Citation: Heng-Ye Gong, Yan-Gui Chen, Xing-Su Yu, Hong Xiao, Jin-Peng Xiao, Yong Wang, Xin-Tao Shuai. Co-delivery of Doxorubicin and Afatinib with pH-responsive Polymeric Nanovesicle for Enhanced Lung Cancer Therapy[J]. Chinese Journal of Polymer Science, ;2019, 37(12): 1224-1233. doi: 10.1007/s10118-019-2272-6 shu

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

a.
PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, China
b.
HEC Pharma Co., Ltd., Dongguan 523871, China
c.
Reproductive Center, Guangdong Women's Health Care Center, Guangzhou 511400, China

Corresponding author: Xin-Tao Shuai, shuaixt@mail.sysu.edu.cn
Received Date: 17 March 2019
Revised Date: 3 April 2019
Available Online: 4 June 2019

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
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. doi: 10.3322/caac.v68.6
2. [2]
  Pesch, B.; Kendzia, B.; Gustavsson, P.; Jöckel, K. H.; Johnen, G.; Pohlabeln, H.; Olsson, A.; Ahrens, W.; Gross, I. M.; Brüske, I.; Wichmann, H. E.; Merletti, F.; Richiardi, L.; Simonato, L.; Fortes, C.; Siemiatycki, J.; Parent, M. E.; Consonni, D.; Landi, M. T.; Caporaso, N.; Zaridze, D.; Cassidy, A.; Szeszenia-Dabrowska, N.; Rudnai, P.; Lissowska, J.; Stücker, I.; Fabianova, E.; Dumitru, R. S.; Bencko, V.; Foretova, L.; Janout, V.; Rudin, C. M.; Brennan, P.; Boffetta, P.; Straif, K.; Brüning, T. Cigarette smoking and lung cancer—relative risk estimates for the major histological types from a pooled analysis of case–control studies. Int. J. Cancer. 2012, 131, 1210-1219. doi: 10.1002/ijc.v131.5
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 doi: 10.1016/j.lungcan.2014.04.007
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 first-line chemotherapy for non-small cell lung cancer. Cancer Treat. Rev. 2016,44, 42-50. doi: 10.1016/j.ctrv.2016.01.003
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. doi: 10.1016/j.jtho.2015.11.014
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, 2010, p. 467−488.
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. doi: 10.1158/1078-0432.CCR-14-2594
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. doi: 10.1016/j.jtho.2016.10.003
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. doi: 10.1016/j.actbio.2017.11.010
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. doi: 10.1088/0957-4484/26/14/145101
11. [11]
  Kemp, J. A.; Shim, M. S.; Heo, C. Y.; Kwon, Y. J.; "Combo" nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv. Drug Deliv. Rev. 2016, 98, 3-18. doi: 10.1016/j.addr.2015.10.019
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.
13. [13]
  Maione, P.; Sacco, P. C.; Sgambato, A.; Casaluce, F.; Rossi, A.; Gridelli, C.; 2015 Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application. Ther. Adv. Med. Oncol. 2015, 7, 263-273.
14. [14]
  Lee, M.; Ye, A.; Gardino, A.; Heijink, A. M.; Sorger, P.; Macbeath, G.; Yaffe, M.; Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 2012, 149, 780-794. doi: 10.1016/j.cell.2012.03.031
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. doi: 10.1016/j.addr.2013.07.012
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. doi: 10.1016/j.jconrel.2016.03.001
17. [17]
  Hu, C. J.; Zhang, L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem. Pharmacol. 2012, 83, 1104-1111. doi: 10.1016/j.bcp.2012.01.008
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
19. [19]
  Li, Z., Li, J., Huang, J., Zhang, J., Cheng, D. and Shuai, X. Synthesis and characterization of pHʜresponsive copolypeptides vesicles for sirna and chemotherapeutic drug coʜdelivery Macromol. Biosci. 2015, 15 1497-506
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. doi: 10.1016/j.molmed.2015.01.001
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.
22. [22]
  Le Z.; Chen Y.; Han H.; Tian H.; Zhao P.; Yang C.; He Z.; Liu L.; Leong K. W.; Mao H.; Hydrogen-bonded tannic acid-based anticancer nanoparticle for enhancement of oral chemotherapy. ACS Appl. Mater. Interfaces 2018, 10, 42186-97. doi: 10.1021/acsami.8b18979
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.
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. doi: 10.1021/acs.chemrev.5b00346
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.
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.
27. [27]
  Dai, J.; Lin, S.; Cheng, D.; Zou, S.; Xin, S.; 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. doi: 10.1002/anie.v50.40
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. doi: 10.1016/j.biomaterials.2014.10.044
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. doi: 10.1016/j.ijpharm.2015.04.056
30. [30]
  Zhang, L.; Xiao, H.; Li, J.; Cheng, D.; Shuai, X.; Co-delivery of doxorubicin and arsenite with reduction and pH dual-sensitive vesicle for synergistic cancer therapy. Nanoscale 2016, 8, 12608-12617. doi: 10.1039/C5NR07868G
31. [31]
  Iqbal, M.; Zafar, N.; Fessi, H.; Elaissari, A.; Double emulsion solvent evaporation techniques used for drug encapsulation. Int. J. Pharmaceut. 2015, 496, 173-190. doi: 10.1016/j.ijpharm.2015.10.057
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.
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.
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. doi: 10.1039/C8TB01829D
35. [35]
  Sun, W.; Chen, X.; Xie, C.; Wang, Y; Lin, L.; Zhu, K.; Shuai, X. 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. doi: 10.1021/acs.biomac.8b00272
1. [1]
  Tingting Hu , Chao Shen , Xueyan Wang , Fengbo Wu , Zhiyao He . Tumor microenvironment-sensitive polymeric nanoparticles for synergetic chemo-photo therapy. Chinese Chemical Letters, 2024, 35(11): 109562-. doi: 10.1016/j.cclet.2024.109562
2. [2]
  Jianye Kang , Xinyu Yang , Xuhao Yang , Jiahui Sun , Yuhang Liu , Shutao Wang , Wenlong Song . Carbon dots-enhanced pH-responsive lubricating hydrogel based on reversible dynamic covalent bondings. Chinese Chemical Letters, 2024, 35(5): 109297-. doi: 10.1016/j.cclet.2023.109297
3. [3]
  Yan Liu , Yang Wang , Jiayi Zhu , Xuxian Su , Xudong Lin , Liang Xu , Xiwen Xing . Employing pH-responsive RNA triplex to control CRISPR/Cas9-mediated gene manipulation in mammalian cells. Chinese Chemical Letters, 2024, 35(9): 109427-. doi: 10.1016/j.cclet.2023.109427
4. [4]
  Jiaxu Wang , Jinxie Zhang , Xiuping Wang , Jingying Wang , Lina Chen , Jiahui Cao , Wei Cao , Siyu Liang , Ping Luan , Ke Zheng , Xiao-Kun Ouyang , Li Gao , Xiaowen Ou , Fan Zhang , Meitong Ou , Lin Mei . CaCO₃-coated hollow mesoporous silica nanoparticles for pH-responsive fungicides release. Chinese Chemical Letters, 2024, 35(12): 109697-. doi: 10.1016/j.cclet.2024.109697
5. [5]
  Ningyue Xu , Jun Wang , Lei Liu , Changyang Gong . Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy: A review of recent advances. Chinese Chemical Letters, 2024, 35(8): 109225-. doi: 10.1016/j.cclet.2023.109225
6. [6]
  Hao Sun , Shengke Li , Qian Liu , Minzan Zuo , Xueqi Tian , Kaiya Wang , Xiao-Yu Hu . Supramolecular prodrug vesicles for selective antimicrobial therapy employing a chemo-photodynamic strategy. Chinese Chemical Letters, 2025, 36(3): 109999-. doi: 10.1016/j.cclet.2024.109999
7. [7]
  Jiayin Zhou , Depeng Liu , Longqiang Li , Min Qi , Guangqiang Yin , Tao Chen . Responsive organic room-temperature phosphorescence materials for spatial-time-resolved anti-counterfeiting. Chinese Chemical Letters, 2024, 35(11): 109929-. doi: 10.1016/j.cclet.2024.109929
8. [8]
  Yunjie Dang , Yanru Feng , Xiao Chen , Chaoxing He , Shujie Wei , Dingyang Liu , Jinlong Qi , Huaxing Zhang , Shaokun Yang , Zhiyun Niu , Bai Xiang . Development of a multi-level pH-responsive lipid nanoplatform for efficient co-delivery of siRNA and small-molecule drugs in tumor treatment. Chinese Chemical Letters, 2024, 35(12): 109660-. doi: 10.1016/j.cclet.2024.109660
9. [9]
  Shuheng Zhang , Yuanyuan Zhang , Wanyu Wang , Yuzhu Hu , Xinchuan Chen , Bilan Wang , Xiang Gao . A combination strategy of DOX and VEGFR-2 targeted inhibitor based on nanomicelle for enhancing lymphoma therapy. Chinese Chemical Letters, 2024, 35(12): 109658-. doi: 10.1016/j.cclet.2024.109658
10. [10]
  Yu Qin , Mingyang Huang , Chenlu Huang , Hannah L. Perry , Linhua Zhang , Dunwan Zhu . O₂-generating multifunctional polymeric micelles for highly efficient and selective photodynamic-photothermal therapy in melanoma. Chinese Chemical Letters, 2024, 35(7): 109171-. doi: 10.1016/j.cclet.2023.109171
11. [11]
  Yiran Tao , Chunlei Dai , Zhaoxiang Xie , Xinru You , Kaiwen Li , Jun Wu , Hai Huang . Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer. Chinese Chemical Letters, 2024, 35(8): 109170-. doi: 10.1016/j.cclet.2023.109170
12. [12]
  Shuang Liang , Jianjun Yao , Dan Liu , Mengli Zhou , Yong Cui , Zhaohui Wang . Tumor-responsive covalent organic polymeric nanoparticles enhancing STING activation for cancer immunotherapy. Chinese Chemical Letters, 2025, 36(3): 109856-. doi: 10.1016/j.cclet.2024.109856
13. [13]
  Di ZHANG , Tianxiang XIE , Xu HE , Wanyu WEI , Qi FAN , Jie QIAO , Gang JIN , Ningbo LI . Construction and antitumor activity of pH/GSH dual-responsive magnetic nanodrug. Chinese Journal of Inorganic Chemistry, 2025, 41(4): 786-796. doi: 10.11862/CJIC.20240329
14. [14]
  Rui Wang , He Qi , Haijiao Zheng , Qiong Jia . Light/pH dual-responsive magnetic metal-organic frameworks composites for phosphorylated peptide enrichment. Chinese Chemical Letters, 2024, 35(7): 109215-. doi: 10.1016/j.cclet.2023.109215
15. [15]
  Ling-Ling Wu , Xiangchuan Meng , Qingyang Zhang , Xiaowan Han , Feiya Yang , Qinghua Wang , Hai-Yu Hu , Nianzeng Xing . Heavy-atom engineered hypoxia-responsive probes for precisive photoacoustic imaging and cancer therapy. Chinese Chemical Letters, 2024, 35(4): 108663-. doi: 10.1016/j.cclet.2023.108663
16. [16]
  Jinyu Guo , Yandai Lin , Shaohua He , Yueqing Chen , Fenglu Li , Renjie Ruan , Gaoxing Pan , Hexin Nan , Jibin Song , Jin Zhang . Utilizing dual-responsive iridium(Ⅲ) complex for hepatocellular carcinoma: Integrating photoacoustic imaging with chemotherapy and photodynamic therapy. Chinese Chemical Letters, 2024, 35(9): 109537-. doi: 10.1016/j.cclet.2024.109537
17. [17]
  Ze Wang , Hao Liang , Annan Liu , Xingchen Li , Lin Guan , Lei Li , Liang He , Andrew K. Whittaker , Bai Yang , Quan Lin . Strength through unity: Alkaline phosphatase-responsive AIEgen nanoprobe for aggregation-enhanced multi-mode imaging and photothermal therapy of metastatic prostate cancer. Chinese Chemical Letters, 2025, 36(2): 109765-. doi: 10.1016/j.cclet.2024.109765
18. [18]
  Yue Pan , Wenping Si , Yahao Li , Haotian Tan , Ji Liang , Feng Hou . Promoting exciton dissociation by metal ion modification in polymeric carbon nitride for photocatalysis. Chinese Chemical Letters, 2024, 35(12): 109877-. doi: 10.1016/j.cclet.2024.109877
19. [19]
  Ziruo Zhou , Wenyu Guo , Tingyu Yang , Dandan Zheng , Yuanxing Fang , Xiahui Lin , Yidong Hou , Guigang Zhang , Sibo Wang . Defect and nanostructure engineering of polymeric carbon nitride for visible-light-driven CO2 reduction. Chinese Journal of Structural Chemistry, 2024, 43(3): 100245-100245. doi: 10.1016/j.cjsc.2024.100245
20. [20]
  Xue Zheng , Jizhen Xie , Xing Zhang , Weiting Sun , Heyang Zhao , Yantuan Li , Cheng Wang . Corrigendum to "An overview of polymeric nanomicelles in clinical trials and on the market" [Chinese Chemical Letters 32 (2021) 243-257]. Chinese Chemical Letters, 2025, 36(2): 110545-. doi: 10.1016/j.cclet.2024.110545

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(736)
HTML views(4)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142