Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer

Sachin      Kumar; Faizana      Fayaz; Faheem   Hyder   Pottoo; Sakshi      Bajaj; Satish      Manchanda; Himangini      Bansal
Abstract

Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines’ profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.
Keywords: Nanoparticles, Hepatocellular carcinoma, Phytochemicals, Curcumin, Quercetin, Epigallocatechin-3-gallate, Berberine, Apigenin, Triptolide, Resveratrol.
Graphical Abstract

[1] 
IARC; Cancer today., 2020.Available from:  . https://gco.iarc.fr/today/online-analysis-pie (Accessed on Feb 22,
2020)
[2] 
Wang, C.H.; Wey, K.C.; Mo, L.R.; Chang, K.K.; Lin, R.C.; Kuo, J.J. Current trends and recent advances in diagnosis, therapy, and prevention of hepatocellular carcinoma. Asian Pac. J. Cancer Prev.,  2015, 16(9), 3595-3604.
[http://dx.doi.org/10.7314/APJCP.2015.16.9.3595] [PMID:  25987009] 
[3] 
Sia, D.; Villanueva, A.; Friedman, S.L.; Llovet, J.M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology,  2017, 152(4), 745-761.
[http://dx.doi.org/10.1053/j.gastro.2016.11.048] [PMID:  28043904] 
[4] 
Zhou, Y.; Li, Y.; Zhou, T.; Zheng, J.; Li, S.; Li, H.B. Bin. Dietary natural products for prevention and treatment of liver cancer. Nutrients,  2016, 8(3), 156.
[http://dx.doi.org/10.3390/nu8030156] [PMID:  26978396] 
[5] 
Soerjomataram, I.; Oomen, D.; Lemmens, V.; Oenema, A.; Benetou, V.; Trichopoulou, A.; Coebergh, J.W.; Barendregt, J.; de Vries, E. Increased consumption of fruit and vegetables and future cancer incidence in selected European countries. Eur. J. Cancer,  2010, 46(14), 2563-2580.
[http://dx.doi.org/10.1016/j.ejca.2010.07.026] [PMID:  20843486] 
[6] 
Turati, F.; Rossi, M.; Pelucchi, C.; Levi, F.; La Vecchia, C. Fruit
and vegetables and cancer risk: a review of southern European
studies. Br. J. Nutr., ,  2015, 113(S2 Suppl. 2), S102-S110..
[http://dx.doi.org/10.1017/S0007114515000148] [PMID: 26148912] 
[7] 
Takke, A.; Shende, P. Nanotherapeutic silibinin: An insight of phytomedicine in healthcare reformation. Nanomedicine (Lond.),  2019, 21, 102057
[http://dx.doi.org/10.1016/j.nano.2019.102057] [PMID:  31340181] 
[8] 
Patel, A.; Khan, F.A.; Sikdar, A.; Mondal, A.; Shukla, S.D.; Khurana, S. Test for non-synergistic interactions in phytomedicine, just as you do for isolated compounds. J. Exp. Neurosci.,  2018, 12, 1179069518767654
[http://dx.doi.org/10.1177/1179069518767654] [PMID:  29706766] 
[9] 
Khan, H.; Ullah, H.; Nabavi, S.M. Mechanistic insights of hepatoprotective effects of curcumin: Therapeutic updates and future prospects. Food Chem. Toxicol.,  2019, 124, 182-191.
[http://dx.doi.org/10.1016/j.fct.2018.12.002] [PMID:  30529260] 
[10] 
Reyes-Farias, M.; Carrasco-Pozo, C. The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int. J. Mol. Sci.,  2019, 20(13), 1-19.
[http://dx.doi.org/10.3390/ijms20133177] [PMID:  31261749] 
[11] 
Salehi, B.; Venditti, A.; Sharifi-Rad, M.; Kręgiel, D.; Sharifi-Rad, J.; Durazzo, A.; Lucarini, M.; Santini, A.; Souto, E.B.; Novellino, E.; Antolak, H.; Azzini, E.; Setzer, W.N.; Martins, N. The therapeutic potential of Apigenin. Int. J. Mol. Sci.,  2019, 20(6), E1305
[http://dx.doi.org/10.3390/ijms20061305] [PMID:  30875872] 
[12] 
Yang, Y.M.; Kim, S.Y.K.; Seki, E. Inflammation and liver cancer: molecular mechanisms and therapeutic targets. Semin. Liver Dis.,  2019, 39(1), 26-42.
[http://dx.doi.org/10.1055/s-0038-1676806] [PMID:  30809789] 
[13] 
Shafabakhsh, R.; Pourhanifeh, M.H.; Mirzaei, H.R.; Sahebkar, A.; Asemi, Z.; Mirzaei, H. Targeting regulatory T cells by curcumin: A potential for cancer immunotherapy. Pharmacol. Res.,  2019, 147(April), 104353
[http://dx.doi.org/10.1016/j.phrs.2019.104353] [PMID:  31306775] 
[14] 
Salminen, A.; Kaarniranta, K.; Kauppinen, A. Phytochemicals inhibit the immunosuppressive functions of myeloid-derived suppressor cells (MDSC): Impact on cancer and age-related chronic inflammatory disorders. Int. Immunopharmacol.,  2018, 61, 231-240.
[http://dx.doi.org/10.1016/j.intimp.2018.06.005] [PMID:  29894862] 
[15] 
Ma, Z; Xia, Y; Hu, C; Yu, M; Yi, H. Quercetin promotes the
survival of granulocytic myeloid-derived suppressor cells via the
ESR2/STAT3 signaling pathway. Biomed Pharmacother.,,  2020, 125(2019), 109922..
[http://dx.doi.org/10.1016/j.biopha.2020.109922] 
[16] 
Ghițu, A.; Schwiebs, A.; Radeke, H.H.; Avram, S.; Zupko, I.; Bor, A.; Pavel, I.Z.; Dehelean, C.A.; Oprean, C.; Bojin, F.; Farcas, C.; Soica, C.; Duicu, O.; Danciu, C. A comprehensive assessment of apigenin as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. Nutrients,  2019, 11(4), E858
[http://dx.doi.org/10.3390/nu11040858] [PMID:  30995771] 
[17] 
Wei, Q.Y.; He, K.M.; Chen, J.L.; Xu, Y.M.; Lau, A.T.Y. Phytofabrication of nanoparticles as novel drugs for anticancer applications. Molecules,  2019, 24(23), E4246
[http://dx.doi.org/10.3390/molecules24234246] [PMID:  31766544] 
[18] 
Shao, D.; Li, J.; Zheng, X.; Pan, Y.; Wang, Z.; Zhang, M.; Chen, Q.X.; Dong, W.F.; Chen, L. Janus “nano-bullets” for magnetic targeting liver cancer chemotherapy. Biomaterials,  2016, 100, 118-133.
[http://dx.doi.org/10.1016/j.biomaterials.2016.05.030] [PMID:  27258482] 
[19] 
Tang, P.; Sun, Q.; Yang, H.; Tang, B.; Pu, H.; Li, H. Honokiol nanoparticles based on epigallocatechin gallate functionalized chitin to enhance therapeutic effects against liver cancer. Int. J. Pharm.,  2018, 545(1-2), 74-83.
[http://dx.doi.org/10.1016/j.ijpharm.2018.04.060] [PMID:  29715531] 
[20] 
Zan, Y.; Dai, Z.; Liang, L.; Deng, Y.; Dong, L. Co-delivery of plantamajoside and sorafenib by a multi-functional nanoparticle to combat the drug resistance of hepatocellular carcinoma through reprograming the tumor hypoxic microenvironment. Drug Deliv.,  2019, 26(1), 1080-1091.
[http://dx.doi.org/10.1080/10717544.2019.1654040] [PMID:  31735093] 
[21] 
Harshita; Barkat, MA; Rizwanullah, M. Paclitaxel-loaded nanolipidic carriers with improved oral bioavailability and anticancer activity against human liver carcinoma. AAPS PharmSciTech,  2019, 20(2), 87.
[22] 
Barkat, M.A.; Beg, S.; Pottoo, F.H.; Ahmad, F.J. Nanopaclitaxel therapy: an evidence based review on the battle for next-generation formulation challenges. Nanomedicine (Lond.),  2019, 14(10), 1323-1341.
[http://dx.doi.org/10.2217/nnm-2018-0313] [PMID:  31124758] 
[23] 
Navya, P.N.; Kaphle, A.; Srinivas, S.P.; Bhargava, S.K.; Rotello, V.M.; Daima, H.K. Current trends and challenges in cancer management and therapy using designer nanomaterials. Nano Converg.,  2019, 6(1), 23.
[http://dx.doi.org/10.1186/s40580-019-0193-2] [PMID:  31304563] 
[24] 
Turato, C.; Balasso, A.; Carloni, V.; Tiribelli, C.; Mastrotto, F.; Mazzocca, A.; Pontisso, P. New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma. J. Control. Release,  2017, 268, 184-197.
[http://dx.doi.org/10.1016/j.jconrel.2017.10.027] [PMID:  29051062] 
[25] 
Duan, X.; Li, Y. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small,  2013, 9(9-10), 1521-1532.
[http://dx.doi.org/10.1002/smll.201201390] [PMID:  23019091] 
[26] 
Sharma, S.; Javed, M.N.; Pottoo, F.H.; Rabbani, S.A.; Barkat, M.A. Harshita; Sarafroz, M.; Amir, M. Bioresponse inspired nanomaterials for targeted drug and gene delivery. Pharm. Nanotechnol.,  2019, 7(3), 220-233.
[http://dx.doi.org/10.2174/2211738507666190429103814] [PMID:  31486751] 
[27] 
Mishra, S.; Sharma, S.; Javed, M.N.; Pottoo, F.H.; Barkat, M.A. Harshita; Alam, M.S.; Amir, M.; Sarafroz, M. Bioinspired nanocomposites: applications in disease diagnosis and treatment. Pharm. Nanotechnol.,  2019, 7(3), 206-219.
[http://dx.doi.org/10.2174/2211738507666190425121509] [PMID:  31030662] 
[28] 
Rawal, S.; Patel, M.M. Threatening cancer with nanoparticle aided combination oncotherapy. J. Control. Release,  2019, 301(March), 76-109.
[http://dx.doi.org/10.1016/j.jconrel.2019.03.015] [PMID:  30890445] 
[29] 
Rahman, M.; Akhter, S.; Ahmad, M.Z.; Ahmad, J.; Addo, R.T.; Ahmad, F.J.; Pichon, C. Emerging advances in cancer nanotheranostics with graphene nanocomposites: opportunities and challenges. Nanomedicine (Lond.),  2015, 10(15), 2405-2422.
[http://dx.doi.org/10.2217/nnm.15.68] [PMID:  26252175] 
[30] 
Kumar, V.; Bhatt, P.C.; Rahman, M.; Kaithwas, G.; Choudhry, H.; Al-Abbasi, F.A.; Anwar, F.; Verma, A. Fabrication, optimization, and characterization of umbelliferone β-D-galactopyranoside-loaded PLGA nanoparticles in treatment of hepatocellular carcinoma: in vitro and in vivo studies. Int. J. Nanomedicine,  2017, 12, 6747-6758.
[http://dx.doi.org/10.2147/IJN.S136629] [PMID:  28932118] 
[31] 
Pandey, P.; Rahman, M.; Bhatt, P.C.; Beg, S.; Paul, B.; Hafeez, A.; Al-Abbasi, F.A.; Nadeem, M.S.; Baothman, O.; Anwar, F.; Kumar, V. Implication of nano-antioxidant therapy for treatment of hepatocellular carcinoma using PLGA nanoparticles of rutin. Nanomedicine (Lond.),  2018, 13(8), 849-870.
[http://dx.doi.org/10.2217/nnm-2017-0306] [PMID:  29565220] 
[32] 
Rahman, M.; Al-Ghamdi, S.A.; Alharbi, K.S.; Beg, S.; Sharma, K.; Anwar, F.; Al-Abbasi, F.A.; Kumar, V. Ganoderic acid loaded nano-lipidic carriers improvise treatment of hepatocellular carcinoma. Drug Deliv.,  2019, 26(1), 782-793.
[http://dx.doi.org/10.1080/10717544.2019.1606865] [PMID:  31357897] 
[33] 
Akhter, S.; Ahmad, Z.; Singh, A.; Ahmad, I.; Rahman, M.; Anwar, M.; Jain, G.K.; Ahmad, F.J.; Khar, R.K. Cancer targeted metallic nanoparticle: targeting overview, recent advancement and toxicity concern. Curr. Pharm. Des.,  2011, 17(18), 1834-1850.
[http://dx.doi.org/10.2174/138161211796391001] [PMID:  21568874] 
[34] 
Beg, S.; Rahman, M.; Jain, A.; Saini, S.; Midoux, P.; Pichon, C.; Ahmad, F.J.; Akhter, S. Nanoporous metal organic frameworks as hybrid polymer-metal composites for drug delivery and biomedical applications. Drug Discov. Today,  2017, 22(4), 625-637.
[http://dx.doi.org/10.1016/j.drudis.2016.10.001] [PMID:  27742533] 
[35] 
Ahmad, N.; Ahmad, R.; Alam, M.A.; Ahmad, F.J.; Amir, M.; Pottoo, F.H.; Sarafroz, M.; Jafar, M.; Umar, K. Daunorubicin oral bioavailability enhancement by surface coated natural biodegradable macromolecule chitosan based polymeric nanoparticles. Int. J. Biol. Macromol.,  2019, 128(11), 825-838.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.01.142] [PMID:  30690115] 
[36] 
Pottoo, F.H.; Javed, M.N.; Rahman, J.U.; Abu-Izneid, T.; Khan, F.A. Targeted delivery of miRNA based therapeuticals in the clinical management of Glioblastoma Multiforme. Semin. Cancer Biol.,  In Press
[PMID:  32302695] [http://dx.doi.org/10.1016/j.semcancer.2020.04.001] 
[37] 
Ansari, M.A.; Badrealam, K.F.; Alam, A.; Tufail, S.; Khalique, G.; Equbal, M.J.; Alzohairy, M.A.; Almatroudi, A.; Alomary, M.N.; Pottoo, F.H. Recent nano-based therapeutic intervention of bioactive sesquiterpenes: prospects in cancer therapeutics. Curr. Pharm. Des.,  2020, 26(11), 1138-1144.
[http://dx.doi.org/10.2174/1381612826666200116151522] [PMID:  31951164] 
[38] 
Harshita; Barkat, M.A.; Das, S.S.; Pottoo, F.H.; Beg, S.; Rahman, Z. Lipid-based nanosystem as intelligent carriers for versatile drug delivery applications. Curr. Pharm. Des.,  2020, 26(11), 1167-1180.
[http://dx.doi.org/10.2174/1381612826666200206094529] [PMID:  32026769] 
[39] 
Ansari, M.A.; Chung, I-M.; Rajakumar, G.; Alzohairy, M.A.; Alomary, M.N.; Thiruvengadam, M.; Pottoo, F.H.; Ahmad, N. Current nanoparticle approaches in nose to brain drug delivery and anticancer therapy - A review. Curr. Pharm. Des.,  2020, 26(11), 1128-1137.
[http://dx.doi.org/10.2174/1381612826666200116153912] [PMID:  31951165] 
[40] 
Pottoo, F.H.; Sharma, S.; Javed, M.N.; Barkat, M.A. Harshita; Alam, M.S.; Naim, M.J.; Alam, O.; Ansari, M.A.; Barreto, G.E.; Ashraf, G.M. Lipid-based nanoformulations in the treatment of neurological disorders. Drug Metab. Rev.,  2020, 52(1), 185-204.
[http://dx.doi.org/10.1080/03602532.2020.1726942] [PMID:  32116044] 
[41] 
Judson, I.; Radford, J.A.; Harris, M.; Blay, J.Y.; van Hoesel, Q.; le Cesne, A.; van Oosterom, A.T.; Clemons, M.J.; Kamby, C.; Hermans, C.; Whittaker, J.; Donato di Paola, E.; Verweij, J.; Nielsen, S. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur. J. Cancer,  2001, 37(7), 870-877.
[http://dx.doi.org/10.1016/S0959-8049(01)00050-8] [PMID:  11313175] 
[42] 
Xiao, K.; Suby, N.; Li, Y.; Lam, K.S. Telodendrimer-based nanocarriers for the treatment of ovarian cancer. Ther. Deliv.,  2013, 4(10), 1279-1292.
[http://dx.doi.org/10.4155/tde.13.91] [PMID:  24116912] 
[43] 
Sahoo, S.K.; Labhasetwar, V. Nanotech approaches to drug delivery and imaging. Drug Discov. Today,  2003, 8(24), 1112-1120.
[http://dx.doi.org/10.1016/S1359-6446(03)02903-9] [PMID:  14678737] 
[44] 
Liu, Z.; Winters, M.; Holodniy, M.; Dai, H. siRNA delivery into human T cells and primary cells with carbon-nanotube transporters. Angew. Chem. Int. Ed. Engl.,  2007, 46(12), 2023-2027.
[http://dx.doi.org/10.1002/anie.200604295] [PMID:  17290476] 
[45] 
De Souza, R.; Zahedi, P.; Allen, C.J.; Piquette-Miller, M. Polymeric drug delivery systems for localized cancer chemotherapy. Drug Deliv.,  2010, 17(6), 365-375.
[http://dx.doi.org/10.3109/10717541003762854] [PMID:  20429844] 
[46] 
Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-based nanoparticles: an overview of biomedical applications. J. Control. Release,  2012, 161(2), 505-522.
[http://dx.doi.org/10.1016/j.jconrel.2012.01.043] [PMID:  22353619] 
[47] 
Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev.,  2011, 63(3), 136-151.
[http://dx.doi.org/10.1016/j.addr.2010.04.009] [PMID:  20441782] 
[48] 
Yurkovetskiy, A.V.; Fram, R.J. XMT-1001, a novel polymeric camptothecin pro-drug in clinical development for patients with advanced cancer. Adv. Drug Deliv. Rev.,  2009, 61(13), 1193-1202.
[http://dx.doi.org/10.1016/j.addr.2009.01.007] [PMID:  19682517] 
[49] 
Shuhendler, A.J.; Cheung, R.Y.; Manias, J.; Connor, A.; Rauth, A.M.; Wu, X.Y. A novel doxorubicin-mitomycin C co-encapsulated nanoparticle formulation exhibits anti-cancer synergy in multidrug resistant human breast cancer cells. Breast Cancer Res. Treat.,  2010, 119(2), 255-269.
[http://dx.doi.org/10.1007/s10549-008-0271-3] [PMID:  19221875] 
[50] 
Rawal, S.U. Patel, MM Lipid nanoparticulate systems.  In: Lipid Nanocarriers for Drug Targeting; Elsevier Inc.: Amsterdam, 2018, pp. 49-138.
[http://dx.doi.org/10.1016/B978-0-12-813687-4.00002-5] 
[51] 
Chen, W.; Xiao, Z.; Zhao, Y.; Huang, L.; Du, G. HIF-1α inhibition sensitizes pituitary adenoma cells to temozolomide by regulating MGMT expression. Oncol. Rep.,  2013, 30(5), 2495-2501.
[http://dx.doi.org/10.3892/or.2013.2689] [PMID:  23970362] 
[52] 
Tejashri, G.; Amrita, B.; Darshana, J. Cyclodextrin based nanosponges for pharmaceutical use: a review. Acta Pharm.,  2013, 63(3), 335-358.
[http://dx.doi.org/10.2478/acph-2013-0021] [PMID:  24152895] 
[53] 
Lagoa, R.; Silva, J.; Rodrigues, J.R.; Bishayee, A. Advances in phytochemical delivery systems for improved anticancer activity. Biotechnol. Adv.,  2020, 38, 107382
[http://dx.doi.org/10.1016/j.biotechadv.2019.04.004] [PMID:  30978386] 
[54] 
Abu Lila, A.S.; Ishida, T. Liposomal delivery systems: Design optimization and current applications. Biol. Pharm. Bull.,  2017, 40(1), 1-10.
[http://dx.doi.org/10.1248/bpb.b16-00624] [PMID:  28049940] 
[55] 
Otto, D.P.; de Villiers, M.M. Poly(amidoamine) dendrimers as a pharmaceutical excipient. are we there yet? J. Pharm. Sci.,  2018, 107(1), 75-83.
[http://dx.doi.org/10.1016/j.xphs.2017.10.011] [PMID:  29045886] 
[56] 
Chauhan, A.S. Dendrimers for drug delivery. Molecules,  2018, 23(4), E938
[http://dx.doi.org/10.3390/molecules23040938] [PMID:  29670005] 
[57] 
Cagel, M.; Tesan, F.C.; Bernabeu, E.; Salgueiro, M.J.; Zubillaga, M.B.; Moretton, M.A.; Chiappetta, D.A. Polymeric mixed micelles as nanomedicines: Achievements and perspectives. Eur. J. Pharm. Biopharm.,  2017, 113(113), 211-228.
[http://dx.doi.org/10.1016/j.ejpb.2016.12.019] [PMID:  28087380] 
[58] 
Harik, V.M. Geometry of carbon nanotubes and mechanisms of phagocytosis and toxic effects. Toxicol. Lett.,  2017, 273, 69-85.
[http://dx.doi.org/10.1016/j.toxlet.2017.03.016] [PMID:  28341208] 
[59] 
Mahajan, S.; Patharkar, A.; Kuche, K.; Maheshwari, R.; Deb, P.K.; Kalia, K.; Tekade, R.K. Functionalized carbon nanotubes as emerging delivery system for the treatment of cancer. Int. J. Pharm.,  2018, 548(1), 540-558.
[http://dx.doi.org/10.1016/j.ijpharm.2018.07.027] [PMID:  29997043] 
[60] 
Silva, C.O.; Pinho, J.O.; Lopes, J.M.; Almeida, A.J.; Gaspar, M.M.; Reis, C. Current trends in cancer nanotheranostics: Metallic, polymeric, and lipid-based systems. Pharmaceutics,  2019, 11(1), E22
[http://dx.doi.org/10.3390/pharmaceutics11010022] [PMID:  30625999] 
[61] 
Ahlawat, J.; Henriquez, G.; Narayan, M. Enhancing the delivery of chemotherapeutics: Role of biodegradable polymeric nanoparticles. Molecules,  2018, 23(9), 1-20.
[http://dx.doi.org/10.3390/molecules23092157] [PMID:  30150595] 
[62] 
Ekladious, I.; Colson, Y.L.; Grinstaff, M.W. Polymer-drug conjugate therapeutics: advances, insights and prospects. Nat. Rev. Drug Discov.,  2019, 18(4), 273-294.
[http://dx.doi.org/10.1038/s41573-018-0005-0] [PMID:  30542076] 
[63] 
Bose, R.J.C.; Ravikumar, R.; Karuppagounder, V.; Bennet, D.; Rangasamy, S.; Thandavarayan, R.A. Lipid-polymer hybrid nanoparticle-mediated therapeutics delivery: advances and challenges. Drug Discov. Today,  2017, 22(8), 1258-126.
[http://dx.doi.org/10.1016/j.drudis.2017.05.015] [PMID:  28600191] 
[64] 
Banerjee, S.; Pillai, J. Solid lipid matrix mediated nanoarchitectonics for improved oral bioavailability of drugs. Expert Opin. Drug Metab. Toxicol.,  2019, 15(6), 499-515.
[http://dx.doi.org/10.1080/17425255.2019.1621289] [PMID:  31104522] 
[65] 
Ganesan, P.; Ramalingam, P.; Karthivashan, G.; Ko, Y.T.; Choi, D.K. Recent developments in solid lipid nanoparticle and surface-modified solid lipid nanoparticle delivery systems for oral delivery of phyto-bioactive compounds in various chronic diseases. Int. J. Nanomedicine,  2018, 13, 1569-1583.
[http://dx.doi.org/10.2147/IJN.S155593] [PMID:  29588585] 
[66] 
Bayda, S.; Hadla, M.; Palazzolo, S.; Riello, P.; Corona, G.; Toffoli, G.; Rizzolio, F. Inorganic nanoparticles for cancer therapy: a transition from lab to clinic. Curr. Med. Chem.,  2018, 25(34), 4269-4303.
[http://dx.doi.org/10.2174/0929867325666171229141156] [PMID:  29284391] 
[67] 
Adeoye, O.; Cabral-Marques, H. Cyclodextrin nanosystems in oral drug delivery: A mini review. Int. J. Pharm.,  2017, 531(2), 521-531.
[http://dx.doi.org/10.1016/j.ijpharm.2017.04.050] [PMID:  28455134] 
[68] 
Sherje, A.P.; Dravyakar, B.R.; Kadam, D.; Jadhav, M. Cyclodextrin-based nanosponges: A critical review. Carbohydr. Polym.,  2017, 173(1), 37-49.
[http://dx.doi.org/10.1016/j.carbpol.2017.05.086] [PMID:  28732878] 
[69] 
Aggarwal, B.B.; Sundaram, C.; Malani, N.; Ichikawa, H. Curcumin: the Indian solid gold. Adv. Exp. Med. Biol.,  2007, 595, 1-75.
[http://dx.doi.org/10.1007/978-0-387-46401-5_1] [PMID:  17569205] 
[70] 
Duvoix, A.; Blasius, R.; Delhalle, S.; Schnekenburger, M.; Morceau, F.; Henry, E.; Dicato, M.; Diederich, M. Chemopreventive and therapeutic effects of curcumin. Cancer Lett.,  2005, 223(2), 181-190.
[http://dx.doi.org/10.1016/j.canlet.2004.09.041] [PMID:  15896452] 
[71] 
Wilken, R.; Veena, M.S.; Wang, M.B.; Srivatsan, E.S. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer,  2011, 10(1), 12.
[http://dx.doi.org/10.1186/1476-4598-10-12] [PMID:  21299897] 
[72] 
Devasena, T.; Rajasekaran, K.N.; Gunasekaran, G.; Viswanathan, P.; Menon, V.P. Anticarcinogenic effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione a curcumin analog on DMH-induced colon cancer model. Pharmacol. Res.,  2003, 47(2), 133-140.
[http://dx.doi.org/10.1016/S1043-6618(02)00283-9] [PMID:  12543061] 
[73] 
Inano, H.; Onoda, M.; Inafuku, N.; Kubota, M.; Kamada, Y.; Osawa, T.; Kobayashi, H.; Wakabayashi, K. Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with γ-rays. Carcinogenesis,  1999, 20(6), 1011-1018.
[http://dx.doi.org/10.1093/carcin/20.6.1011] [PMID:  10357781] 
[74] 
Li, N.; Chen, X.; Liao, J.; Yang, G.; Wang, S.; Josephson, Y.; Han, C.; Chen, J.; Huang, M.T.; Yang, C.S. Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin. Carcinogenesis,  2002, 23(8), 1307-1313.
[http://dx.doi.org/10.1093/carcin/23.8.1307] [PMID:  12151348] 
[75] 
Chuang, S.E.; Kuo, M.L.; Hsu, C.H.; Chen, C.R.; Lin, J.K.; Lai, G.M.; Hsieh, C.Y.; Cheng, A.L. Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis,  2000, 21(2), 331-335.
[http://dx.doi.org/10.1093/carcin/21.2.331] [PMID:  10657978] 
[76] 
S. Darvesh A B. Aggarwal B. Bishayee A. Curcumin and liver cancer: A review. Curr. Pharm. Biotechnol.,  2011, 13(1), 218-228.
[77] 
Sharma, R.A.; McLelland, H.R.; Hill, K.A.; Ireson, C.R.; Euden, S.A.; Manson, M.M.; Pirmohamed, M.; Marnett, L.J.; Gescher, A.J.; Steward, W.P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res.,  2001, 7(7), 1894-1900.
[PMID:  11448902] 
[78] 
Sharma, R.A.; Euden, S.A.; Platton, S.L.; Cooke, D.N.; Shafayat, A.; Hewitt, H.R.; Marczylo, T.H.; Morgan, B.; Hemingway, D.; Plummer, S.M.; Pirmohamed, M.; Gescher, A.J.; Steward, W.P. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res.,  2004, 10(20), 6847-6854.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0744] [PMID:  15501961] 
[79] 
Garcea, G.; Jones, D.J.L.; Singh, R.; Dennison, A.R.; Farmer, P.B.; Sharma, R.A.; Steward, W.P.; Gescher, A.J.; Berry, D.P. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br. J. Cancer,  2004, 90(5), 1011-1015.
[http://dx.doi.org/10.1038/sj.bjc.6601623] [PMID:  14997198] 
[80] 
Lao, C.D.; Ruffin, M.T., IV; Normolle, D.; Heath, D.D.; Murray, S.I.; Bailey, J.M.; Boggs, M.E.; Crowell, J.; Rock, C.L.; Brenner, D.E. Dose escalation of a curcuminoid formulation. BMC Complement. Altern. Med.,  2006, 6, 10.
[http://dx.doi.org/10.1186/1472-6882-6-10] [PMID:  16545122] 
[81] 
Mohanty, C.; Das, M.; Sahoo, S.K. Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin. Expert Opin. Drug Deliv.,  2012, 9(11), 1347-1364.
[http://dx.doi.org/10.1517/17425247.2012.724676] [PMID:  22971222] 
[82] 
Bisht, S.; Feldmann, G.; Soni, S.; Ravi, R.; Karikar, C.; Maitra, A.; Maitra, A. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J. Nanobiotechnology,  2007, 5, 3.
[http://dx.doi.org/10.1186/1477-3155-5-3] [PMID:  17439648] 
[83] 
Bortel, N.; Armeanu-Ebinger, S.; Schmid, E.; Kirchner, B.; Frank, J.; Kocher, A.; Schiborr, C.; Warmann, S.; Fuchs, J.; Ellerkamp, V. Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways. Oncotarget,  2015, 6(38), 40680-40691.
[http://dx.doi.org/10.18632/oncotarget.5673] [PMID:  26515460] 
[84] 
Farazuddin, M.; Dua, B.; Zia, Q.; Khan, A.A.; Joshi, B.; Owais, M. Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals. Int. J. Nanomedicine,  2014, 9(1), 1139-1152.
[PMID:  24627632] 
[85] 
Wu, T.H.; Yen, F.L.; Lin, L.T.; Tsai, T.R.; Lin, C.C.; Cham, T.M. Preparation, physicochemical characterization, and antioxidant effects of quercetin nanoparticles. Int. J. Pharm.,  2008, 346(1-2), 160-168.
[http://dx.doi.org/10.1016/j.ijpharm.2007.06.036] [PMID:  17689897] 
[86] 
Lichota, A.; Gwozdzinski, L.; Gwozdzinski, K. Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency. Eur. J. Med. Chem.,  2019, 176, 68-91.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.075] [PMID:  31096120] 
[87] 
Shafabakhsh, R.; Asemi, Z. Quercetin: a natural compound for ovarian cancer treatment. J. Ovarian Res.,  2019, 12(1), 55.
[http://dx.doi.org/10.1186/s13048-019-0530-4] [PMID:  31202269] 
[88] 
Kumar, S.; Barua, C.C.; Das, S. Evaluation of anti-inflammatory activity of alternanthera brasiliana leaves. Int. J. Pharma. Bio. Sci.,  2014, 5(1), 33-41.
[89] 
Bae, J.H.; Kim, J.Y.; Kim, M.J.; Chang, S.H.; Park, Y.S.; Son, C.H.; Park, S.J.; Chung, J.S.; Lee, E.Y.; Kim, S.H.; Kang, C.D. Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. J. Immunother.,  2010, 33(4), 391-401.
[http://dx.doi.org/10.1097/CJI.0b013e3181d32f22] [PMID:  20386467] 
[90] 
Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr.,  2006, 136(11), 2715-2721.
[http://dx.doi.org/10.1093/jn/136.11.2715] [PMID:  17056790] 
[91] 
Shi, M.; Wang, F.S.; Wu, Z.Z. Synergetic anticancer effect of combined quercetin and recombinant adenoviral vector expressing human wild-type p53, GM-CSF and B7-1 genes on hepatocellular carcinoma cells in vitro. World J. Gastroenterol.,  2003, 9(1), 73-78.
[http://dx.doi.org/10.3748/wjg.v9.i1.73] [PMID:  12508355] 
[92] 
Brito, A.F.; Ribeiro, M.; Abrantes, A.M.; Mamede, A.C.; Laranjo, M.; Casalta-Lopes, J.E.; Gonçalves, A.C.; Sarmento-Ribeiro, A.B.; Tralhão, J.G.; Botelho, M.F. New approach for treatment of primary liver tumors: The role of quercetin. Nutr. Cancer,  2016, 68(2), 250-266.
[http://dx.doi.org/10.1080/01635581.2016.1145245] [PMID:  26943884] 
[93] 
Granado-Serrano, A.B.; Angeles Martín, M.; Bravo, L.; Goya, L.; Ramos, S. Time-course regulation of quercetin on cell survival/proliferation pathways in human hepatoma cells. Mol. Nutr. Food Res.,  2008, 52(4), 457-464.
[http://dx.doi.org/10.1002/mnfr.200700203] [PMID:  18324708] 
[94] 
Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin modulates NF-κ B and AP-1/JNK pathways to induce cell death in human hepatoma cells. Nutr. Cancer,  2010, 62(3), 390-401.
[http://dx.doi.org/10.1080/01635580903441196] [PMID:  20358477] 
[95] 
Dai, W.; Gao, Q.; Qiu, J.; Yuan, J.; Wu, G.; Shen, G. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. Tumour Biol.,  2016, 37(5), 6307-6313.
[http://dx.doi.org/10.1007/s13277-015-4501-0] [PMID:  26628295] 
[96] 
Kim, J.Y.; Kim, E.H.; Park, S.S.; Lim, J.H.; Kwon, T.K.; Choi, K.S. Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation. J. Cell. Biochem.,  2008, 105(6), 1386-1398.
[http://dx.doi.org/10.1002/jcb.21958] [PMID:  18980244] 
[97] 
Igbe, I.; Shen, X.F.; Jiao, W.; Qiang, Z.; Deng, T.; Li, S.; Liu, W.L.; Liu, H.W.; Zhang, G.L.; Wang, F. Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase. Oncotarget,  2017, 8(69), 113734-113748.
[http://dx.doi.org/10.18632/oncotarget.22556] [PMID:  29371942] 
[98] 
Chen, Z.; Huang, C.; Ma, T.; Jiang, L.; Tang, L.; Shi, T.; Zhang, S.; Zhang, L.; Zhu, P.; Li, J.; Shen, A. Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. Phytomedicine,  2018, 43(43), 37-45.  [Internet]. 
[http://dx.doi.org/10.1016/j.phymed.2018.03.040] [PMID:  29747752] 
[99] 
Gugler, R.; Leschik, M.; Dengler, H.J. Disposition of quercetin in man after single oral and intravenous doses. Eur. J. Clin. Pharmacol.,  1975, 9(2-3), 229-234.
[http://dx.doi.org/10.1007/BF00614022] [PMID:  1233267] 
[100] 
Ader, P.; Wessmann, A.; Wolffram, S. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic. Biol. Med.,  2000, 28(7), 1056-1067.
[http://dx.doi.org/10.1016/S0891-5849(00)00195-7] [PMID:  10832067] 
[101] 
Hollman, P.C.H.; van Trijp, J.M.P.; Mengelers, M.J.B.; de Vries, J.H.M.; Katan, M.B. Bioavailability of the dietary antioxidant flavonol quercetin in man. Cancer Lett.,  1997, 114(1-2), 139-140.
[http://dx.doi.org/10.1016/S0304-3835(97)04644-2] [PMID:  9103273] 
[102] 
Ferry, D.R.; Smith, A.; Malkhandi, J.; Fyfe, D.W.; deTakats, P.G.; Anderson, D.; Baker, J.; Kerr, D.J. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res.,  1996, 2(4), 659-668.
[PMID:  9816216] 
[103] 
Muther, R.S.; Bennett, W.M. Effects of dimethyl sulfoxide on renal function in man. JAMA,  1980, 244(18), 2081-2083.
[http://dx.doi.org/10.1001/jama.1980.03310180047034] [PMID:  7001051] 
[104] 
Rijtema, M.; Mosig, D.; Drukker, A.; Guignard, J.P. The effects of dimethyl sulfoxide on renal function of the newborn rabbit. Biol. Neonate,  1999, 76(6), 355-361.
[http://dx.doi.org/10.1159/000014179] [PMID:  10567764] 
[105] 
Ren, K.W.; Li, Y.H.; Wu, G.; Ren, J.Z.; Lu, H.B.; Li, Z.M.; Han, X.W. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells. Int. J. Oncol.,  2017, 50(4), 1299-1311.
[http://dx.doi.org/10.3892/ijo.2017.3886] [PMID:  28259895] 
[106] 
Yuan, Z.P.; Chen, L.J.; Fan, L.Y.; Tang, M.H.; Yang, G.L.; Yang, H.S.; Du, X.B.; Wang, G.Q.; Yao, W.X.; Zhao, Q.M.; Ye, B.; Wang, R.; Diao, P.; Zhang, W.; Wu, H.B.; Zhao, X.; Wei, Y.Q. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res.,  2006, 12(10), 3193-3199.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2365] [PMID:  16707620] 
[107] 
Robins, S.J.; Fasulo, J.M.; Pritzker, C.R.; Patton, G.M. Hepatic transport and secretion of unesterified cholesterol in the rat is traced by the plant sterol, sitostanol. J. Lipid Res.,  1996, 37(1), 15-21.
[PMID:  8820098] 
[108] 
Varshosaz, J.; Jafarian, A.; Salehi, G.; Zolfaghari, B. Comparing different sterol containing solid lipid nanoparticles for targeted delivery of quercetin in hepatocellular carcinoma. J. Liposome Res.,  2014, 24(3), 191-203.
[http://dx.doi.org/10.3109/08982104.2013.868476] [PMID:  24354715] 
[109] 
Mandal, A.K.; Ghosh, D.; Sarkar, S.; Ghosh, A.; Swarnakar, S.; Das, N. Nanocapsulated quercetin downregulates rat hepatic MMP-13 and controls diethylnitrosamine-induced carcinoma. Nanomedicine (Lond.),  2014, 9(15), 2323-2337.
[http://dx.doi.org/10.2217/nnm.14.11] [PMID:  24593002] 
[110] 
Ghosh, A.; Ghosh, D.; Sarkar, S.; Mandal, A.K.; Thakur Choudhury, S.; Das, N. Anticarcinogenic activity of nanoencapsulated quercetin in combating diethylnitrosamine-induced hepatocarcinoma in rats. Eur. J. Cancer Prev.,  2012, 21(1), 32-41.
[http://dx.doi.org/10.1097/CEJ.0b013e32834a7e2b] [PMID:  21968689] 
[111] 
Abd-Rabou, A.A.; Ahmed, H.H. CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: A novel approach for induction of apoptosis in HepG2 cell line. Adv. Med. Sci.,  2017, 62(2), 357-367.
[http://dx.doi.org/10.1016/j.advms.2017.01.003] [PMID:  28521254] 
[112] 
Abdelmoneem, M.A.; Elnaggar, M.A.; Hammady, R.S.; Kamel, S.M.; Helmy, M.W.; Abdulkader, M.A.; Zaky, A.; Fang, J.Y.; Elkhodairy, K.A.; Elzoghby, A.O. Dual-targeted lactoferrin shell-oily core nanocapsules for synergistic targeted/herbal therapy of hepatocellular carcinoma. ACS Appl. Mater. Interfaces,  2019, 11(30), 26731-26744.
[http://dx.doi.org/10.1021/acsami.9b10164] [PMID:  31268657] 
[113] 
Wang, C.; Su, L.; Wu, C.; Wu, J.; Zhu, C.; Yuan, G. RGD peptide targeted lipid-coated nanoparticles for combinatorial delivery of sorafenib and quercetin against hepatocellular carcinoma. Drug Dev. Ind. Pharm.,  2016, 42(12), 1938-1944.
[http://dx.doi.org/10.1080/03639045.2016.1185435] [PMID:  27142812] 
[114] 
Oliveira, M.R.; Nabavi, S.F.; Daglia, M.; Rastrelli, L.; Nabavi, S.M. Epigallocatechin gallate and mitochondria-A story of life and death. Pharmacol. Res.,  2016, 104, 70-85.
[http://dx.doi.org/10.1016/j.phrs.2015.12.027] [PMID:  26731017] 
[115] 
Afzal, M.; Safer, A.M.; Menon, M. Green tea polyphenols and their potential role in health and disease. Inflammopharmacology,  2015, 23(4), 151-161.
[http://dx.doi.org/10.1007/s10787-015-0236-1] [PMID:  26164000] 
[116] 
Bimonte, S.; Albino, V.; Piccirillo, M.; Nasto, A.; Molino, C.; Palaia, R.; Cascella, M. Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: experimental findings and translational perspectives. Drug Des. Devel. Ther.,  2019, 13, 611-621.
[http://dx.doi.org/10.2147/DDDT.S180079] [PMID:  30858692] 
[117] 
Moody, R.; Wilson, K.; Jaworowski, A.; Plebanski, M. Natural compounds with potential to modulate cancer therapies and self-reactive immune cells. Cancers (Basel),  2020, 12(3), 1-24.
[http://dx.doi.org/10.3390/cancers12030673] [PMID:  32183059] 
[118] 
Zhang, G.; Miura, Y.; Yagasaki, K. Suppression of adhesion and invasion of hepatoma cells in culture by tea compounds through antioxidative activity. Cancer Lett.,  2000, 159(2), 169-173.
[http://dx.doi.org/10.1016/S0304-3835(00)00545-0] [PMID:  10996728] 
[119] 
Nishikawa, T.; Nakajima, T.; Moriguchi, M.; Jo, M.; Sekoguchi, S.; Ishii, M.; Takashima, H.; Katagishi, T.; Kimura, H.; Minami, M.; Itoh, Y.; Kagawa, K.; Okanoue, T. A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins. J. Hepatol.,  2006, 44(6), 1074-1082.
[http://dx.doi.org/10.1016/j.jhep.2005.11.045] [PMID:  16481065] 
[120] 
Zhang, Y.; Owusu, L.; Duan, W.; Jiang, T.; Zang, S.; Ahmed, A.; Xin, Y. Anti-metastatic and differential effects on protein expression of epigallocatechin-3-gallate in HCCLM6 hepatocellular carcinoma cells. Int. J. Mol. Med.,  2013, 32(4), 959-964.
[http://dx.doi.org/10.3892/ijmm.2013.1446] [PMID:  23863984] 
[121] 
Zhang, Q.; Tang, X.; Lu, Q.; Zhang, Z.; Rao, J.; Le, A.D. Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Mol. Cancer Ther.,  2006, 5(5), 1227-1238.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0490] [PMID:  16731755] 
[122] 
Lee, S.J.; Lee, K.W.; Hur, H.J.; Chun, J.I.; Kim, S.Y.; Lee, H.J. Phenolic phytochemicals derived from red pine (pinus densiflora) inhibit the invasion and migration of sk-hep-1. Ann. N. Y. Acad. Sci.,  2007, 544, 536-544.
[123] 
Shimizu, M.; Shirakami, Y.; Sakai, H.; Tatebe, H.; Nakagawa, T.; Hara, Y.; Weinstein, I.B.; Moriwaki, H. EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett.,  2008, 262(1), 10-18.
[http://dx.doi.org/10.1016/j.canlet.2007.11.026] [PMID:  18164805] 
[124] 
Huang, C.; Tsai, S.; Wang, Y.; Pan, M.; Kao, J. EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol. Nutr. Food Res.,  2009, 53(9), 1156-1165.
[125] 
Liang, G.; Tang, A.; Lin, X.; Li, L.; Zhang, S.; Huang, Z.; Tang, H.; Li, Q.Q. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int. J. Oncol.,  2010, 37(1), 111-123.
[PMID:  20514403] 
[126] 
Li, S.; Wu, L.; Feng, J.; Li, J.; Liu, T.; Zhang, R.; Xu, S.; Cheng, K.; Zhou, Y.; Zhou, S.; Kong, R.; Chen, K.; Wang, F.; Xia, Y.; Lu, J.; Zhou, Y.; Dai, W.; Guo, C. In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity. Sci. Rep.,  2016, 6, 28479.
[http://dx.doi.org/10.1038/srep28479] [PMID:  27349173] 
[127] 
Stalmach, A.; Troufflard, S.; Serafini, M.; Crozier, A. Absorption, metabolism and excretion of Choladi green tea flavan-3-ols by humans. Mol. Nutr. Food Res.,  2009, 53(Suppl. 1), S44-S53.
[http://dx.doi.org/10.1002/mnfr.200800169] [PMID:  18979506] 
[128] 
Roowi, S.; Stalmach, A.; Mullen, W.; Lean, M.E.J.; Edwards, C.A.; Crozier, A. Green tea flavan-3-ols: colonic degradation and urinary excretion of catabolites by humans. J. Agric. Food Chem.,  2010, 58(2), 1296-1304.
[http://dx.doi.org/10.1021/jf9032975] [PMID:  20041649] 
[129] 
Li, N.; Taylor, L.S.; Mauer, L.J. Degradation kinetics of catechins in green tea powder: effects of temperature and relative humidity. J. Agric. Food Chem.,  2011, 59(11), 6082-6090.
[http://dx.doi.org/10.1021/jf200203n] [PMID:  21495730] 
[130] 
Ishii, T.; Ichikawa, T.; Minoda, K.; Kusaka, K.; Ito, S.; Suzuki, Y.; Akagawa, M.; Mochizuki, K.; Goda, T.; Nakayama, T. Human serum albumin as an antioxidant in the oxidation of (-)-epigallocatechin gallate: participation of reversible covalent binding for interaction and stabilization. Biosci. Biotechnol. Biochem.,  2011, 75(1), 100-106.
[http://dx.doi.org/10.1271/bbb.100600] [PMID:  21228463] 
[131] 
Giunta, B.; Hou, H.; Zhu, Y.; Salemi, J.; Ruscin, A.; Shytle, R.D.; Tan, J. Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci. Lett.,  2010, 471(3), 134-138.
[http://dx.doi.org/10.1016/j.neulet.2010.01.026] [PMID:  20096749] 
[132] 
Peters, C.M.; Green, R.J.; Janle, E.M.; Ferruzzi, M.G. Formulation with ascorbic acid and sucrose modulates catechin bioavailability from green tea. Food Res. Int.,  2010, 43(1), 95-102.
[http://dx.doi.org/10.1016/j.foodres.2009.08.016] [PMID:  20161530] 
[133] 
Dube, A.; Nicolazzo, J.A.; Larson, I. Chitosan nanoparticles enhance the intestinal absorption of the green tea catechins (+)-catechin and (-)-epigallocatechin gallate. Eur. J. Pharm. Sci.,  2010, 41(2), 219-225.
[http://dx.doi.org/10.1016/j.ejps.2010.06.010] [PMID:  20600878] 
[134] 
Hu, B.; Ting, Y.; Yang, X.; Tang, W.; Zeng, X.; Huang, Q. Nanochemoprevention by encapsulation of (-)-epigallocatechin-3-gallate with bioactive peptides/chitosan nanoparticles for enhancement of its bioavailability. Chem. Commun. (Camb.),  2012, 48(18), 2421-2423.
[http://dx.doi.org/10.1039/c2cc17295j] [PMID:  22266839] 
[135] 
Auyeung, K.K-W.; Ko, J.K-S. Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation. Int. J. Mol. Med.,  2009, 24(4), 571-577.
[PMID:  19724899] 
[136] 
Halimani, M.; Chandran, S.P.; Kashyap, S.; Jadhav, V.M.; Prasad, B.L.V.; Hotha, S.; Maiti, S. Dendritic effect of ligand-coated nanoparticles: enhanced apoptotic activity of silica-berberine nanoconjugates. Langmuir,  2009, 25(4), 2339-2347.
[http://dx.doi.org/10.1021/la802761b] [PMID:  19146398] 
[137] 
Vuddanda, P.R.; Chakraborty, S.; Singh, S. Berberine: a potential phytochemical with multispectrum therapeutic activities. Expert Opin. Investig. Drugs,  2010, 19(10), 1297-1307.
[http://dx.doi.org/10.1517/13543784.2010.517745] [PMID:  20836620] 
[138] 
Wang, Y.; Liu, Y.; Du, X.; Ma, H.; Yao, J. The anti-cancer mechanisms of berberine: A review. Cancer Manag. Res.,  2020, 12, 695-702.
[http://dx.doi.org/10.2147/CMAR.S242329] [PMID:  32099466] 
[139] 
Hwang, J.M.; Kuo, H.C.; Tseng, T.H.; Liu, J.Y.; Chu, C.Y. Berberine induces apoptosis through a mitochondria/caspases pathway in human hepatoma cells. Arch. Toxicol.,  2006, 80(2), 62-73.
[http://dx.doi.org/10.1007/s00204-005-0014-8] [PMID:  16189662] 
[140] 
Chu, Q.; Jiang, Y.; Zhang, W.; Xu, C.; Du, W.; Tuguzbaeva, G.; Qin, Y.; Li, A.; Zhang, L.; Sun, G.; Cai, Y.; Feng, Q.; Li, G.; Li, Y.; Du, Z.; Bai, Y.; Yang, B. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma. Oncotarget,  2016, 7(51), 84658-84665.
[http://dx.doi.org/10.18632/oncotarget.12384] [PMID:  27705930] 
[141] 
Li, M.; Zhang, M.; Zhang, Z.L.; Liu, N.; Han, X.Y.; Liu, Q.C.; Deng, W.J.; Liao, C.X. Induction of apoptosis by berberine in hepatocellular carcinoma HepG2 cells via downregulation of NF-κB. Oncol. Res.,  2017, 25(2), 233-239.
[http://dx.doi.org/10.3727/096504016X14742891049073] [PMID:  28277195] 
[142] 
Li, J.; Li, O.; Kan, M.; Zhang, M.; Shao, D.; Pan, Y.; Zheng, H.; Zhang, X.; Chen, L.; Liu, S. Berberine induces apoptosis by suppressing the arachidonic acid metabolic pathway in hepatocellular carcinoma. Mol. Med. Rep.,  2015, 12(3), 4572-4577.
[http://dx.doi.org/10.3892/mmr.2015.3926] [PMID:  26081696] 
[143] 
Sengupta, D.; Chowdhury, K.D.; Sarkar, A.; Paul, S.; Sadhukhan, G.C. Berberine and S allyl cysteine mediated amelioration of DEN + CCl4 induced hepatocarcinoma.  In: Biochimica et Biophysica Acta - General Subjects; Elsevier B.V.: Amsterdam, 2014, Vol. 1840, pp. 219-244.
[http://dx.doi.org/10.1016/j.bbagen.2013.08.020] 
[144] 
Wang, X.; Wang, N.; Li, H.; Liu, M.; Cao, F.; Yu, X.; Zhang, J.; Tan, Y.; Xiang, L.; Feng, Y. Up-regulation of PAI-1 and down-regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. Int. J. Mol. Sci.,  2016, 17(4), 577.
[http://dx.doi.org/10.3390/ijms17040577] [PMID:  27092498] 
[145] 
Tsang, C.M.; Cheung, K.C.P.; Cheung, Y.C.; Man, K.; Lui, V.W.Y.; Tsao, S.W.; Feng, Y. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochim. Biophys. Acta,  2015, 1852(3), 541-551.
[http://dx.doi.org/10.1016/j.bbadis.2014.12.004] [PMID:  25496992] 
[146] 
Li, F.; Dong, X.; Lin, P.; Jiang, J. Regulation of Akt/FoxO3a/Skp2 axis is critically involved in berberine-induced cell cycle arrest in hepatocellular carcinoma cells. Int. J. Mol. Sci.,  2018, 19(2), E327
[http://dx.doi.org/10.3390/ijms19020327] [PMID:  29360760] 
[147] 
Luo, Y.; Tian, G.; Zhuang, Z.; Chen, J.; You, N.; Zhuo, L.; Liang, B.; Song, Y.; Zang, S.; Liu, J.; Yang, J.; Ge, W.; Shi, J. Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice. Am. J. Transl. Res.,  2019, 11(5), 2668-2682.
[PMID:  31217846] 
[148] 
Morishita, A.; Masaki, T. miRNA in hepatocellular carcinoma. Hepatol. Res.,  2015, 45(2), 128-141.
[http://dx.doi.org/10.1111/hepr.12386] [PMID:  25040738] 
[149] 
Pottoo, F.H.; Barkat, M.A. Harshita,; Ansari, M.A.; Javed, M.N.; Sajid Jamal, Q.M.; Kamal, M.A.  . Nanotechnological based miRNA intervention in the therapeutic management of neuroblastoma. Semin. Cancer Biol., 2019.
[http://dx.doi.org/10.1016/j.semcancer.2019.09.017] [PMID:  31562954] 
[150] 
Lo, T.F.; Tsai, W.C.; Chen, S.T. MicroRNA-21-3p, a berberine-induced miRNA, directly down-regulates human methionine adenosyltransferases 2A and 2B and inhibits hepatoma cell growth. PLoS One,  2013, 8(9), e75628
[http://dx.doi.org/10.1371/journal.pone.0075628] [PMID:  24098708] 
[151] 
Li, J.; Aung, L.H.H.; Long, B.; Qin, D.; An, S.; Li, P. miR-23a binds to p53 and enhances its association with miR-128 promoter. Sci. Rep.,  2015, 5, 16422.
[http://dx.doi.org/10.1038/srep16422] [PMID:  26553132] 
[152] 
Ayati, S.H.; Fazeli, B.; Momtazi-Borojeni, A.A.; Cicero, A.F.G.; Pirro, M.; Sahebkar, A. Regulatory effects of berberine on microRNome in Cancer and other conditions. Crit. Rev. Oncol. Hematol.,  2017, 116, 147-158.
[http://dx.doi.org/10.1016/j.critrevonc.2017.05.008] [PMID:  28693796] 
[153] 
Zuo, F.; Nakamura, N.; Akao, T.; Hattori, M. Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry. Drug Metab. Dispos.,  2006, 34(12), 2064-2072.
[http://dx.doi.org/10.1124/dmd.106.011361] [PMID:  16956957] 
[154] 
Liu, Y.T.; Hao, H.P.; Xie, H.G.; Lai, L.; Wang, Q.; Liu, C.X.; Wang, G.J. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab. Dispos.,  2010, 38(10), 1779-1784.
[http://dx.doi.org/10.1124/dmd.110.033936] [PMID:  20634337] 
[155] 
Zhang, Y.; Li, X.; Zou, D.; Liu, W.; Yang, J.; Zhu, N.; Huo, L.; Wang, M.; Hong, J.; Wu, P.; Ren, G.; Ning, G. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J. Clin. Endocrinol. Metab.,  2008, 93(7), 2559-2565.
[http://dx.doi.org/10.1210/jc.2007-2404] [PMID:  18397984] 
[156] 
Chen, C.M.; Chang, H.C. Determination of berberine in plasma, urine and bile by high-performance liquid chromatography. J. Chromatogr. B Biomed. Appl.,  1995, 665(1), 117-123.
[http://dx.doi.org/10.1016/0378-4347(94)00517-9] [PMID:  7795781] 
[157] 
Lin, Y.C.; Kuo, J.Y.; Hsu, C.C.; Tsai, W.C.; Li, W.C.; Yu, M.C.; Wen, H.W. Optimizing manufacture of liposomal berberine with evaluation of its antihepatoma effects in a murine xenograft model. Int. J. Pharm.,  2013, 441(1-2), 381-388.
[http://dx.doi.org/10.1016/j.ijpharm.2012.11.017] [PMID:  23220078] 
[158] 
Abdelmoneem, M.A.; Mahmoud, M.; Zaky, A.; Helmy, M.W.; Sallam, M.; Fang, J.Y.; Elkhodairy, K.A.; Elzoghby, A.O. Dual-targeted casein micelles as green nanomedicine for synergistic phytotherapy of hepatocellular carcinoma. J. Control. Release,  2018, 287, 78-93.
[http://dx.doi.org/10.1016/j.jconrel.2018.08.026] [PMID:  30138716] 
[159] 
Zhang, F.; Jia, Y.; Zheng, X.; Shao, D.; Zhao, Y.; Wang, Z. Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence. Acta Biomaterialia. Elsevier Ltd: Amsterdan,  2019, Vol. 100, pp 352-364.
[http://dx.doi.org/10.1016/j.actbio.2019.09.034] 
[160] 
Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr.,  2017, 8(3), 423-435.
[http://dx.doi.org/10.3945/an.116.012948] [PMID:  28507008] 
[161] 
Tang, D.; Chen, K.; Huang, L.; Li, J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin. Drug Metab. Toxicol.,  2017, 13(3), 323-330.
[http://dx.doi.org/10.1080/17425255.2017.1251903] [PMID:  27766890] 
[162] 
Bajaj, S.; Wakode, S.R.; Khan, W.; Manchanda, S.; Kumar, S. Simultaneous HPTLC analysis and in vitro antileishmanic activity of various secondary metabolites in extract of the traditional medicinal herb Artabotrys hexapetalus (L.f.). Ayu,  2018, 39(2), 92-100.
[http://dx.doi.org/10.4103/ayu.AYU_158_17] [PMID:  30783364] 
[163] 
He, M.; Min, J.W.; Kong, W.L.; He, X.H.; Li, J.X.; Peng, B.W. A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia,  2016, 115, 74-85.
[http://dx.doi.org/10.1016/j.fitote.2016.09.011] [PMID:  27693342] 
[164] 
Javadi, B.; Sahebkar, A. Natural products with anti-inflammatory and immunomodulatory activities against autoimmune myocarditis. Pharmacol. Res.,  2017, 124, 34-42.
[http://dx.doi.org/10.1016/j.phrs.2017.07.022] [PMID:  28757189] 
[165] 
Kasiri, N.; Rahmati, M.; Ahmadi, L.; Eskandari, N. The significant impact of apigenin on different aspects of autoimmune disease. Inflammopharmacology,  2018, 26(6), 1359-1373.
[http://dx.doi.org/10.1007/s10787-018-0531-8] [PMID:  30229507] 
[166] 
Li, R.; Zhao, D.; Qu, R.; Fu, Q.; Ma, S. The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice. Neurosci. Lett.,  2015, 594, 17-22.
[http://dx.doi.org/10.1016/j.neulet.2015.03.040] [PMID:  25800110] 
[167] 
Nabavi, S.F.; Khan, H.; D’onofrio, G.; Šamec, D.; Shirooie, S.; Dehpour, A.R.; Argüelles, S.; Habtemariam, S.; Sobarzo-Sanchez, E. Apigenin as neuroprotective agent: Of mice and men. Pharmacol. Res.,  2018, 128, 359-365.
[http://dx.doi.org/10.1016/j.phrs.2017.10.008] [PMID:  29055745] 
[168] 
Wang, J.; Liu, Y.T.; Xiao, L.; Zhu, L.; Wang, Q.; Yan, T. Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway. Inflammation,  2014, 37(6), 2085-2090.
[http://dx.doi.org/10.1007/s10753-014-9942-x] [PMID:  24958013] 
[169] 
Basios, N.; Lampropoulos, P.; Papalois, A.; Lambropoulou, M.; Pitiakoudis, M.K.; Kotini, A.; Simopoulos, C.; Tsaroucha, A.K. Apigenin attenuates inflammation in experimentally induced acute pancreatitis-associated lung injury. J. Invest. Surg.,  2016, 29(3), 121-127.
[http://dx.doi.org/10.3109/08941939.2015.1088603] [PMID:  26631908] 
[170] 
Yan, X.; Qi, M.; Li, P.; Zhan, Y.; Shao, H. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci.,  2017, 7(1), 50.
[http://dx.doi.org/10.1186/s13578-017-0179-x] [PMID:  29034071] 
[171] 
Salmani, J.M.M.; Zhang, X.P.; Jacob, J.A.; Chen, B.A. Apigenin’s anticancer properties and molecular mechanisms of action: Recent advances and future prospectives. Chin. J. Nat. Med.,  2017, 15(5), 321-329.
[http://dx.doi.org/10.1016/S1875-5364(17)30052-3] [PMID:  28558867] 
[172] 
Kim, B.R.; Jeon, Y.K.; Nam, M.J. A mechanism of apigenin-induced apoptosis is potentially related to anti-angiogenesis and anti-migration in human hepatocellular carcinoma cells. Food Chem. Toxicol.,  2011, 49(7), 1626-1632.
[http://dx.doi.org/10.1016/j.fct.2011.04.015] [PMID:  21515330] 
[173] 
Cai, J.; Zhao, X.L.; Liu, A.W.; Nian, H.; Zhang, S.H. Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns. Phytomedicine,  2011, 18(5), 366-373.
[http://dx.doi.org/10.1016/j.phymed.2010.08.006] [PMID:  20850954] 
[174] 
Kim, E.Y.; Kim, A.K. Apigenin sensitizes Huh-7 human hepatocellular carcinoma cells to TRAIL-induced apoptosis. Biomol. Ther. (Seoul),  2012, 20(1), 62-67.
[http://dx.doi.org/10.4062/biomolther.2012.20.1.062] [PMID:  24116276] 
[175] 
Qin, Y.; Zhao, D.; Zhou, H.G.; Wang, X.H.; Zhong, W.L.; Chen, S.; Gu, W.G.; Wang, W.; Zhang, C.H.; Liu, Y.R.; Liu, H.J.; Zhang, Q.; Guo, Y.Q.; Sun, T.; Yang, C. Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma. Oncotarget,  2016, 7(27), 41421-41431.
[http://dx.doi.org/10.18632/oncotarget.9404] [PMID:  27203387] 
[176] 
Yang, J.; Pi, C.; Wang, G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed. Pharmacother.,  2018, 103(April), 699-707.
[http://dx.doi.org/10.1016/j.biopha.2018.04.072] [PMID:  29680738] 
[177] 
Li, Y.; Cheng, X.; Chen, C.; Huijuan, W.; Zhao, H.; Liu, W.; Xiang, Z.; Wang, Q. Apigenin, a flavonoid constituent derived from P. villosa, inhibits hepatocellular carcinoma cell growth by CyclinD1/CDK4 regulation via p38 MAPK-p21 signaling. Pathol. Res. Pract.,  2020, 216(1), 152701
[http://dx.doi.org/10.1016/j.prp.2019.152701] [PMID:  31780054] 
[178] 
Nishinaka, T.; Miura, T.; Okumura, M.; Nakao, F.; Nakamura, H.; Terada, T. Regulation of aldo-keto reductase AKR1B10 gene expression: involvement of transcription factor Nrf2. Chem. Biol. Interact.,  2011, 191(1-3), 185-191.
[http://dx.doi.org/10.1016/j.cbi.2011.01.026] [PMID:  21277289] 
[179] 
Tang, X.; Wang, H.; Fan, L.; Wu, X.; Xin, A.; Ren, H.; Wang, X.J. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic. Biol. Med.,  2011, 50(11), 1599-1609.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.03.008] [PMID:  21402146] 
[180] 
Gao, A.M.; Ke, Z.P.; Wang, J.N.; Yang, J.Y.; Chen, S.Y.; Chen, H. Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis,  2013, 34(8), 1806-1814.
[http://dx.doi.org/10.1093/carcin/bgt108] [PMID:  23563091] 
[181] 
Hu, X.Y.; Liang, J.Y.; Guo, X.J.; Liu, L.; Guo, Y.B. 5-Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma. Clin. Exp. Pharmacol. Physiol.,  2015, 42(2), 146-153.
[http://dx.doi.org/10.1111/1440-1681.12333] [PMID:  25363523] 
[182] 
Li, B.; Robinson, D.H.; Birt, D.F. Evaluation of properties of apigenin and [G-3H]apigenin and analytic method development. J. Pharm. Sci.,  1997, 86(6), 721-725.
[http://dx.doi.org/10.1021/js960383s] [PMID:  9188055] 
[183] 
Zhang, J.; Liu, D.; Huang, Y.; Gao, Y.; Qian, S. Biopharmaceutics classification and intestinal absorption study of apigenin. Int. J. Pharm.,  2012, 436(1-2), 311-317.
[http://dx.doi.org/10.1016/j.ijpharm.2012.07.002] [PMID:  22796171] 
[184] 
Ross, J.A.; Kasum, C.M. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr.,  2002, 22(1), 19-34.
[http://dx.doi.org/10.1146/annurev.nutr.22.111401.144957] [PMID:  12055336] 
[185] 
Gradolatto, A.; Basly, J-P.; Berges, R.; Teyssier, C.; Chagnon, M-C.; Siess, M-H.; Canivenc-Lavier, M.C. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab. Dispos.,  2005, 33(1), 49-54.
[http://dx.doi.org/10.1124/dmd.104.000893] [PMID:  15466493] 
[186] 
Ding, S.M.; Zhang, Z.H.; Song, J.; Cheng, X.D.; Jiang, J.; Jia, X.B. Enhanced bioavailability of apigenin via preparation of a carbon nanopowder solid dispersion. Int. J. Nanomedicine,  2014, 9(1), 2327-2333.
[http://dx.doi.org/10.2147/IJN.S60938] [PMID:  24872695] 
[187] 
Bhattacharya, S.; Mondal, L.; Mukherjee, B.; Dutta, L.; Ehsan, I.; Debnath, M.C.; Gaonkar, R.H.; Pal, M.M.; Majumdar, S. Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats. Nanomedicine (Lond.),  2018, 14(6), 1905-1917.
[http://dx.doi.org/10.1016/j.nano.2018.05.011] [PMID:  29802937] 
[188] 
Kupchan, S.M.; Court, W.A.; Dailey, R.G., Jr; Gilmore, C.J.; Bryan, R.F. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. J. Am. Chem. Soc.,  1972, 94(20), 7194-7195.
[http://dx.doi.org/10.1021/ja00775a078] [PMID:  5072337] 
[189] 
Li, X.J.; Jiang, Z.Z.; Zhang, L.Y. Triptolide: progress on research in pharmacodynamics and toxicology. J. Ethnopharmacol.,  2014, 155(1), 67-79.
[http://dx.doi.org/10.1016/j.jep.2014.06.006] [PMID:  24933225] 
[190] 
Chan, E.W.; Cheng, S.C.; Sin, F.W.; Xie, Y. Triptolide induced cytotoxic effects on human promyelocytic leukemia, T cell lymphoma and human hepatocellular carcinoma cell lines. Toxicol. Lett.,  2001, 122(1), 81-87.
[http://dx.doi.org/10.1016/S0378-4274(01)00353-8] [PMID:  11397559] 
[191] 
Wang, H.; Ma, D.; Wang, C.; Zhao, S.; Liu, C. Triptolide inhibits invasion and tumorigenesis of hepatocellular carcinoma MHCC-97H cells through NF-κB signaling. Med. Sci. Monit.,  2016, 22, 1827-1836.
[http://dx.doi.org/10.12659/MSM.898801] [PMID:  27239780] 
[192] 
Ditsworth, D.; Zong, W.X. NF-kappaB: key mediator of inflammation-associated cancer. Cancer Biol. Ther.,  2004, 3(12), 1214-1216.
[http://dx.doi.org/10.4161/cbt.3.12.1391] [PMID:  15611628] 
[193] 
Sun, Y.Y.; Xiao, L.; Wang, D.; Ji, Y.C.; Yang, Y.P.; Ma, R.; Chen, X.H. Triptolide inhibits viability and induces apoptosis in liver cancer cells through activation of the tumor suppressor gene p53. Int. J. Oncol.,  2017, 50(3), 847-852.
[http://dx.doi.org/10.3892/ijo.2017.3850] [PMID:  28098861] 
[194] 
Li, S.G.; Shi, Q.W.; Yuan, L.Y.; Qin, L.P.; Wang, Y.; Miao, Y.Q.; Chen, Z.; Ling, C.Q.; Qin, W.X. C-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res.,  2018, 37(1), 51.
[http://dx.doi.org/10.1186/s13046-018-0698-2] [PMID:  29523159] 
[195] 
Zhou, Z.L.; Yang, Y.X.; Ding, J.; Li, Y.C.; Miao, Z.H. Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms. Nat. Prod. Rep.,  2012, 29(4), 457-475.
[http://dx.doi.org/10.1039/c2np00088a] [PMID:  22270059] 
[196] 
Hou, W.; Liu, B.; Xu, H. Triptolide: Medicinal chemistry, chemical biology and clinical progress. Eur. J. Med. Chem.,  2019, 176, 378-392.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.032] [PMID:  31121546] 
[197] 
Ling, D.; Xia, H.; Park, W.; Hackett, M.J.; Song, C.; Na, K.; Hui, K.M.; Hyeon, T. pH-sensitive nanoformulated triptolide as a targeted therapeutic strategy for hepatocellular carcinoma. ACS Nano,  2014, 8(8), 8027-8039.
[http://dx.doi.org/10.1021/nn502074x] [PMID:  25093274] 
[198] 
Zhang, Y.Q.; Shen, Y.; Liao, M.M.; Mao, X.; Mi, G.J.; You, C.; Guo, Q.Y.; Li, W.J.; Wang, X.Y.; Lin, N.; Webster, T.J. Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: Enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms. Nanomedicine (Lond.),  2019, 15(1), 86-97.
[http://dx.doi.org/10.1016/j.nano.2018.09.002] [PMID:  30244085] 
[199] 
Zhao, X.; Tong, W.; Song, X.; Jia, R.; Li, L.; Zou, Y.; He, C.; Liang, X.; Lv, C.; Jing, B.; Lin, J.; Yin, L.; Ye, G.; Yue, G.; Wang, Y.; Yin, Z. Antiviral effect of resveratrol in piglets infected with virulent pseudorabies virus. Viruses,  2018, 10(9), E457
[http://dx.doi.org/10.3390/v10090457] [PMID:  30150559] 
[200] 
Kumar, S.; Bodla, R.; Kant, R. Non-targeted analysis and cytotoxic activity of hamelia patens jacq. Int. J. Pharm. Sci. Res.,  2018, 9(3), 1093.
[http://dx.doi.org/10.13040/IJPSR.0975-8232.9] 
[201] 
Gupta, S.C.; Kunnumakkara, A.B.; Aggarwal, S.; Aggarwal, B.B. inflammation, a double-edge sword for cancer and other age-related diseases. Front. Immunol.,  2018, 9, 2160.
[http://dx.doi.org/10.3389/fimmu.2018.02160] [PMID:  30319623] 
[202] 
Ko, J.H.; Sethi, G.; Um, J.Y.; Shanmugam, M.K.; Arfuso, F.; Kumar, A.P.; Bishayee, A.; Ahn, K.S. The role of resveratrol in cancer therapy. Int. J. Mol. Sci.,  2017, 18(12), 1-36.
[http://dx.doi.org/10.3390/ijms18122589] [PMID:  29194365] 
[203] 
Chaplin, A.; Carpéné, C.; Mercader, J. Resveratrol, metabolic syndrome, and gut microbiota. Nutrients,  2018, 10(11), 1-29.
[http://dx.doi.org/10.3390/nu10111651] [PMID:  30400297] 
[204] 
Bonnefont-Rousselot, D. Resveratrol and cardiovascular diseases. Nutrients,  2016, 8(5), 1-24.
[http://dx.doi.org/10.3390/nu8050250] [PMID:  27144581] 
[205] 
Han, Y.; Jo, H.; Cho, J.H.; Dhanasekaran, D.N.; Song, Y.S. Resveratrol as a tumor-suppressive nutraceutical modulating tumor microenvironment and malignant behaviors of cancer. Int. J. Mol. Sci.,  2019, 20(4), 1-18.
[http://dx.doi.org/10.3390/ijms20040925] [PMID:  30791624] 
[206] 
Honari, M.; Shafabakhsh, R.; Reiter, R.J.; Mirzaei, H.; Asemi, Z. Resveratrol is a promising agent for colorectal cancer prevention and treatment: focus on molecular mechanisms. Cancer Cell Int.,  2019, 19(1), 180.
[http://dx.doi.org/10.1186/s12935-019-0906-y] [PMID:  31341423] 
[207] 
Yang, Y.; Paik, J.H.; Cho, D.; Cho, J.A.; Kim, C.W. Resveratrol induces the suppression of tumor-derived CD4+CD25+ regulatory T cells. Int. Immunopharmacol.,  2008, 8(4), 542-547.
[http://dx.doi.org/10.1016/j.intimp.2007.12.006] [PMID:  18328445] 
[208] 
Lee-Chang, C.; Bodogai, M.; Martin-Montalvo, A.; Wejksza, K.; Sanghvi, M.; Moaddel, R.; de Cabo, R.; Biragyn, A. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J. Immunol.,  2013, 191(8), 4141-4151.
[http://dx.doi.org/10.4049/jimmunol.1300606] [PMID:  24043896] 
[209] 
Li, W.; Miao, S.; Miao, M.; Li, R.; Cao, X.; Zhang, K.; Huang, G.; Fu, B. Hedgehog signaling activation in hepatic stellate cells promotes angiogenesis and vascular mimicry in hepatocellular carcinoma. Cancer Invest.,  2016, 34(9), 424-430.
[http://dx.doi.org/10.1080/07357907.2016.1227442] [PMID:  27657189] 
[210] 
Lei, J.; Fan, L.; Wei, G.; Chen, X.; Duan, W.; Xu, Q.; Sheng, W.; Wang, K.; Li, X. Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer. Tumour Biol.,  2015, 36(4), 3119-3126.
[http://dx.doi.org/10.1007/s13277-014-2948-z] [PMID:  25501705] 
[211] 
Yan, Y.; Zhou, C.; Li, J.; Chen, K.; Wang, G.; Wei, G.; Chen, M.; Li, X. Resveratrol inhibits hepatocellular carcinoma progression driven by hepatic stellate cells by targeting Gli-1. Mol. Cell. Biochem.,  2017, 434(1-2), 17-24.
[http://dx.doi.org/10.1007/s11010-017-3031-z] [PMID:  28455791] 
[212] 
Gherardi, E.; Birchmeier, W.; Birchmeier, C.; Vande Woude, G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer,  2012, 12(2), 89-103.
[http://dx.doi.org/10.1038/nrc3205] [PMID:  22270953] 
[213] 
Peters, S.; Adjei, A.A. MET: a promising anticancer therapeutic target. Nat. Rev. Clin. Oncol.,  2012, 9(6), 314-326.
[http://dx.doi.org/10.1038/nrclinonc.2012.71] [PMID:  22566105] 
[214] 
Gao, F.; Deng, G.; Liu, W.; Zhou, K.; Li, M. Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway. Oncol. Rep.,  2017, 37(2), 1203-1211.
[http://dx.doi.org/10.3892/or.2017.5347] [PMID:  28075467] 
[215] 
Chai, R.; Fu, H.; Zheng, Z.; Liu, T.; Ji, S.; Li, G. Resveratrol inhibits proliferation and migration through SIRT1 mediated posttranslational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol. Med. Rep.,  2017, 16(6), 8037-8044.
[http://dx.doi.org/10.3892/mmr.2017.7612] [PMID:  28983625] 
[216] 
Zhang, B.; Yin, X.; Sui, S. Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide 3kinase/protein kinase B pathway. Oncol. Rep.,  2018, 40(5), 2758-2765.
[http://dx.doi.org/10.3892/or.2018.6648] [PMID:  30132535] 
[217] 
Amri, A.; Chaumeil, J.C.; Sfar, S.; Charrueau, C. Administration of resveratrol: What formulation solutions to bioavailability limitations? J. Control. Release,  2012, 158(2), 182-193.
[http://dx.doi.org/10.1016/j.jconrel.2011.09.083] [PMID:  21978644] 
[218] 
Santos, A.C.; Pereira, I.; Pereira-Silva, M.; Ferreira, L.; Caldas, M.; Collado-González, M.; Magalhães, M.; Figueiras, A.; Ribeiro, A.J.; Veiga, F. Nanotechnology-based formulations for resveratrol delivery: Effects on resveratrol in vivo bioavailability and bioactivity. Colloids Surf. B Biointerfaces,  2019, 180, 127-140.
[http://dx.doi.org/10.1016/j.colsurfb.2019.04.030] [PMID:  31035056] 
[219] 
Francioso, A.; Mastromarino, P.; Masci, A.; d’Erme, M.; Mosca, L. Chemistry, stability and bioavailability of resveratrol. Med. Chem.,  2014, 10(3), 237-245.
[http://dx.doi.org/10.2174/15734064113096660053] [PMID:  24329932] 
[220] 
Zupančič, Š.; Lavrič, Z.; Kristl, J. Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature. Eur. J. Pharm. Biopharm.,  2015, 93, 196-204.
[http://dx.doi.org/10.1016/j.ejpb.2015.04.002] [PMID:  25864442] 
[221] 
Zhang, D.; Zhang, J.; Zeng, J.; Li, Z.; Zuo, H.; Huang, C.; Zhao, X. Nano-gold loaded with resveratrol enhance the anti-hepatoma effect of resveratrol in vitro and in vivo. J. Biomed. Nanotechnol.,  2019, 15(2), 288-300.
[http://dx.doi.org/10.1166/jbn.2019.2682] [PMID:  30596551] 
[222] 
Anwar, D.M.; Khattab, S.N.; Helmy, M.W.; Kamal, M.K.; Bekhit, A.A.; Elkhodairy, K.A.; Elzoghby, A.O. Lactobionic/folate dual-targeted amphiphilic maltodextrin-based micelles for targeted codelivery of sulfasalazine and resveratrol to hepatocellular carcinoma. Bioconjug. Chem.,  2018, 29(9), 3026-3041.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00428] [PMID:  30110148] 
[223] 
Racanelli, V.; Rehermann, B. The liver as an immunological organ. Hepatology,  2006, 43(2)(Suppl. 1), S54-S62.
[http://dx.doi.org/10.1002/hep.21060] [PMID:  16447271] 
[224] 
Zhang, Y.N.; Poon, W.; Tavares, A.J.; McGilvray, I.D.; Chan, W.C.W. Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination. J. Control. Release,  2016, 240, 332-348.
[http://dx.doi.org/10.1016/j.jconrel.2016.01.020] [PMID:  26774224] 
[225] 
Peng, J.; Wang, K.; Tan, W.; He, X.; He, C.; Wu, P.; Liu, F. Identification of live liver cancer cells in a mixed cell system using galactose-conjugated fluorescent nanoparticles. Talanta,  2007, 71(2), 833-840.
[http://dx.doi.org/10.1016/j.talanta.2006.05.064] [PMID:  19071382] 
[226] 
Xu, Z.; Chen, L.; Gu, W.; Gao, Y.; Lin, L.; Zhang, Z.; Xi, Y.; Li, Y. The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma. Biomaterials,  2009, 30(2), 226-232.
[http://dx.doi.org/10.1016/j.biomaterials.2008.09.014] [PMID:  18851881] 
[227] 
Yang, Y.; Yuan, S.X.; Zhao, L.H.; Wang, C.; Ni, J.S.; Wang, Z.G.; Lin, C.; Wu, M.C.; Zhou, W.P. Ligand-directed stearic acid grafted chitosan micelles to increase therapeutic efficacy in hepatic cancer. Mol. Pharm.,  2015, 12(2), 644-652.
[http://dx.doi.org/10.1021/mp500723k] [PMID:  25495890] 
[228] 
Yang, K.W.; Li, X.R.; Yang, Z.L.; Li, P.Z.; Wang, F.; Liu, Y. Novel polyion complex micelles for liver-targeted delivery of diammonium glycyrrhizinate: in vitro and in vivo characterization. J. Biomed. Mater. Res. A,  2009, 88(1), 140-148.
[http://dx.doi.org/10.1002/jbm.a.31866] [PMID:  18260143] 
[229] 
Wu, J.; Sun, T.M.; Yang, X.Z.; Zhu, J.; Du, X.J.; Yao, Y.D.; Xiong, M.H.; Wang, H.X.; Wang, Y.C.; Wang, J. Enhanced drug delivery to hepatocellular carcinoma with a galactosylated core-shell polyphosphoester nanogel. Biomater. Sci.,  2013, 1(11), 1143-1150.
[http://dx.doi.org/10.1039/c3bm60099h] [PMID:  32481937] 
[230] 
Yu, F.; Jiang, T.; Zhang, J.; Cheng, L.; Wang, S. Galactosylated liposomes as oligodeoxynucleotides carrier for hepatocyte-selective targeting. Pharmazie,  2007, 62(7), 528-533.
[PMID:  17718195] 
[231] 
Gupta, S.; Agarwal, A.; Gupta, N.K.; Saraogi, G.; Agrawal, H.; Agrawal, G.P. Galactose decorated PLGA nanoparticles for hepatic delivery of acyclovir. Drug Dev. Ind. Pharm.,  2013, 39(12), 1866-1873.
[http://dx.doi.org/10.3109/03639045.2012.662510] [PMID:  22397550] 
[232] 
Popielarski, S.R.; Hu-Lieskovan, S.; French, S.W.; Triche, T.J.; Davis, M.E. A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 2. In vitro and in vivo uptake results. Bioconjug. Chem.,  2005, 16(5), 1071-1080.
[http://dx.doi.org/10.1021/bc0501146] [PMID:  16173782] 
[233] 
Cheng, M.; He, B.; Wan, T.; Zhu, W.; Han, J.; Zha, B.; Chen, H.; Yang, F.; Li, Q.; Wang, W.; Xu, H.; Ye, T. 5-Fluorouracil nanoparticles inhibit hepatocellular carcinoma via activation of the p53 pathway in the orthotopic transplant mouse model. PLoS One,  2012, 7(10), e47115
[http://dx.doi.org/10.1371/journal.pone.0047115] [PMID:  23077553] 
[234] 
Liang, H.F.; Chen, S.C.; Chen, M.C.; Lee, P.W.; Chen, C.T.; Sung, H.W. Paclitaxel-loaded poly(γ-glutamic acid)-poly(lactide) nanoparticles as a targeted drug delivery system against cultured HepG2 cells. Bioconjug. Chem.,  2006, 17(2), 291-299.
[http://dx.doi.org/10.1021/bc0502107] [PMID:  16536458] 
[235] 
Wang, S.N.; Deng, Y.H.; Xu, H.; Wu, H.B.; Qiu, Y.K.; Chen, D.W. Synthesis of a novel galactosylated lipid and its application to the hepatocyte-selective targeting of liposomal doxorubicin. Eur. J. Pharm. Biopharm.,  2006, 62(1), 32-38.
[http://dx.doi.org/10.1016/j.ejpb.2005.07.004] [PMID:  16226883] 
[236] 
Guhagarkar, S.A.; Gaikwad, R.V.; Samad, A.; Malshe, V.C.; Devarajan, P.V. Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting. Int. J. Pharm.,  2010, 401(1-2), 113-122.
[http://dx.doi.org/10.1016/j.ijpharm.2010.09.012] [PMID:  20854883] 
[237] 
Qi, X.R.; Yan, W.W.; Shi, J. Hepatocytes targeting of cationic liposomes modified with soybean sterylglucoside and polyethylene glycol. World J. Gastroenterol.,  2005, 11(32), 4947-4952.
[http://dx.doi.org/10.3748/wjg.v11.i32.4947] [PMID:  16124043] 
[238] 
Kren, B.T.; Unger, G.M.; Sjeklocha, L.; Trossen, A.A.; Korman, V.; Diethelm-Okita, B.M.; Reding, M.T.; Steer, C.J. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice. J. Clin. Invest.,  2009, 119(7), 2086-2099.
[http://dx.doi.org/10.1172/JCI34332] [PMID:  19509468] 
[239] 
Qi, W.W.; Yu, H.Y.; Guo, H.; Lou, J.; Wang, Z.M.; Liu, P.; Sapin-Minet, A.; Maincent, P.; Hong, X.C.; Hu, X.M.; Xiao, Y.L. Doxorubicin-loaded glycyrrhetinic acid modified recombinant human serum albumin nanoparticles for targeting liver tumor chemotherapy. Mol. Pharm.,  2015, 12(3), 675-683.
[http://dx.doi.org/10.1021/mp500394v] [PMID:  25584860] 
[240] 
Tian, Q.; Zhang, C.N.; Wang, X.H.; Wang, W.; Huang, W.; Cha, R.T.; Wang, C.H.; Yuan, Z.; Liu, M.; Wan, H.Y.; Tang, H. Glycyrrhetinic acid-modified chitosan/poly(ethylene glycol) nanoparticles for liver-targeted delivery. Biomaterials,  2010, 31(17), 4748-4756.
[http://dx.doi.org/10.1016/j.biomaterials.2010.02.042] [PMID:  20303163] 
[241] 
Huang, W.; Wang, W.; Wang, P.; Tian, Q.; Zhang, C.; Wang, C.; Yuan, Z.; Liu, M.; Wan, H.; Tang, H. Glycyrrhetinic acid-modified poly(ethylene glycol)-b-poly(γ-benzyl l-glutamate) micelles for liver targeting therapy. Acta Biomater.,  2010, 6(10), 3927-3935.
[http://dx.doi.org/10.1016/j.actbio.2010.04.021] [PMID:  20438873] 
[242] 
Guo, H.; Lai, Q.; Wang, W.; Wu, Y.; Zhang, C.; Liu, Y.; Yuan, Z. Functional alginate nanoparticles for efficient intracellular release of doxorubicin and hepatoma carcinoma cell targeting therapy. Int. J. Pharm.,  2013, 451(1-2), 1-11.
[http://dx.doi.org/10.1016/j.ijpharm.2013.04.025] [PMID:  23618965] 
[243] 
Cheong, S.J.; Lee, C.M.; Kim, S.L.; Jeong, H.J.; Kim, E.M.; Park, E.H.; Kim, D.W.; Lim, S.T.; Sohn, M.H. Superparamagnetic iron oxide nanoparticles-loaded chitosan-linoleic acid nanoparticles as an effective hepatocyte-targeted gene delivery system. Int. J. Pharm.,  2009, 372(1-2), 169-176.
[http://dx.doi.org/10.1016/j.ijpharm.2009.01.009] [PMID:  19429277] 
[244] 
Longmuir, K.J.; Haynes, S.M.; Baratta, J.L.; Kasabwalla, N.; Robertson, R.T. Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate. Int. J. Pharm.,  2009, 382(1-2), 222-233.
[http://dx.doi.org/10.1016/j.ijpharm.2009.07.030] [PMID:  19664697] 
[245] 
Gao, D.Y.; Lin, TsT.; Sung, Y.C.; Liu, Y.C.; Chiang, W.H.; Chang, C.C.; Liu, J.Y.; Chen, Y. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Biomaterials,  2015, 67, 194-203. [Internet]. 
[http://dx.doi.org/10.1016/j.biomaterials.2015.07.035] [PMID:  26218745] 
[246] 
Mezghrani, O.; Tang, Y.; Ke, X.; Chen, Y.; Hu, D.; Tu, J.; Zhao, L.; Bourkaib, N. Hepatocellular carcinoma dually-targeted nanoparticles for reduction triggered intracellular delivery of doxorubicin. Int. J. Pharm.,  2015, 478(2), 553-568.
[http://dx.doi.org/10.1016/j.ijpharm.2014.10.041] [PMID:  25455765] 
[247] 
Zhang, X.; Zhang, Q.; Peng, Q.; Zhou, J.; Liao, L.; Sun, X.; Zhang, L.; Gong, T. Hepatitis B virus preS1-derived lipopeptide functionalized liposomes for targeting of hepatic cells. Biomaterials,  2014, 35(23), 6130-6141.
[http://dx.doi.org/10.1016/j.biomaterials.2014.04.037] [PMID:  24797877] 
[248] 
Rui, M.; Guo, W.; Ding, Q.; Wei, X.; Xu, J.; Xu, Y. Recombinant high-density lipoprotein nanoparticles containing gadolinium-labeled cholesterol for morphologic and functional magnetic resonance imaging of the liver. Int. J. Nanomedicine,  2012, 7, 3751-3768.
[http://dx.doi.org/10.2147/IJN.S33139] [PMID:  22888232] 
[249] 
Skajaa, T.; Cormode, D.P.; Jarzyna, P.A.; Delshad, A.; Blachford, C.; Barazza, A.; Fisher, E.A.; Gordon, R.E.; Fayad, Z.A.; Mulder, W.J. The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis. Biomaterials,  2011, 32(1), 206-213.
[http://dx.doi.org/10.1016/j.biomaterials.2010.08.078] [PMID:  20926130] 
[250] 
Kim, S.I.; Shin, D.; Choi, T.H.; Lee, J.C.; Cheon, G.J.; Kim, K.Y.; Park, M.; Kim, M. Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. Mol. Ther.,  2007, 15(6), 1145-1152.
[http://dx.doi.org/10.1038/sj.mt.6300168] [PMID:  17440441] 
[251] 
Renaud, G.; Hamilton, R.L.; Havel, R.J. Hepatic metabolism of colloidal gold-low-density lipoprotein complexes in the rat: evidence for bulk excretion of lysosomal contents into bile. Hepatology,  1989, 9(3), 380-392.
[http://dx.doi.org/10.1002/hep.1840090307] [PMID:  2920994] 
[252] 
Wu, F.; Wuensch, S.A.; Azadniv, M.; Ebrahimkhani, M.R.; Crispe, I.N. Galactosylated LDL nanoparticles: a novel targeting delivery system to deliver antigen to macrophages and enhance antigen specific T cell responses. Mol. Pharm.,  2009, 6(5), 1506-1517.
[http://dx.doi.org/10.1021/mp900081y] [PMID:  19637876] 
[253] 
Fischer, H.C.; Hauck, T.S.; Gómez-Aristizábal, A.; Chan, W.C.W. Exploring primary liver macrophages for studying quantum dot interactions with biological systems. Adv. Mater.,  2010, 22(23), 2520-2524.
[http://dx.doi.org/10.1002/adma.200904231] [PMID:  20491094] 
[254] 
Akhter, A.; Hayashi, Y.; Sakurai, Y.; Ohga, N.; Hida, K.; Harashima, H. Ligand density at the surface of a nanoparticle and different uptake mechanism: two important factors for successful siRNA delivery to liver endothelial cells. Int. J. Pharm.,  2014, 475(1-2), 227-237.
[http://dx.doi.org/10.1016/j.ijpharm.2014.08.048] [PMID:  25169077] 
[255] 
Du, S.L.; Pan, H.; Lu, W.Y.; Wang, J.; Wu, J.; Wang, J.Y. Cyclic Arg-Gly-Asp peptide-labeled liposomes for targeting drug therapy of hepatic fibrosis in rats. J. Pharmacol. Exp. Ther.,  2007, 322(2), 560-568.
[http://dx.doi.org/10.1124/jpet.107.122481] [PMID:  17510318] 
[256] 
Adrian, J.E.; Kamps, J.A.A.M.; Poelstra, K.; Scherphof, G.L.; Meijer, D.K.F.; Kaneda, Y. Delivery of viral vectors to hepatic stellate cells in fibrotic livers using HVJ envelopes fused with targeted liposomes. J. Drug Target.,  2007, 15(1), 75-82.
[http://dx.doi.org/10.1080/10611860601141481] [PMID:  17365276] 
[257] 
Sato, Y.; Murase, K.; Kato, J.; Kobune, M.; Sato, T.; Kawano, Y.; Takimoto, R.; Takada, K.; Miyanishi, K.; Matsunaga, T.; Takayama, T.; Niitsu, Y. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat. Biotechnol.,  2008, 26(4), 431-442.
[http://dx.doi.org/10.1038/nbt1396] [PMID:  18376398] 
[258] 
Duong, H.T.T.; Dong, Z.; Su, L.; Boyer, C.; George, J.; Davis, T.P.; Wang, J. The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension. Small,  2015, 11(19), 2291-2304.
[http://dx.doi.org/10.1002/smll.201402870] [PMID:  25641921] 
[259] 
Zhang, Z.; Wang, C.; Zha, Y.; Hu, W.; Gao, Z.; Zang, Y.; Chen, J.; Zhang, J.; Dong, L. Corona-directed nucleic acid delivery into hepatic stellate cells for liver fibrosis therapy. ACS Nano,  2015, 9(3), 2405-2419.
[http://dx.doi.org/10.1021/nn505166x] [PMID:  25587629] 
[260] 
Wang, Q.B.; Han, Y.; Jiang, T.T.; Chai, W.M.; Chen, K.M.; Liu, B.Y.; Wang, L.F.; Zhang, C.; Wang, D.B. MR Imaging of activated hepatic stellate cells in liver injured by CCl4 of rats with integrin-targeted ultrasmall superparamagnetic iron oxide. Eur. Radiol.,  2011, 21(5), 1016-1025.
[http://dx.doi.org/10.1007/s00330-010-1988-z] [PMID:  20972894] 
[261] 
Kamps, J.A.A.M.; Morselt, H.W.M.; Swart, P.J.; Meijer, D.K.F.; Scherphof, G.L. Massive targeting of liposomes, surface-modified with anionized albumins, to hepatic endothelial cells. Proc. Natl. Acad. Sci. USA,  1997, 94(21), 11681-11685.
[http://dx.doi.org/10.1073/pnas.94.21.11681] [PMID:  9326670] 
[262] 
Li, F.; Li, Q.H.; Wang, J.Y.; Zhan, C.Y.; Xie, C.; Lu, W.Y. Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats. J. Control. Release,  2012, 159(2), 261-270.
[http://dx.doi.org/10.1016/j.jconrel.2011.12.023] [PMID:  22226772] 
[263] 
Starvaggi Cucuzza, L.; Motta, M.; Miretti, S.; Accornero, P.; Baratta, M. Curcuminoid-phospholipid complex induces apoptosis in mammary epithelial cells by STAT-3 signaling. Exp. Mol. Med.,  2008, 40(6), 647-657.
[http://dx.doi.org/10.3858/emm.2008.40.6.647] [PMID:  19116450] 
[264] 
Agrawal, M.; Saraf, S.; Saraf, S.; Antimisiaris, S.G.; Chougule, M.B.; Shoyele, S.A.; Alexander, A. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release,  2018, 281(May), 139-177.
[http://dx.doi.org/10.1016/j.jconrel.2018.05.011] [PMID:  29772289] 
[265] 
Andres, S.; Pevny, S.; Ziegenhagen, R.; Bakhiya, N.; Schäfer, B.; Hirsch-Ernst, K.I.; Lampen, A. Safety aspects of the use of quercetin as a dietary supplement. Mol. Nutr. Food Res.,  2018, 62(1), 1-15.
[http://dx.doi.org/10.1002/mnfr.201700447] [PMID:  29127724] 
[266] 
Li, F.; Wang, Y.; Li, D.; Chen, Y.; Qiao, X.; Fardous, R.; Lewandowski, A.; Liu, J.; Chan, T.H.; Dou, Q.P. Perspectives on the recent developments with green tea polyphenols in drug discovery. Expert Opin. Drug Discov.,  2018, 13(7), 643-660.
[PMID:  29688074] 
[267] 
Li, H.; Wang, Z.; Zhang, J.; Yuan, C.; Zhang, H.; Hou, X.; Zhang, D. Enhanced shRNA delivery by the combination of polyethylenimine, ultrasound, and nanobubbles in liver cancer. Technol. Health Care,  2019, 27(S1), 263-272.
[http://dx.doi.org/10.3233/THC-199025] [PMID:  31045545] 
[268] 
Ebrahim Attia, A.B.; Oh, P.; Yang, C.; Tan, J.P.K.; Rao, N.; Hedrick, J.L.; Yang, Y.Y.; Ge, R. Insights into EPR effect versus lectin-mediated targeted delivery: biodegradable polycarbonate micellar nanoparticles with and without galactose surface decoration. Small,  2014, 10(21), 4281-4286.
[PMID:  25091699] 
[269] 
Shi, J.; Kantoff, P.W.; Wooster, R.; Farokhzad, O.C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer,  2017, 17(1), 20-37.
[http://dx.doi.org/10.1038/nrc.2016.108] [PMID:  27834398] 
[270] 
Hansen, A.E.; Petersen, A.L.; Henriksen, J.R.; Boerresen, B.; Rasmussen, P.; Elema, D.R.; af Rosenschöld, P.M.; Kristensen, A.T.; Kjær, A.; Andresen, T.L. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano,  2015, 9(7), 6985-6995.
[http://dx.doi.org/10.1021/acsnano.5b01324] [PMID:  26022907] 
[271] 
Wilhelm, S.; Tavares, A.J.; Dai, Q.; Ohta, S.; Julie, A.; Dvorak, H.F. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater.,  2016, 1, 16014.
[http://dx.doi.org/10.1038/natrevmats.2016.14] 
[272] 
Rolland, J.P.; Maynor, B.W.; Euliss, L.E.; Exner, A.E.; Denison, G.M.; DeSimone, J.M. Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials. J. Am. Chem. Soc.,  2005, 127(28), 10096-10100.
[http://dx.doi.org/10.1021/ja051977c] [PMID:  16011375] 
[273] 
Karnik, R.; Gu, F.; Basto, P.; Cannizzaro, C.; Dean, L.; Kyei-manu, W. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett.,  2008, 8(9), 2906-2912.
[274] 
Kim, Y.; Lee Chung, B.; Ma, M.; Mulder, W.J.M.; Fayad, Z.A.; Farokhzad, O.C.; Langer, R. Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices. Nano Lett.,  2012, 12(7), 3587-3591.
[http://dx.doi.org/10.1021/nl301253v] [PMID:  22716029] 
[275] 
Xu, J.; Wong, D.H.C.; Byrne, J.D.; Chen, K.; Bowerman, C.; DeSimone, J.M. Future of the particle replication in nonwetting templates (PRINT) technology. Angew. Chem. Int. Ed. Engl.,  2013, 52(26), 6580-6589.
[http://dx.doi.org/10.1002/anie.201209145] [PMID:  23670869] 
[276] 
Sharpless, N.E.; Depinho, R.A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov.,  2006, 5(9), 741-754.
[http://dx.doi.org/10.1038/nrd2110] [PMID:  16915232] 
[277] 
Choi, S.Y.C.; Lin, D.; Gout, P.W.; Collins, C.C.; Xu, Y.; Wang, Y. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv. Drug Deliv. Rev.,  2014, 79-80, 222-237.
[http://dx.doi.org/10.1016/j.addr.2014.09.009] [PMID:  25305336] 
[278] 
Lin, D.; Wyatt, A.W.; Xue, H.; Wang, Y.; Dong, X.; Haegert, A.; Wu, R.; Brahmbhatt, S.; Mo, F.; Jong, L.; Bell, R.H.; Anderson, S.; Hurtado-Coll, A.; Fazli, L.; Sharma, M.; Beltran, H.; Rubin, M.; Cox, M.; Gout, P.W.; Morris, J.; Goldenberg, L.; Volik, S.V.; Gleave, M.E.; Collins, C.C.; Wang, Y. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res.,  2014, 74(4), 1272-1283.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2921-T] [PMID:  24356420] 
[279] 
Rongvaux, A.; Willinger, T.; Martinek, J.; Strowig, T.; Gearty, S.V.; Teichmann, L.L.; Saito, Y.; Marches, F.; Halene, S.; Palucka, A.K.; Manz, M.G.; Flavell, R.A. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol.,  2014, 32(4), 364-372.
[http://dx.doi.org/10.1038/nbt.2858] [PMID:  24633240] 
[280] 
Hubbard, G.K.; Mutton, L.N.; Khalili, M.; McMullin, R.P.; Hicks, J.L.; Bianchi-Frias, D.; Horn, L.A.; Kulac, I.; Moubarek, M.S.; Nelson, P.S.; Yegnasubramanian, S.; De Marzo, A.M.; Bieberich, C.J. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res.,  2016, 76(2), 283-292.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-3280] [PMID:  26554830] 
Cite As
Current Topics in Medicinal Chemistry

Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer

Abstract

Graphical Abstract
