Glycyrrhetinic Acid and TAT Peptide Modified Dual-functional Liposomes for Treatment of Hepatocellular Cancer

Author(s): Sixi Huang, Di Ren, Xinrong Wu, Ming Li, Xuesong Yu, Xiaoling Nie, Ying Wang*, Yan Wang*

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 27 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Surgery remains the front-line therapeutic strategy to treat early hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC patients are high. 10- Hydroxycamptothecin (10-HCPT) is a known anti-HCC agent but its poor solubility and bioavailability have limited its clinical use.

Objective: In this study, we developed a novel nanoliposome encapsulated 10-hydroxycamptothecin modified with glycyrrhetinic acid (GA) and TAT peptide (GA/TAT-HCPT-LP) for the treatment of HCC. Dual modified GA and TAT can enhance tumor targeting and tumor penetration.

Methods: The GA/TAT-HCPT-LP NPs were synthesized using the thin-film dispersion method. GA/TAT-HCPT-LP were characterized for particle size, zeta potential and morphology. Drug release from the GA/TAT-HCPT-LP liposomes was measured by dialysis. Cell-uptake was assessed by microscopy and flow cytometry. Cell proliferation, migration and apoptosis were measured to evaluate in vitro antitumor activity of GA/TAT-HCPT-LP via CCK-8 assays, Transwell assays, and flow cytometry, respectively. The in vivo distribution of GA/TAT-HCPT-LP was evaluated in HCC animal models. Tumor- bearing mouse models were used to assess the in vivo therapeutic efficacy of GA/TAT-HCPT-LP.

Results: The mean particle size and mean zeta potential of GA/TAT-HCPT-LP were 135.55 ± 2.76 nm and -4.57 ± 0.23 mV, respectively. Transmission electron micrographs (TEM) showed that the GA/TAT-HCPT-LP had a near spherical shape and a double-membrane structure. GA/TAT-HCPT-LP led to slow and continuous drug release, and could bind to HepG2 cells more readily than other groups. Compared to control groups, treatment with GA/TAT-HCPT-LP had a significantly large effect on inhibiting cell proliferation, tumor cell migration and cell apoptosis. In vivo assays showed that GA/TATHCPT- LP selectively accumulated in tumor tissue with obvious antitumor efficacy.

Conclusion: In conclusion, the synthesized GA/TAT-HCPT-LP could effectively target tumor cells and enhance cell penetration, highlighting its potential for hepatocellular cancer therapy.

Keywords: Liposomes, 10-hydroxycamptothecin, Glycyrrhetinic acid, TAT peptide, Hepatocellular cancer, Tumor-targeting.

[1]
Ryerson, A.B.; Eheman, C.R.; Altekruse, S.F.; Ward, J.W.; Jemal, A.; Sherman, R.L.; Henley, S.J.; Holtzman, D.; Lake, A.; Noone, A.M.; Anderson, R.N.; Ma, J.; Ly, K.N.; Cronin, K.A.; Penberthy, L.; Kohler, B.A. Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer, 2016, 122(9), 1312-1337.
[http://dx.doi.org/10.1002/cncr.29936] [PMID: 26959385]
[2]
Bollard, J.; Miguela, V.; Ruiz de Galarreta, M.; Venkatesh, A.; Bian, C.B.; Roberto, M.P.; Tovar, V.; Sia, D.; Molina-Sánchez, P.; Nguyen, C.B.; Nakagawa, S.; Llovet, J.M.; Hoshida, Y.; Lujambio, A. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut, 2017, 66(7), 1286-1296.
[http://dx.doi.org/10.1136/gutjnl-2016-312268] [PMID: 27849562]
[3]
Dutta, R.; Mahato, R.I. Recent advances in hepatocellular carcinoma therapy. Pharmacol. Ther., 2017, 173, 106-117.
[http://dx.doi.org/10.1016/j.pharmthera.2017.02.010] [PMID: 28174094]
[4]
Chen, G.; Li, J.; Cai, Y.; Zhan, J.; Gao, J.; Song, M.; Shi, Y.; Yang, Z. A Glycyrrhetinic acid-modified curcumin supramolecular hydrogel for liver tumor targeting therapy. Sci. Rep., 2017, 7, 44210.
[http://dx.doi.org/10.1038/srep44210] [PMID: 28281678]
[5]
Li, Q.; Liu, C.; Zhao, X.; Zu, Y.; Wang, Y.; Zhang, B.; Zhao, D.; Zhao, Q.; Su, L.; Gao, Y.; Sun, B. Preparation, characterization and targeting of micronized 10-hydroxycamptothecin-loaded folate-conjugated human serum albumin nanoparticles to cancer cells. Int. J. Nanomedicine, 2011, 6, 397-405.
[PMID: 21499429]
[6]
Yang, X.; Liu, Y.; Zhao, Y.; Han, M.; Guo, Y.; Kuang, H.; Wang, X. A stabilizer-free and organic solvent-free method to prepare 10-hydroxycamptothecin nanocrystals: in vitro and in vivo evaluation. Int. J. Nanomedicine, 2016, 11, 2979-2994.
[http://dx.doi.org/10.2147/IJN.S102726] [PMID: 27382284]
[7]
Yao, R.; Liu, L.; Deng, S.; Ren, W. Preparation of carboxymethylchitosan nanoparticles with Acid-sensitive bond based on solid dispersion of 10-hydroxycamptothecin. ISRN Pharm., 2011, 2011624704
[http://dx.doi.org/10.5402/2011/624704] [PMID: 22389854]
[8]
Bao, H.; Zhang, Q.; Xu, H.; Yan, Z. Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies. Int. J. Nanomedicine, 2016, 11, 929-940.
[9]
Rezaee, Z.; Yadollahpour, A.; Bayati, V.; Negad Dehbashi, F. Gold nanoparticles and electroporation impose both separate and synergistic radiosensitizing effects in HT-29 tumor cells: an in vitro study. Int. J. Nanomedicine, 2017, 12, 1431-1439.
[http://dx.doi.org/10.2147/IJN.S128996] [PMID: 28260889]
[10]
Mohandas, R.; Gayathri, R.; Priya, V. Cancer nanotechnology: A review. Drug Invent. Today, 2018, 10, 2719-2726.
[11]
Yadollahpour, A.; Jalilifar, M.; Rashidi, S. A review of the feasibility and clinical applications of magnetic nanoparticles as contrast agents in magnetic resonance imaging. Int. J. Pharm. Technol., 2016, 8, 14737-14748.
[12]
Yadollahpour, A.; Venkateshwarlu, G. Applications of gadolinium nanoparticles in magnetic resonance imaging: a review on recent advances in clinical imaging. Int. J. Pharm. Technol., 2016, 8, 11379-11393.
[13]
Yadollahpour, A.; Hosseini, S.A.A.; Jalilifar, M.; Rashidi, S.; Rai, B.M.M. Magnetic nanoparticle-based drug and gene delivery: a review of recent advances and clinical applications. Int. J. Pharm. Technol., 2016, 8, 11451-11466.
[14]
Yadollahpour, A.; Rashidi, S. Magnetic nanoparticles: a review of chemical and physical characteristics important in medical applications. Orient. J. Chem., 2015, 31, 25-30.
[http://dx.doi.org/10.13005/ojc/31.Special-Issue1.03]
[15]
Lin, Y.; Wang, Y.; Lv, J.; Wang, N.; Wang, J.; Li, M. Targeted acetylcholinesterase-responsive drug carriers with long duration of drug action and reduced hepatotoxicity. Int. J. Nanomedicine, 2019, 14, 5817-5829.
[http://dx.doi.org/10.2147/IJN.S215404] [PMID: 31440049]
[16]
Tong, R.; Cheng, J. Anticancer polymeric nanomedicines. Polym. Rev. (Phila. Pa.), 2007, 47, 345-381.
[http://dx.doi.org/10.1080/15583720701455079]
[17]
Maeng, J.H.; Lee, D.H.; Jung, K.H.; Bae, Y.H.; Park, I.S.; Jeong, S.; Jeon, Y.S.; Shim, C.K.; Kim, W.; Kim, J.; Lee, J.; Lee, Y.M.; Kim, J.H.; Kim, W.H.; Hong, S.S. Multifunctional doxorubicin loaded superparamagnetic iron oxide nanoparticles for chemotherapy and magnetic resonance imaging in liver cancer. Biomaterials, 2010, 31(18), 4995-5006.
[http://dx.doi.org/10.1016/j.biomaterials.2010.02.068] [PMID: 20347138]
[18]
Elbayoumi, T.A.; Torchilin, V.P. Current trends in liposome research. Methods Mol. Biol., 2010, 605, 1-27.
[http://dx.doi.org/10.1007/978-1-60327-360-2_1] [PMID: 20072870]
[19]
Bozzuto, G.; Molinari, A. Liposomes as nanomedical devices. Int. J. Nanomedicine, 2015, 10, 975-999.
[http://dx.doi.org/10.2147/IJN.S68861] [PMID: 25678787]
[20]
Riaz, M.K.; Riaz, M.A.; Zhang, X.; Lin, C.; Wong, K.H.; Chen, X.; Zhang, G.; Lu, A.; Yang, Z. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: a review. Int. J. Mol. Sci., 2018, 19(1), 19.
[http://dx.doi.org/10.3390/ijms19010195] [PMID: 29315231]
[21]
Zhang, P.; Zhang, L.; Qin, Z.; Hua, S.; Guo, Z.; Chu, C.; Lin, H.; Zhang, Y.; Li, W.; Zhang, X.; Chen, X.; Liu, G. Genetically engineered liposome-like nanovesicles as active targeted transport platform. Adv. Mater., 2018, 30(7), 30.
[http://dx.doi.org/10.1002/adma.201705350] [PMID: 29280210]
[22]
Kamaly, N.; Miller, A.D. Paramagnetic liposome nanoparticles for cellular and tumour imaging. Int. J. Mol. Sci., 2010, 11(4), 1759-1776.
[http://dx.doi.org/10.3390/ijms11041759] [PMID: 20480040]
[23]
Deshpande, P.P.; Biswas, S.; Torchilin, V.P. Current trends in the use of liposomes for tumor targeting. Nanomedicine (Lond.), 2013, 8(9), 1509-1528.
[http://dx.doi.org/10.2217/nnm.13.118] [PMID: 23914966]
[24]
Brindha, D.R. S.; A., H. Isolation of chitosan from fish scales of catla catla and synthesis, characterization and screening for larvicidal potential of chitosan-based silver nanoparticles. Drug Invent. Today, 2018, 10, 1357-1362.
[25]
Kumar, R.; Aadil, K.R.; Ranjan, S.; Kumar, V.B. Advances in nanotechnology and nanomaterials based strategies for neural tissue engineering. J. Drug Deliv. Sci. Technol., 2020, 57101617
[http://dx.doi.org/10.1016/j.jddst.2020.101617]
[26]
Sinha, J.; Das, N.; Basu, M.K. Liposomal antioxidants in combating ischemia-reperfusion injury in rat brain. Biomed. Pharmacother., 2001, 55(5), 264-271.
[http://dx.doi.org/10.1016/S0753-3322(01)00060-9] [PMID: 11428552]
[27]
Kong, G.; Anyarambhatla, G.; Petros, W.P.; Braun, R.D.; Colvin, O.M.; Needham, D.; Dewhirst, M.W. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res., 2000, 60(24), 6950-6957.
[PMID: 11156395]
[28]
Maruyama, K. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects. Adv. Drug Deliv. Rev., 2011, 63(3), 161-169.
[http://dx.doi.org/10.1016/j.addr.2010.09.003] [PMID: 20869415]
[29]
Yadollahpour, A. Magnetic nanoparticles in medicine: a review of synthesis methods and important characteristics. Orient. J. Chem., 2015, 31, 271-277.
[http://dx.doi.org/10.13005/ojc/31.Special-Issue1.33]
[30]
Kebebe, D.; Liu, Y.; Wu, Y.; Vilakhamxay, M.; Liu, Z.; Li, J. Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers. Int. J. Nanomedicine, 2018, 13, 1425-1442.
[http://dx.doi.org/10.2147/IJN.S156616] [PMID: 29563797]
[31]
Yingchoncharoen, P.; Kalinowski, D.S.; Richardson, D.R. Lipid-based drug delivery systems in cancer therapy: what is available and what is yet to come. Pharmacol. Rev., 2016, 68(3), 701-787.
[http://dx.doi.org/10.1124/pr.115.012070] [PMID: 27363439]
[32]
Zhou, L.; Zou, M.; Zhu, K.; Ning, S.; Xia, X. Development of 11-dga-3-o-gal-modified cantharidin liposomes for treatment of hepatocellular Carcinoma. Molecules, 2019, 24(17), 24.
[http://dx.doi.org/10.3390/molecules24173080] [PMID: 31450608]
[33]
Chen, J.; Jiang, H.; Wu, Y.; Li, Y.; Gao, Y. A novel glycyrrhetinic acid-modified oxaliplatin liposome for liver-targeting and in vitro/vivo evaluation. Drug Des. Devel. Ther., 2015, 9, 2265-2275.
[PMID: 25945038]
[34]
Lv, Y.; Li, J.; Chen, H.; Bai, Y.; Zhang, L. Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier. Int. J. Nanomedicine, 2017, 12, 4361-4370.
[http://dx.doi.org/10.2147/IJN.S135626] [PMID: 28652738]
[35]
Shin, M.C.; Zhang, J.; Min, K.A.; Lee, K.; Byun, Y.; David, A.E.; He, H.; Yang, V.C. Cell-penetrating peptides: achievements and challenges in application for cancer treatment. J. Biomed. Mater. Res. A, 2014, 102(2), 575-587.
[http://dx.doi.org/10.1002/jbm.a.34859] [PMID: 23852939]
[36]
Habault, J.; Poyet, J.L. Recent advances in cell penetrating peptide-based anticancer therapies. Molecules, 2019, 24(5), 24.
[http://dx.doi.org/10.3390/molecules24050927] [PMID: 30866424]
[37]
Koren, E.; Apte, A.; Jani, A.; Torchilin, V.P. Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity. J. Control. Release, 2012, 160(2), 264-273.
[http://dx.doi.org/10.1016/j.jconrel.2011.12.002] [PMID: 22182771]
[38]
Torchilin, V.P.; Rammohan, R.; Weissig, V.; Levchenko, T.S. In: TAT Peptide on the Surface of Liposomes Affords Their Efficient Intracellular Delivery Even at Low Temperature and in the Presence of Metabolic Inhibitors. Proceedings of the National Academy of Sciences of the United States of America, , pp. 8786-8791.
[http://dx.doi.org/10.1073/pnas.151247498]
[39]
Takara, K.; Hatakeyama, H.; Ohga, N.; Hida, K.; Harashima, H. Design of a dual-ligand system using a specific ligand and cell penetrating peptide, resulting in a synergistic effect on selectivity and cellular uptake. Int. J. Pharm., 2010, 396(1-2), 143-148.
[http://dx.doi.org/10.1016/j.ijpharm.2010.05.002] [PMID: 20457236]
[40]
Zhu, Y.; Cheng, L.; Cheng, L.; Huang, F.; Hu, Q.; Li, L.; Tian, C.; Wei, L.; Chen, D. Folate and TAT peptide co-modified liposomes exhibit receptor-dependent highly efficient intracellular transport of payload in vitro and in vivo. Pharm. Res., 2014, 31(12), 3289-3303.
[http://dx.doi.org/10.1007/s11095-014-1418-z] [PMID: 24858397]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 27
Year: 2020
Page: [2493 - 2505]
Pages: 13
DOI: 10.2174/1568026620666200722110244
Price: $65

Article Metrics

PDF: 30
HTML: 3
EPUB: 2
PRC: 2