Advances in Nanoliposomes for the Diagnosis and Treatment of Liver Cancer

Figures & data

Table 1 Active Targeting of HCC Through VCAM-1, GA-R, ASGPR as Well as Others Receptors

	Target Points	Nanomaterials	References
Microvascular endothelial cells	VCAM-1	Dexamethasone loaded anti-VCAM-1 SAINT-O-Somes	^Citation40
HCC cells	GA-R	GA and PNAmodified doxorubicin-loaded liposomes (DOX-GA/PNA-Lips)	^Citation41
		Glycyrrhetinic acid-modified oxaliplatin liposome (GA-OX)	^Citation42
	ASGPR	Galactose Modified Liposomes (Gal-LP)	^Citation43
		Celastrol-Loaded Galactosylated Liposomes (C-GPL)	^Citation44
		ASF-lipoplexes	^Citation45
		Lactobionic acid coupled liposomes (LA-LP)	^Citation46
		Gal-doxorubicin/vimentin siRNA liposome (Gal-DOX/siRNA-L)	^Citation47
		Lactoferrin-modified-Stealth liposome (Lf-Stealth-LIPO)	^Citation48
	Pin1	Liposome-Encapsulated Pin1 Inhibitor (API-LP)	^Citation49
	FA	Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin (DM-NCTD/FA-PEG)	^Citation50
	TfR	Tf-targeted anti-miR-221 liposome (Tf-RL)	^Citation51
		Transferrin-guided polycarbonate-based polymersomal doxorubicin (Tf-Ps-Dox)	^Citation52
	LDLR	Liposomes loaded with Cholesteryl-succinyl-5-fluorouracil conjugate (5-FUC liposome)	^Citation53
	EGFR	GE11 peptide-functionalized polymersomal doxorubicin (GE11-PS-DOX)	^Citation54
		Targeted LPD conjugated with anti-EGFR Fab’ co-delivering ADR and RRM2 siRNA (ADR-RRM2-TLPD)	^Citation55

Abbreviations: HCC, hepatocellular carcinoma; VCAM-1, vascular cell adhesion molecule-1; GA-R, glycyrrhetinic acid receptors; ASGPR, asialoglycoprotein receptor; Pin1, peptidyl-prolyl cis/trans isomerase; FA, folic acid; TfR, transferrin receptor; LDLR, low-density lipoprotein receptor; EGFR, epidermal growth factor receptor; SAINT-C18, 1-methyl-4-(cis-9-dioleyl) methyl-pyridinium-chloride; PNA, peanut agglutinin; ASF, asialofetuin; LPD, liposome-polycation-DNA complex; ADR, Adriamycin; RRM2, ribonucleotide reductase M2, siRNA, small interfering RNA.

Figure 1 Liposomes act on tumor microvascular endothelial cells and HCC cells.

Note: The liposome targeting ligand recognizes the receptor then undergoes internalization and release of the delivered cargo, thus exerts therapeutic effects.

Abbreviations: VCAM-1, vascular cell adhesion molecule-1; GA-R, glycyrrhetinic acid receptors; ASGPR, asialoglycoprotein receptor; Pin1, peptidyl-prolyl cis/trans isomerase; FA, folic acid; TfR, transferrin receptor; LDLR, low-density lipoprotein receptor; EGFR, epidermal growth factor receptor.

Figure 2 Mechanism of liposome combined gene therapy.

Notes: Encapsulating siRNA, mRNA, or DNA in liposomes. siRNA binds to certain enzymes and proteins in the cell to form an RNA-induced silencing complex (RISC) that binds to the target mRNA, cutting it off and degrading it. mRNA enters the cell and expresses proteins. cas9/tracrRNA/rNcrRNA targets DNA to cause double-stranded breaks (DSB) in DNA, resulting in gene editing. Reprinted from Advanced Drug Delivery Reviews, 159, Witzigmann D, Kulkarni JA, Leung J, Chen S, Cullis PR, van der Meel R. Lipid nanoparticle technology for therapeutic gene regulation in the liver, 344-363, Copyright 2022, with permission from Elsevier.⁹²

Abbreviations: siRNA, small interfering RNA; mRNA, message RNA; cas9, clustered regularly interspaced short palindromic repeat-associated nuclease 9; crRNA, CRISPR RNA; tracrRNA, trans-acting crRNA.

Figure 3 Ultrasound induces thermal, mechanical and chemical effects.

Note: It is worth emphasizing that these effects are not independent, but occur simultaneously and interact with each other.

Li RR, Kowalski PS, Morselt HWM, et al. Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia. PLoS One. 2018;13(5):e0196976. doi:10.1371/journal.pone.0196976

 PubMed Web of Science ®Google Scholar

Li XC, Diao WB, Xue HT, et al. Improved efficacy of doxorubicin delivery by a novel dual-ligand-modified liposome in hepatocellular carcinoma. Cancer Lett. 2020;489:163–173. doi:10.1016/j.canlet.2020.06.017

 PubMed Web of Science ®Google Scholar

Chen JD, Jiang H, Wu Y, Li YD, Gao Y. A novel glycyrrhetinic acid-modified oxaliplatin liposome for liver-targeting and in vitro/vivo evaluation. Drug Des Dev Ther. 2015;9:2265–2275. doi:10.2147/Dddt.S81722

 PubMed Web of Science ®Google Scholar

Lian B, Wei H, Pan RY, et al. Galactose modified liposomes for effective co-delivery of doxorubicin and combretastatin A4. Int J Nanomed. 2021;16:457–467. doi:10.2147/Ijn.S283793

 PubMed Web of Science ®Google Scholar

Chen XY, Hu XX, Hu JJ, Qiu ZP, Yuan M, Zheng GH. Celastrol-loaded galactosylated liposomes effectively inhibit AKT/c-met-triggered rapid hepatocarcinogenesis in mice. Mol Pharm. 2020;17(3):738–747. doi:10.1021/acs.molpharmaceut.9b00428

 PubMed Web of Science ®Google Scholar

Farinha D, de Lima MCP, Faneca H. Specific and efficient gene delivery mediated by an asialofetuin-associated nanosystem. Int J Pharm. 2014;473(1–2):366–374. doi:10.1016/j.ijpharm.2014.07.019

 PubMed Web of Science ®Google Scholar

Bansal D, Yadav K, Pandey V, Ganeshpurkar A, Agnihotri A, Dubey N. Lactobionic acid coupled liposomes: an innovative strategy for targeting hepatocellular carcinoma. Drug Deliv. 2016;23(1):140–146. doi:10.3109/10717544.2014.907373

 PubMed Web of Science ®Google Scholar

Oh HR, Jo HY, Park JS, et al. Galactosylated liposomes for targeted co-delivery of doxorubicin/vimentin siRNA to hepatocellular carcinoma. Nanomaterials (Basel). 2016;6(8):141. doi:10.3390/nano6080141

 PubMedGoogle Scholar

Pireddu R, Pibiri M, Valenti D, et al. A novel lactoferrin-modified stealth liposome for hepatoma-delivery of triiodothyronine. Int J Pharm. 2018;537(1–2):257–267. doi:10.1016/j.ijpharm.2017.12.048

 PubMed Web of Science ®Google Scholar

Sun D, Tan SY, Xiong YL, et al. MicroRNA biogenesis is enhanced by liposome-encapsulated Pin1 inhibitor in hepatocellular carcinoma. Theranostics. 2019;9(16):4704–4716. doi:10.7150/thno.34588

 PubMed Web of Science ®Google Scholar

Liu MC, Liu L, Wang XR, et al. Folate receptor-targeted liposomes loaded with a diacid metabolite of norcantharidin enhance antitumor potency for H22 hepatocellular carcinoma both in vitro and in vivo. Int J Nanomed. 2016;11:1395–1412. doi:10.2147/Ijn.S96862

 PubMed Web of Science ®Google Scholar

Zhang WD, Peng FQ, Zhou TT, et al. Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes. Int J Nanomed. 2015;10:4825–4836. doi:10.2147/Ijn.S79598

 PubMed Web of Science ®Google Scholar

Wei YH, Gu XL, Cheng L, Meng FH, Storm G, Zhong ZY. Low-toxicity transferrin-guided polymersomal doxorubicin for potent chemotherapy of orthotopic hepatocellular carcinoma in vivo. Acta Biomater. 2019;92:196–204. doi:10.1016/j.actbio.2019.05.034

 PubMed Web of Science ®Google Scholar

Alanazi SA, Harisa GI, Badran MM, et al. Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition. Bioengineered. 2021;12(1):914–926. doi:10.1080/21655979.2021.1896202

 PubMed Web of Science ®Google Scholar

Fang Y, Yang WJ, Cheng L, Meng FH, Zhang J, Zhong ZY. EGFR-targeted multifunctional polymersomal doxorubicin induces selective and potent suppression of orthotopic human liver cancer in vivo. Acta Biomater. 2017;64:323–333. doi:10.1016/j.actbio.2017.10.013

 PubMed Web of Science ®Google Scholar

Gao J, Chen HW, Yu YS, et al. Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of Adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials. 2013;34(38):10084–10098. doi:10.1016/j.biomaterials.2013.08.088

 PubMed Web of Science ®Google Scholar

Witzigmann D, Kulkarni JA, Leung J, Chen S, Cullis PR, Van Der Meel R. Lipid nanoparticle technology for therapeutic gene regulation in the liver. Adv Drug Deliv Rev. 2020;159:344–363. doi:10.1016/j.addr.2020.06.026

 PubMed Web of Science ®Google Scholar