Recent progress in nanomedicine for hepatocellular carcinoma therapy_Journal of Biomedical Engineering

Authors：

 XIONG Qingqing ^1,3 , WANG Jian ^2,3 , BAI Yang ^1,2 , SONG Tianqiang ^1,2

1. Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, P.R.China;
2. Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, P.R.China;
3. National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, P.R.China;

Corresponding author：

XIONG Qingqing, Email: xqqpumc@163.com

Keywords：

nanomedicine; hepatocellular carcinoma; targeting; combination therapy

DOI：

10.7507/1001-5515.201705008

Video：

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with insidious onset, insensitive to chemotherapy and poor prognosis, which make its clinical treatment face an enormous challenge. In recent years, with the rapid development of nanotechnology, increasing kinds of nanomedicine come to the forefront in biomedical fields. Through rational design, nanomedicine can be prepared in suitable size and modified with specific liver targeting ligands. Moreover, various therapeutic agents of different mechanisms can be co-loaded into the same nanosystem, thus achieving the synergistic therapeutic effects towards HCC. Nanomedicine is able to enhance drug bioavailability and liver-targeting effect as well as reduce the side effects to normal tissues, which provide a great potential in HCC therapy. This review summarizes the recent progress in the application of nanomedicine for HCC therapy from two aspects: their liver-targeting design strategies and the recent progress in combination therapy of HCC.

Citation： XIONG Qingqing, WANG Jian, BAI Yang, SONG Tianqiang. Recent progress in nanomedicine for hepatocellular carcinoma therapy. Journal of Biomedical Engineering, 2018, 35(2): 314-319. doi: 10.7507/1001-5515.201705008 Copy

1.	Yang Judong, Roberts L R. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol Hepatol, 2010, 7(8): 448-458.
2.	Galle P R, Tovoli F, Foerster F, et al. The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy. J Hepatol, 2017, 67(1): 173-183.
3.	Benson A B 3rd, D’Angelica M I, Abbott D E, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw, 2017, 15(5): 563-573.
4.	Llovet J M, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008, 359(4): 378-390.
5.	Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2015, 16(13): 1344-1354.
6.	Bouattour M, Soubrane O, de Gramont A, et al. Adjuvant therapies in advanced hepatocellular carcinoma: moving forward from the STORM. Trials, 2016, 17(1): 563.
7.	Dutta R, Mahato R I. Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther, 2017, 173: 106-117.
8.	Iyer A K, Khaled G, Fang Jun, et al. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today, 2006, 11(17/18): 812-818.
9.	Dai Yunlu, Xu Can, Sun Xiaolian, et al. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem Soc Rev, 2017, 46(12): 3830-3852.
10.	Zhang Jing, Wang Tianqi, Mu Shengjun, et al. Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy. Nanomedicine (Lond), 2017, 12(8): 911-925.
11.	Liu Minchen, Liu Lin, Wang Xiarong, et al. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo. Int J Nanomedicine, 2016, 11: 1395-1412.
12.	Zhang Jinming, Zhang Min, Ji Juan, et al. Glycyrrhetinic acid-mediated polymeric drug delivery targeting the acidic microenvironment of hepatocellular carcinoma. Pharm Res, 2015, 32(10): 3376-3390.
13.	Tsend-Ayush A, Zhu Xiumei, Ding Yu, et al. Lactobionic acid-conjugated TPGS nanoparticles for enhancing therapeutic efficacy of etoposide against hepatocellular carcinoma. Nanotechnology, 2017, 28(19): 195602.
14.	Zhang Cong, An Tong, Wang Dan, et al. Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(beta-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma. J Control Release, 2016, 226: 193-204.
15.	Xiong Qingqing, Cui Mangmang, Bai Yang, et al. A supramolecular nanoparticle system based on β-cyclodextrin-conjugated poly-l-lysine and hyaluronic acid for co-delivery of gene and chemotherapy agent targeting hepatocellular carcinoma. Colloids Surf B Biointerfaces, 2017, 155: 93-103.
16.	Wang J, Wang Hangxiang, Li Jie, et al. iRGD-decorated polymeric nanoparticles for the efficient delivery of vandetanib to hepatocellular carcinoma: preparation and in vitro and in vivo evaluation. ACS Appl Mater Interfaces, 2016, 8(30): 19228-19237.
17.	Li Yanli, Hu Yan, Xiao Jie, et al. Investigation of SP94 peptide as a specific probe for hepatocellular carcinoma imaging and therapy. Sci Rep, 2016, 6: 33511.
18.	Gao Jie, Xia Yu, Chen Huaiwen, et al. Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma. Nanomedicine (Lond), 2014, 9(2): 279-293.
19.	Zhang Xiaoran, Li Jinxiu, Yan Meixing. Targeted hepatocellular carcinoma therapy: transferrin modified, self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin. Drug Dev Ind Pharm, 2016, 42(10): 1590-1599.
20.	Liu Lanxia, Dong Xia, Zhu Dunwan, et al. TAT-LHRH conjugated low molecular weight chitosan as a gene carrier specific for hepatocellular carcinoma cells. Int J Nanomedicine, 2014, 9: 2879-2889.
21.	Liu Zhongbing, Ke Famin, Duan Chenggang, et al. Mannan-conjugated adenovirus enhanced gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. Bioconjug Chem, 2013, 24(8): 1387-1397.
22.	Jiang Jianxin, Chen Huaiwen, Yu Chao, et al. The promotion of salinomycin delivery to hepatocellular carcinoma cells through EGFR and CD133 aptamers conjugation by PLGA nanoparticles. Nanomedicine (Lond), 2015, 10(12): 1863-1879.
23.	Chen Chen, Ke Jiyuan, Zhou X E, et al. Structural basis for molecular recognition of folic acid by folate receptors. Nature, 2013, 500(7463): 486-489.
24.	Cai Yuee, Xu Yingqi, Chan H F, et al. Glycyrrhetinic acid mediated drug delivery carriers for hepatocellular carcinoma therapy. Mol Pharm, 2016, 13(3): 699-709.
25.	Shi Bin, Abrams M, Sepp-Lorenzino L. Expression of asialoglycoprotein receptor 1 in human hepatocellular carcinoma. J Histochem Cytochem, 2013, 61(12): 901-909.
26.	Pranatharthiharan S, Patel M D, Malshe V C, et al. Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma. Drug Deliv, 2017, 24(1): 20-29.
27.	Oishi N, Yamashita T, Kaneko S. Molecular biology of liver cancer stem cells. Liver Cancer, 2014, 3(2): 71-84.
28.	Marelli U K, Rechenmacher F, Sobahi T R, et al. Tumor targeting via integrin ligands. Front Oncol, 2013, 3: 222.
29.	Yin Hong, Yang Jie, Zhang Qing, et al. iRGD as a tumor—penetrating peptide for cancer therapy (Review). Mol Med Rep, 2017, 15(5): 2925-2930.
30.	Lo A, Lin C T, Wu H C. Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery. Mol Cancer Ther, 2008, 7(3): 579-589.
31.	Liu Xiaomin, Wang Ping, Zhang Caiyan, et al. Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget, 2017, 8(30): 50209-50220.
32.	Fan Gaowei, Zhang Kuo, Ding Jiansheng, et al. Prognostic value of EGFR and KRAS in circulating tumor DNA in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget, 2017, 8(20): 33922-33932.
33.	Berasain C, Avila M A. The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis. J Gastroenterol, 2014, 49(1): 9-23.
34.	Tortorella S, Karagiannis T C. Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J Membr Biol, 2014, 247(4): 291-307.
35.	Sun Hongguang, Zu Youli. Aptamers and their applications in nanomedicine. Small, 2015, 11(20): 2352-2364.
36.	Sun Duanping, Lu Jing, Zhong Yuwen, et al. Sensitive electrochemical aptamer cytosensor for highly specific detection of cancer cells based on the hybrid nanoelectrocatalysts and enzyme for signal amplification. Biosens Bioelectron, 2016, 75: 301-307.
37.	Trinh T L, Zhu Guizhi, Xiao Xilin, et al. A synthetic aptamer-drug adduct for targeted liver cancer therapy. PLoS One, 2015, 10(11): e0136673.
38.	Wang Fubing, Rong Yuan, Fang Min, et al. Recognition and capture of metastatic hepatocellular carcinoma cells using aptamer-conjugated quantum dots and magnetic particles. Biomaterials, 2013, 34(15): 3816-3827.
39.	Hu Quanyin, Sun Wujin, Wang Chao, et al. Recent advances of cocktail chemotherapy by combination drug delivery systems. Adv Drug Deliv Rev, 2016, 98: 19-34.
40.	Richly H, Schultheis B, Adamietz I A, et al. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase Ⅰ extension trial. Eur J Cancer, 2009, 45(4): 579-587.
41.	Zhang Jinming, Hu Jie, Chan H F, et al. iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy. Nanomedicine, 2016, 12(5): 1303-1311.
42.	Taketomi A. Clinical trials of antiangiogenic therapy for hepatocellular carcinoma. Int J Clin Oncol, 2016, 21(2): 213-218.
43.	Chang Huiju. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma. World J Hepatol, 2015, 7(16): 2029-2040.
44.	Wang Yinsong, Chen Hongli, Liu Yuanyuan, et al. pH-sensitive pullulan-based nanoparticle carrier of methotrexate and combretastatin A4 for the combination therapy against hepatocellular carcinoma. Biomaterials, 2013, 34(29): 7181-7190.
45.	Xu Zhenghong, Zhang Zhiwen, Chen Yi, et al. The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model. Biomaterials, 2010, 31(5): 916-922.
46.	Gao Jie, Chen Huaiwen, Yu Yongsheng, et al. Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials, 2013, 34(38): 10084-10098.
47.	Oh H R, Jo H Y, Park J S, et al. Galactosylated liposomes for targeted co-delivery of doxorubicin/vimentin siRNA to hepatocellular carcinoma[J]. Nanomaterials (Basel), 2016, 6(8): E141.
48.	Hayes C N, Chayama K. MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. Int J Mol Sci, 2016, 17(3): 280.
49.	Yang Ningning, Ekanem N R, Sakyi C A, et al. Hepatocellular carcinoma and microRNA: New perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev, 2015, 81: 62-74.
50.	George J, Patel T. Noncoding RNA as therapeutic targets for hepatocellular carcinoma. Semin Liver Dis, 2015, 35(1): 63-74.
51.	Xu Fei, Liao Jiazhi, Xiang Guangya, et al. MiR-101 and doxorubicin codelivered by liposomes suppressing malignant properties of hepatocellular carcinoma. Cancer Med, 2017, 6(3): 651-661.
52.	Peng Juanjuan, Zhao Lingzhi, Zhu Xingjun, et al. Hollow silica nanoparticles loaded with hydrophobic phthalocyanine for near-infrared photodynamic and photothermal combination therapy. Biomaterials, 2013, 34(32): 7905-7912.
53.	Wu Lingjie, Wu Ming, Zeng Yongyi, et al. Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment. Nanotechnology, 2015, 26(2): 025102.
54.	Zhang Da, Zheng Aixian, Li Juan, et al. Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma. Theranostics, 2017, 7(1): 164-179.
55.	Jin G, Feng Guangxue, Qin Wei, et al. Multifunctional organic nanoparticles with aggregation-induced emission (AIE) characteristics for targeted photodynamic therapy and RNA interference therapy. Chem Commun (Camb), 2016, 52(13): 2752-2755.
56.	Lin Min, Gao Yan, Hornicek F, et al. Near-infrared light activated delivery platform for cancer therapy. Adv Colloid Interface Sci, 2015, 226(Pt B): 123-137.

1. Yang Judong, Roberts L R. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol Hepatol, 2010, 7(8): 448-458.
2. Galle P R, Tovoli F, Foerster F, et al. The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy. J Hepatol, 2017, 67(1): 173-183.
3. Benson A B 3rd, D’Angelica M I, Abbott D E, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Canc Netw, 2017, 15(5): 563-573.
4. Llovet J M, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008, 359(4): 378-390.
5. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2015, 16(13): 1344-1354.
6. Bouattour M, Soubrane O, de Gramont A, et al. Adjuvant therapies in advanced hepatocellular carcinoma: moving forward from the STORM. Trials, 2016, 17(1): 563.
7. Dutta R, Mahato R I. Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther, 2017, 173: 106-117.
8. Iyer A K, Khaled G, Fang Jun, et al. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today, 2006, 11(17/18): 812-818.
9. Dai Yunlu, Xu Can, Sun Xiaolian, et al. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem Soc Rev, 2017, 46(12): 3830-3852.
10. Zhang Jing, Wang Tianqi, Mu Shengjun, et al. Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy. Nanomedicine (Lond), 2017, 12(8): 911-925.
11. Liu Minchen, Liu Lin, Wang Xiarong, et al. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo. Int J Nanomedicine, 2016, 11: 1395-1412.
12. Zhang Jinming, Zhang Min, Ji Juan, et al. Glycyrrhetinic acid-mediated polymeric drug delivery targeting the acidic microenvironment of hepatocellular carcinoma. Pharm Res, 2015, 32(10): 3376-3390.
13. Tsend-Ayush A, Zhu Xiumei, Ding Yu, et al. Lactobionic acid-conjugated TPGS nanoparticles for enhancing therapeutic efficacy of etoposide against hepatocellular carcinoma. Nanotechnology, 2017, 28(19): 195602.
14. Zhang Cong, An Tong, Wang Dan, et al. Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(beta-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma. J Control Release, 2016, 226: 193-204.
15. Xiong Qingqing, Cui Mangmang, Bai Yang, et al. A supramolecular nanoparticle system based on β-cyclodextrin-conjugated poly-l-lysine and hyaluronic acid for co-delivery of gene and chemotherapy agent targeting hepatocellular carcinoma. Colloids Surf B Biointerfaces, 2017, 155: 93-103.
16. Wang J, Wang Hangxiang, Li Jie, et al. iRGD-decorated polymeric nanoparticles for the efficient delivery of vandetanib to hepatocellular carcinoma: preparation and in vitro and in vivo evaluation. ACS Appl Mater Interfaces, 2016, 8(30): 19228-19237.
17. Li Yanli, Hu Yan, Xiao Jie, et al. Investigation of SP94 peptide as a specific probe for hepatocellular carcinoma imaging and therapy. Sci Rep, 2016, 6: 33511.
18. Gao Jie, Xia Yu, Chen Huaiwen, et al. Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma. Nanomedicine (Lond), 2014, 9(2): 279-293.
19. Zhang Xiaoran, Li Jinxiu, Yan Meixing. Targeted hepatocellular carcinoma therapy: transferrin modified, self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin. Drug Dev Ind Pharm, 2016, 42(10): 1590-1599.
20. Liu Lanxia, Dong Xia, Zhu Dunwan, et al. TAT-LHRH conjugated low molecular weight chitosan as a gene carrier specific for hepatocellular carcinoma cells. Int J Nanomedicine, 2014, 9: 2879-2889.
21. Liu Zhongbing, Ke Famin, Duan Chenggang, et al. Mannan-conjugated adenovirus enhanced gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. Bioconjug Chem, 2013, 24(8): 1387-1397.
22. Jiang Jianxin, Chen Huaiwen, Yu Chao, et al. The promotion of salinomycin delivery to hepatocellular carcinoma cells through EGFR and CD133 aptamers conjugation by PLGA nanoparticles. Nanomedicine (Lond), 2015, 10(12): 1863-1879.
23. Chen Chen, Ke Jiyuan, Zhou X E, et al. Structural basis for molecular recognition of folic acid by folate receptors. Nature, 2013, 500(7463): 486-489.
24. Cai Yuee, Xu Yingqi, Chan H F, et al. Glycyrrhetinic acid mediated drug delivery carriers for hepatocellular carcinoma therapy. Mol Pharm, 2016, 13(3): 699-709.
25. Shi Bin, Abrams M, Sepp-Lorenzino L. Expression of asialoglycoprotein receptor 1 in human hepatocellular carcinoma. J Histochem Cytochem, 2013, 61(12): 901-909.
26. Pranatharthiharan S, Patel M D, Malshe V C, et al. Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma. Drug Deliv, 2017, 24(1): 20-29.
27. Oishi N, Yamashita T, Kaneko S. Molecular biology of liver cancer stem cells. Liver Cancer, 2014, 3(2): 71-84.
28. Marelli U K, Rechenmacher F, Sobahi T R, et al. Tumor targeting via integrin ligands. Front Oncol, 2013, 3: 222.
29. Yin Hong, Yang Jie, Zhang Qing, et al. iRGD as a tumor—penetrating peptide for cancer therapy (Review). Mol Med Rep, 2017, 15(5): 2925-2930.
30. Lo A, Lin C T, Wu H C. Hepatocellular carcinoma cell-specific peptide ligand for targeted drug delivery. Mol Cancer Ther, 2008, 7(3): 579-589.
31. Liu Xiaomin, Wang Ping, Zhang Caiyan, et al. Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget, 2017, 8(30): 50209-50220.
32. Fan Gaowei, Zhang Kuo, Ding Jiansheng, et al. Prognostic value of EGFR and KRAS in circulating tumor DNA in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget, 2017, 8(20): 33922-33932.
33. Berasain C, Avila M A. The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis. J Gastroenterol, 2014, 49(1): 9-23.
34. Tortorella S, Karagiannis T C. Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J Membr Biol, 2014, 247(4): 291-307.
35. Sun Hongguang, Zu Youli. Aptamers and their applications in nanomedicine. Small, 2015, 11(20): 2352-2364.
36. Sun Duanping, Lu Jing, Zhong Yuwen, et al. Sensitive electrochemical aptamer cytosensor for highly specific detection of cancer cells based on the hybrid nanoelectrocatalysts and enzyme for signal amplification. Biosens Bioelectron, 2016, 75: 301-307.
37. Trinh T L, Zhu Guizhi, Xiao Xilin, et al. A synthetic aptamer-drug adduct for targeted liver cancer therapy. PLoS One, 2015, 10(11): e0136673.
38. Wang Fubing, Rong Yuan, Fang Min, et al. Recognition and capture of metastatic hepatocellular carcinoma cells using aptamer-conjugated quantum dots and magnetic particles. Biomaterials, 2013, 34(15): 3816-3827.
39. Hu Quanyin, Sun Wujin, Wang Chao, et al. Recent advances of cocktail chemotherapy by combination drug delivery systems. Adv Drug Deliv Rev, 2016, 98: 19-34.
40. Richly H, Schultheis B, Adamietz I A, et al. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase Ⅰ extension trial. Eur J Cancer, 2009, 45(4): 579-587.
41. Zhang Jinming, Hu Jie, Chan H F, et al. iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy. Nanomedicine, 2016, 12(5): 1303-1311.
42. Taketomi A. Clinical trials of antiangiogenic therapy for hepatocellular carcinoma. Int J Clin Oncol, 2016, 21(2): 213-218.
43. Chang Huiju. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma. World J Hepatol, 2015, 7(16): 2029-2040.
44. Wang Yinsong, Chen Hongli, Liu Yuanyuan, et al. pH-sensitive pullulan-based nanoparticle carrier of methotrexate and combretastatin A4 for the combination therapy against hepatocellular carcinoma. Biomaterials, 2013, 34(29): 7181-7190.
45. Xu Zhenghong, Zhang Zhiwen, Chen Yi, et al. The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model. Biomaterials, 2010, 31(5): 916-922.
46. Gao Jie, Chen Huaiwen, Yu Yongsheng, et al. Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials, 2013, 34(38): 10084-10098.
47. Oh H R, Jo H Y, Park J S, et al. Galactosylated liposomes for targeted co-delivery of doxorubicin/vimentin siRNA to hepatocellular carcinoma[J]. Nanomaterials (Basel), 2016, 6(8): E141.
48. Hayes C N, Chayama K. MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. Int J Mol Sci, 2016, 17(3): 280.
49. Yang Ningning, Ekanem N R, Sakyi C A, et al. Hepatocellular carcinoma and microRNA: New perspectives on therapeutics and diagnostics. Adv Drug Deliv Rev, 2015, 81: 62-74.
50. George J, Patel T. Noncoding RNA as therapeutic targets for hepatocellular carcinoma. Semin Liver Dis, 2015, 35(1): 63-74.
51. Xu Fei, Liao Jiazhi, Xiang Guangya, et al. MiR-101 and doxorubicin codelivered by liposomes suppressing malignant properties of hepatocellular carcinoma. Cancer Med, 2017, 6(3): 651-661.
52. Peng Juanjuan, Zhao Lingzhi, Zhu Xingjun, et al. Hollow silica nanoparticles loaded with hydrophobic phthalocyanine for near-infrared photodynamic and photothermal combination therapy. Biomaterials, 2013, 34(32): 7905-7912.
53. Wu Lingjie, Wu Ming, Zeng Yongyi, et al. Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment. Nanotechnology, 2015, 26(2): 025102.
54. Zhang Da, Zheng Aixian, Li Juan, et al. Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma. Theranostics, 2017, 7(1): 164-179.
55. Jin G, Feng Guangxue, Qin Wei, et al. Multifunctional organic nanoparticles with aggregation-induced emission (AIE) characteristics for targeted photodynamic therapy and RNA interference therapy. Chem Commun (Camb), 2016, 52(13): 2752-2755.
56. Lin Min, Gao Yan, Hornicek F, et al. Near-infrared light activated delivery platform for cancer therapy. Adv Colloid Interface Sci, 2015, 226(Pt B): 123-137.

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