
    Liu, D. D.; Yang, F.; Xiong, F.; Gu, N. The smart drug delivery system and its clinical potential. Theranostics 2016, 6, 1306–1323.CrossRefGoogle Scholar
  26. 26.
    Wu, L.; Zou, Y.; Deng, C.; Cheng, R.; Meng, F.; Zhong, Z. Reduction and pH dual-sensitive core-crosslinked polypeptide micelles for triggered doxorubicin release. J. Control. Release 2013, 1, e49.CrossRefGoogle Scholar
  27. 27.
    Dai, J. Interlayer-crosslinked micelle with partially hydrated core showing reduction and pH dual sensitivity for pinpointed intracellular drug release. Angew. Chem. Int. Ed. 2011, 50, 9404–9408.CrossRefGoogle Scholar
  28. 28.
    Cai, L.; Xu, G.; Shi, C.; Guo, D.; Wang, X.; Luo, J. Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment. Biomaterials 2015, 37, 456–468.CrossRefGoogle Scholar
  29. 29.
    Cosco, D.; Paolino, D.; Maiuolo, J.; Marzio, L. D.; Carafa, M.; Ventura, C. A.; Fresta, M. Ultradeformable liposomes as multidrug carrier of resveratrol and 5-fluorouracil for their topical delivery. Int. J. Pharmaceut. 2015, 489, 1–10.CrossRefGoogle Scholar
  30. 30.
    Zhang, L. Co-delivery of doxorubicin and arsenite with reduction and pH dual-sensitive vesicle for synergistic cancer therapy. Nanoscale 2016, 8, 12608–12617.CrossRefGoogle Scholar
  31. 31.
    Iqbal, M. Double emulsion solvent evaporation techniques used for drug encapsulation. Int. J. Pharmaceut. 2015, 496, 173–190.CrossRefGoogle Scholar
  32. 32.
    Hideaki, N.; Fang, J.; Hiroshi, M. Dvelopment of next-generation macromolecular drugs based on the EPR effect: Challenges and pitfalls. Expert Opin. Drug Deliv. 2014, 12, 691.Google Scholar
  33. 33.
    Maurizio, P.; Ivano, B.; David, C.; Claudio, D.; Ernest, G.; Wolfgang, J.; James, T. L.; Homans, S. W.; Horst, K.; Claudio, L. Perspectives on NMR in drug discovery: A technique comes of age. Nat. Rev. Drug Discov. 2018, 7, 738.Google Scholar
  34. 34.
    Xiao, H.; He, J.; Li, X.; Li, B.; Zhang, L.; Wang, Y.; Cheng, D.; Shuai, X. Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer. J. Mater. Chem. B 2018, 6, 7521–7529.CrossRefGoogle Scholar
  35. 35.
    Sun, W. Co-delivery of doxorubicin and anti-BCL-2 siRNA by pH-responsive polymeric vector to overcome drug resistance in in vitro and in vivo HEPG2 hepatoma model. Biomacromolecules 2018, 19, 2248–2256.CrossRefGoogle Scholar

Copyright information

© Chinese Chemical Society Institute of Chemistry, Chinese Academy of Sciences Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Heng-Ye Gong
    • 1
  • Yan-Gui Chen
    • 1
  • Xing-Su Yu
    • 3
  • Hong Xiao
    • 1
  • Jin-Peng Xiao
    • 2
  • Yong Wang
    • 1
  • Xin-Tao Shuai
    • 1
    Email author
  1. 1.PCFM Lab of Ministry of Education, School of Materials Science and EngineeringSun Yat-Sen UniversityGuangzhouChina
  2. 2.HEC Pharma Co., Ltd.DongguanChina
  3. 3.Reproductive CenterGuangdong Women’s Health Care CenterGuangzhouChina

Personalised recommendations