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      Ligand-modified Nanomaterials for Specific Targeting of Hepatocellular Carcinoma



            Hepatocellular carcinoma (HCC) is the leading cause of death globally. Patients with HCC are generally diagnosed at advanced stages, which leads to their dismal survival status. Current treatment strategies for HCC mainly include liver transplantation, local ablative treatment, surgical resection, and systematic therapy with chemotherapeutic reagents. However, the low efficacy and side effects essentially limit the prognosis of HCC patients. In recent years, significant success has been achieved in the nanomedicine area. Nanomaterials could achieve selective and effective targeting of cancer cells by functionalization and surface modification, enhancing their ability to encapsulate drugs and diagnostic agents and bind to specific molecules on the cancer cell surface. This review introduces the representative ligands, such as monoclonal antibodies, peptides, and glycoproteins, extensively used to decorate nanomaterials that target the HCC cell surface.

            Main article text

            1 INTRODUCTION

            Hepatocellular carcinoma (HCC) is the predominant liver malignancy that accounts for over 80% of liver cancer types[1]. According to global cancer statistics, HCC is one of the most commonly diagnosed cancers and a third leading cause of death worldwide, causing more than 800,000 new deaths in 2020[2]. Patients with HCC barely present apparent symptoms, which leads to diagnosis at late stages and limited therapeutic options are available[3]. HCC usually arises from chronic liver diseases with various etiologies, including viral infection of hepatitis C and hepatitis B, non-alcoholic steatohepatitis, and alcoholic liver disease[4,5]. In Asia and Africa, other risk factors such as aflatoxin B1, the potent mycotoxin taken in through food contamination, also contribute to the generation of HCC[6,7]. On the other hand, HCC development is a cumulative result of epigenetic and genetic factors, which ultimately lead to altered molecular regulation, such as elevated expression of growth factor receptors[6].

            Currently, the treatment strategy for HCC is formulated depending on the patient’s status, liver function, and tumor stage[8]. For patients with early-stage HCC, liver transplantation, local ablative treatment, and surgical resection were widely applied[9]. As for patients diagnosed at late stages, trans-arterial chemoembolization and systemic therapies are the only available treatment options[10]. Systematic treatment with chemotherapeutic reagents such as mitomycin C, doxorubicin, or cisplatin are used[11]. Nevertheless, the poor therapeutic responses and severe side effects caused by non-specific targeting generate multiple drug resistance and a high recurrence rate significantly restrain the application of chemotherapy[11]. On the other hand, patients with poor liver status and other contraindications are not suitable for surgical intervention[12].

            Compared to conventional chemotherapy, targeted therapy that inhibits specific cell regulatory signaling has been demonstrated as a promising approach for HCC management[13]. For example, sorafenib is the approved first-line therapeutic agent for HCC and suppresses HCC progression by inhibiting the function of multiple kinases such as RAF/MEK, VEGFR, and PDGFR signaling[14,15]. It is worth noting that nanotechnology facilitates the precise delivery and accumulation of anticancer into tumor sites through encapsulation with the help of nanomaterials[16].

            Nanomaterials, such as polymeric, metallic, and lipid-based nanoparticles, have attracted remarkable attention in cancer therapy due to their significant advantages as a drug delivery system; this is because of their smaller size, large surface area, and high biosafety and biocompatibility[17]. These nanomaterials achieve selective and effective targeting of cancer cells by functionalization and surface modification, enhancing their ability to encapsulate drugs and diagnostic agents and bind to specific molecules on the cancer cell surface[18]. By conjugating ligands or markers that are highly affined to specific complementary receptors that are highly expressed or solely expressed on the cancer cell membrane, nanomaterials could precisely deliver therapeutic agents to tumor sites and exhibit low toxicity to normal tissues[19]. This review summarized the nanomaterials that target the cancer cell surface for HCC treatment (Table 1).

            Table 1.

            Summary of Nanomaterials that Target HCC Cell Surface

            Nanomaterial CompositionType of TargetingComponents That Are Moiety/Stimuli-Responsive Are Being TargetedRemarksRef.
            Gal-modified selenium NPsDecorating moietiesGalHigher accumulation of DOX in HCC cells and cell apoptosis [32]
            Gal-modified noisomeDecorating moietiesGal/pH sensitiveDelivery of tanshinone IIA to HCC cells [33]
            β-d-galactoside-decorated lipid/calcium/phosphate NPsDecorating moietiesβ-d-galactosideDelivery of VEGF siRNA to HCC cells and suppressed angiogenesis in tumor microenvironment [34]
            Gal-decorated TPGS/polydopamine (PDA) materialDecorating moietiesGal/pH sensitive/photothermal therapyAccumulation of DOX and NO in HCC cells and reverse of MDR [35]
            GPC antibody GC33IgGGPC3 mAbAntibody-dependent cellular cytotoxicity [47,48]
            DNA aptamer-incorporated materialDecorating moietiesGPC3Specific targeting of GPC3-positive HCC cells and delivery of gemcitabine to impede tumor growth [49]
            GPC3 mAb-conjugated ADCsDecorating moietiesGPC3 mAbEffective targeting of GPC3-positive HCC cells, drug delivery, and synergetic effect with gemcitabine in HCC treatment [50]
            GPC3-binding peptide based nanoprobeDecorating moietiesGPC3 binding peptideNIR-II imaging, photoacoustic (PA) imaging-guided photothermal therapy (PTT) for HCC [51]
            Transferrin-coated polycarbonate-based polymersomeDecorating moietiesTransferrinAccumulation of DOX in HCC cells, and cytotoxicity [60]
            Transferrin-conjugated nanoparticle with albumin shell and polyvinyl alcohol coreDecorating moietiesTransferrinDelivery of sorafenib and DOX to induce specific death of HCC cells [61]
            Transferrin-coated liposomesDecorating moietiesTransferrinDelivery of microRNA-221 inhibitors to promote HCC cell apoptosis [62,63]
            Fe3O4-ZnO nanomaterialDecorating moietiesTransferrin receptor antibody (TFR Ab)Facilitate chemotherapeutic efficiency of DOX and simultaneously boost sensitivity to radiotherapy [64]
            Glycyrrhizin (GL)-modified O-Carboxymethyl chitosan NPsDecorating moietiesGLDrug accumulation at target site was 10-fold higher than non-modified nanoparticles [68]
            Glycyrrhetinic acid (GA)-modified chitosan micelleDecorating moietiesGA/pH-responsiveAccumulation and pH-responsive of DOX in HCC cells to kill tumor cells [70]
            GA-modified phthalocyanine (SiPC)Decorating moietiesGAEffectively accumulated in HepG2 tumor and perform [71]
            GA-reinforced thiolated polymerDecorating moietiesGAAccumulation of 5-fluorouracil in HCC cells and effective suppression of carbon tetrachloride (CCl4)-induced HCC tumor [72]
            RGD-modified PHBV nanoparticleCell penetrating peptideIntegrin/pH-sensitiveRelease and accumulation of paclitaxel in HCC cells to induce cell death [79]
            R6-conjugated LRVG polypeptideCell penetrating peptideIntestinal epithelial cellsPromote absorption of Tyroserleutide in the intestinal system [80]
            SP94-PS-DOX nanoparticleDecorating moietiesSP94Specific targeting and cytotoxicity toward SMMC-7721 xenograft model [82]
            SP94-functionalized PLGA-PEG-PEI nanoparticlesDecorating moietiesSP94Specific delivery of prodrugs and thymidine kinase (TK)-p53-nitroreductase therapeutic gene to HCC [83]


            Targeting ligands for nanomaterials modification could be peptides, proteins, sugar residues, aptamers, monoclonal antibodies, and other molecules that present specific affinity to target sites. Here, we introduced several representative ligands widely studied in HCC research.

            2.1 Protein Receptors for HCC Targeting
            2.1.1 Asialoglycoprotein Receptor (ASGPR)

            ASGPR is a transmembrane protein abundant in hepatocytes and is explicitly expressed on the basolateral and sinusoidal hepatocellular surface[20,21]. Whereas under pathological states such as inflammation, ASGPR shifts to the canalicular membrane of liver cells[22]. In liver tissues with cirrhosis, the expression of ASGPR and serum level of asialoglycoprotein are notably elevated[23]. Besides, the ASGPR level is enhanced in patients with both early- and late-stage HCC[24,25]. Therefore, ASGPR could be an ideal therapeutic target for HCC treatment. In normal hepatocytes, ASGPR could uptake and clear desialylated proteins in serum[26,27]. On the other hand, ASGPR participates in the interaction and internalization of extracellular glycoproteins with N-acetyl-galactosamine, galactose (Gal), or lactose residues, which makes ASGPR an ideal target for anti-HCC drug delivery and Gal a suitable ligand for decoration of HCC targeting nanomaterials[28,29].

            Various studies have indicated the utilization of the ASGPR-Gal interaction pair in selective hepatic delivery[30,31]. For example, Xia and their colleagues encapsulated doxorubicin (DOX) into a Gal-modified selenium nanoparticle to form a GA-Se@DOX NPS. These nanoparticles are effectively taken up by HCC HepG2 cells through the endocytosis pathway and induce significant cell apoptosis with no apparent damage to major organs[32]. A pH-sensitive noisome modified with Gal remarkably enhanced the selectivity and efficacy of tanshinone IIA delivery to HCC cells, other than other cancer cell types, and this process largely depended on the level of Gal[33]. Huang et al.[34] designed and screened 8 galactoside derivatives to modify a lipid/calcium/phosphate nanoparticle and determined that phenyl β-d-galactoside-decorated nanoparticles presented a superior delivery ability of VEGF siRNA, which subsequently suppressed angiogenesis and improved the tumor microenvironment in an orthotopic HCC mouse model. A multiple functional drug delivery system that loaded nitric oxide (NO) donor and DOX into a Gal-decorated TPGS/PDA shell was designed to overcome multiple-drug resistance (MDR) of HCC cells[35]. This NO-DOX@PDA-TPGS-Gal targets HCC cells through Gal, released DOX and NO under photothermal therapy, which, with TPGS, impeded the P-glycoprotein-related efflux of DOX, hence reversing MDR in HCC cells[35].

            2.1.2 Glypican-3 (GPC3)

            GPC3, also known as a heparan-sulfate proteoglycan, is a member of the glypican family expressed in the membrane and plasma of hepatocytes[36,37]. The GPC3 protein consists of a heparan sulfate chain, glycosyl phosphatidyl inositol (GPI), and a core protein and is attached to the cell membrane through the GPI anchor[38,39]. Studies have indicated that successful GPC3 is overexpressed in HCC cells but rarely detected in normal and cirrhotic hepatocytes[40,41]. Hsu et al.[42] reported that GPC3 is overexpressed in over 70% of HCC cells and is correlated with poor prognosis and modulates proliferation, metastasis, oncogenesis, and morphogenesis of HCC cells. GPC3 interacts with Wnt protein and activates the canonical Wnt/β-catenin signaling transduction, which significantly participates in tumorigenesis[43,44]. Above mentioned findings suggest GPC3 protein as a specific biomarker and target diagnosis and treatment of HCC[45,46].

            The first reagent targeting GPC3 on HCC cells is a humanized mouse anti-GPC3 monoclonal antibody (mAb) (GC33) that could notably and specifically suppress the growth of GPC3-positive HCC xenograft[47,48]. A gemcitabine-incorporated DNA aptamer that targets GPC3 (G12msi) could specifically bind to and internalized by GPC3-positive HCC cells, significantly suppressing HCC tumor growth[49]. Fu et al.[50] proposed the GPC3 antibody as an antibody-drug conjugates (ADCs) component. They screened large drug libraries to construct two GPC3-specific ADCs, which exhibited a synergetic effect with gemcitabine in HCC treatment both in vitro and in vivo. A pH-sensitive self-assembling GPC3-binding peptide-based nanoprobe was developed for NIR-II imaging and PA imaging-guided PTT and sonodynamic therapy of HCC[51].

            2.1.3 Transferrin Receptor (TFR)

            TFR, also known as CD71, is a glycoprotein and the receptor of transferrin, an iron-transporting glycoprotein[52,53]. Transferrin acts as a ligand of TFR and exhibits high affinity, and their combination causes endocytosis of the iron-bound TFR complex, which is followed by the release of iron molecules and recycling of TFR receptors to the cell surface[54]. The liver is a vital organ closely correlated with iron storage and iron metabolism. Abnormal iron metabolism and overexpression of TFR1 mRNA have been observed in HCC cells [55,56]. Moreover, as an essential regulator of cellular iron uptake, TFR1 is regarded as a promising target for efficient HCC therapy[57,58]. Based on the high affinity between transferrin and TFR, transferrin has been widely applied as a ligand for the decoration of nanomaterial for HCC therapy[59].

            A transferrin-coated polycarbonate-based polymersome exhibited specific targeting of TFR-positive SMMC-7221 cells and released DOX to perform cytotoxicity with low toxicity on normal organs[60]. The co-delivery of sorafenib, the first-line medicine for HCC, and DOX by transferrin-conjugated nanoparticles with the albumin shell and polyvinyl alcohol core promoted drug uptake by HepG2 cells, consequently inducing cell death[61]. Besides, transferrin-coated liposomes were used to encapsulate oligonucleotides, such as microRNA-221 inhibitors, to promote HCC cell apoptosis, compared with the non-targeted liposomes[62,63]. Other ligands for TFR targeting have also been widely studied. A Fe3O4@ZnO nanomaterial modified with TFR Ab and loaded with DOX was composited and successfully delivered DOX into HCC cells[64]. This nanocomposite could notably facilitate the chemotherapeutic efficiency of DOX and simultaneously boost sensitivity to radiotherapy[64].

            2.1.4 Glycyrrhetinic Acid Receptor (GAR)

            The GAR was first found on the sinusoidal surface of mammalian hepatocytes and interacted with GA and GL with different affinity[65,66]. Evidence has suggested that GAR is one of the most suitable receptors for HCC treatment due to its specificity, biosafety, and pharmacological potential[67]. GL-modified nanoparticles were internalized preferentially by SMMC-7721 cells, with a ratio 10-times higher than that of non-modified nanoparticles[68]. Therefore, GA-modified or GL-modified liposomes, nanoparticles, and micelles modified with GA were considered ideal drug delivery materials for HCC therapy[69].

            A pH-responsive micelle based on GA-modified chitosan-conjugated DOX successfully targets HepG2 cells and releases DOX in the low pH environment. These micelles presented higher toxicity in HepG2 cells than in normal HUVEC cells[70]. Kim et al.[71] designed a novel photosensitizer composed of silicon SiPC and a GA targeting moiety for photodynamic therapy of liver cancer. This material was confirmed to accumulate in HepG2 tumors in a mouse model effectively and had 60 times higher growth inhibitory effects than the control material[71]. A thiolated polymer nanocarrier reinforced with GA encapsulated and specifically delivered 5-fluorouracil to suppress the tumor growth in a CCl4-induced in vivo HCC model[72].

            2.2 Cell-penetrating Peptide-based Nanomaterials for HCC Treatment

            RGD is a cell-penetrating cyclic peptide composed of Arg-Gly-Asp amino acids and binds to the cell surface integrin receptors, which are abundant in liver cells[73,74]. RGD was first used to adorn nanoparticles for medication delivery into melanoma cells and other cancer cell types[75]. Later studies discovered that when RGD-conjugated nanomaterials were used on liver cancer cells, the internalization ratio of nanomaterials was 500-fold of the non-conjugated materials, as was manifested by the measured fluorescence intensity[76]. The incubation with excess free RGD blocked the function of RGD-conjugated nanomaterials on liver cancer cells. Furthermore, these RGD-conjugated nanomaterials showed a higher affinity to liver cancer cells than cancer cells originating from other organs, including the colon and cervix[77]. Recently, an ultrasound molecular material that loaded hydroxycamptothecin in lipid nanoparticles and decorated with RGD was used for theranostics of HCC, simultaneously exhibiting photoacoustic/ultrasound imaging and anti-proliferative effects[78]. Wu et al.[79] designed a pH-sensitive RGD-modified PHBV nanoparticle loaded with paclitaxel, which targets and responds to the low pH at the HCC tumor site to precisely release paclitaxel, thus, showing remarkable anticancer effect in vivo.

            R6 is another cell-penetrating peptide conjugated with LRVG, a polypeptide that targets intestinal epithelial cells, successfully delivered tyroserleutide, an anti-hepatoma drug, to yield a nanomaterial that could be orally taken and absorbed into the intestinal system. This nanomaterial is then released in HCC cells and affects the endocytic pathway and mitochondria function to suppress tumor growth[80].

            Other peptides such as SP94, FFW, Tv1, and HCC79 were also extensively studied in HCC targeting[81]. For example, SP94-modified polymersome doxorubicin hydrochloride (SP94-PS-DOX) performed much better cytotoxicity toward the SMMC-7721 xenograft model than the non-modified PS nanoparticles[82]. PLGA-PEG-PEI nanoparticles functionalized by SP94 exhibited the excellent delivery ability of prodrugs and TK-p53-nitroreductase therapeutic gene to HCC in vivo, which resulted in remarkable expression of these genes’ subsequent sensitivity to prodrugs. This system realized a synergic suppression of HCC growth[83].

            3 CONCLUSION

            The research and exploration of advanced nanomedicine have provided a powerful approach for specific targeting in HCC therapy compared with traditional methods[84]. Nanomaterials could easily overcome the flaws of a chemical drug, such as poor solubility, rapid clearance, limited permeability, low stability, and deficient tumor-targeting ability[85]. The chemical drug could be easily conjugated with the nanomaterials or encapsulated to overcome the problems[86]. Nanomaterials must be perfected for precision therapy; studies have focused on selecting more suitable ligands for specific targets on tumor cells and elevating drug accumulation at tumor sites. In this review, we introduced several representative cell surface receptors of HCC cells, including ASGPR, GPC3, TFR, and GAR, and their ligands that are widely applied in the decoration of nanomaterials. Other receptors overexpressed on HCC cells, such as a folic acid receptor, somatostatin receptors, and CD44, are also implied in developing materials for HCC-specific targeting[87,88]. We also summarized several peptide ligands, such as RGD, R6, and SP94, for HCC targeting (Figure 1). Thus, various studies have suggested the advantages of nanomaterials with such targeting ligands for anti-HCC therapy.

            Figure 1.

            Illustration of specific targets and ligands for HCC therapy.


            Not applicable.

            Conflicts of Interest

            The author had no conflict of interest.

            Author Contribution

            Yang G solely contributed to this manuscript.

            Abbreviation List

            ADCs, Antibody-drug conjugates

            ASGPR, Asialoglycoprotein receptor

            CCl4, Carbon tetrachloride

            DOX, Doxorubicin

            GA, Glycyrrhetinic acid

            Gal, Galactose

            GAR, Glycyrrhetinic acid receptor

            GL, Glycyrrhizin

            GPC3, Glypican-3

            GPI, Glycosyl phosphatidyl inositol

            HCC, Hepatocellular carcinoma

            MDR, Multiple-drug resistance

            NO, Nitric oxide

            PA, Photoacoustic

            PDA, Polydopamine

            PTT, Photothermal therapy

            SiPC, phthalocyanine

            TFR Ab, Transferrin receptor antibody

            TFR, Transferrin receptor

            TK, Thymidine kinase


            1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020. Vol. 70:7–30. [Cross Ref]

            2. Sung H, Ferlay J, Siegel RL, et al.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021. Vol. 71:209–249. [Cross Ref]

            3. Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, et al.. Hepatocellular carcinoma: From diagnosis to treatment. Surg Oncol. 2016. Vol. 25:74–85. [Cross Ref]

            4. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021. Vol. 149:1–61. [Cross Ref]

            5. Golabi P, Rhea L, Henry L, et al.. Hepatocellular carcinoma and non-alcoholic fatty liver disease. Hepatol Int. 2019. Vol. 13:688–694. [Cross Ref]

            6. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018. Vol. 391:1301–1314. [Cross Ref]

            7. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021. Vol. 7:7[Cross Ref]

            8. Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: Diagnosis, prognosis and treatment response assessment. Cells. 2020. Vol. 9:1370. [Cross Ref]

            9. Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol. 2017. Vol. 34:153–159. [Cross Ref]

            10. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019. Vol. 380:1450–1462. [Cross Ref]

            11. Llovet JM, Montal R, Sia D, et al.. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018. Vol. 15:599–616. [Cross Ref]

            12. Huang A, Yang XR, Chung WY, et al.. Targeted therapy for hepatocellular carcinoma. Signal Transduct Tar. 2020. Vol. 5:146[Cross Ref]

            13. Khemlina G, Ikeda S, Kurzrock R. The biology of hepatocellular carcinoma: Implications for genomic and immune therapies. Mol Cancer. 2017. Vol. 16:149[Cross Ref]

            14. Ricke J, Klümpen HJ, Amthauer H, et al.. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol. 2019. Vol. 71:1164–1174. [Cross Ref]

            15. Yau T, Park JW, Finn RS, et al.. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022. Vol. 23:77–90. [Cross Ref]

            16. Alhalmi A, Beg S, Kohli K, et al.. Nanotechnology based approach for hepatocellular carcinoma targeting. Curr Drug Targets. 2021. Vol. 22:779–792. [Cross Ref]

            17. Usmani A, Mishra A, Ahmad M. Nanomedicines: A theranostic approach for hepatocellular carcinoma. Artif Cell Nanomed B. 2018. Vol. 46:680–690. [Cross Ref]

            18. Wu CH, Lan CH, Wu KL, et al.. Hepatocellular carcinoma-targeted nanoparticles for cancer therapy. Int J Oncol. 2018. Vol. 52:389–401. [Cross Ref]

            19. Elnaggar MH, Abushouk AI, Hassan AHE, et al.. Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma. Semin Cancer Biol. 2021. Vol. 69:91–99. [Cross Ref]

            20. Matsuura S, Nakada H, Sawamura T, et al.. Distribution of an asialoglycoprotein receptor on rat hepatocyte cell surface. J Cell Biol. 1982. Vol. 95:864–75. [Cross Ref]

            21. Stoorvogel W, Geuze HJ, Griffith JM, et al.. Relations between the intracellular pathways of the receptors for transferrin, asialoglycoprotein, and mannose 6-phosphate in human hepatoma cells. J Cell Biol. 1989. Vol. 108:2137–48. [Cross Ref]

            22. Zijderhand-Bleekemolen JE, Schwartz AL, Slot JW, et al.. Ligand- and weak base-induced redistribution of asialoglycoprotein receptors in hepatoma cells. J Cell Biol. 1987. Vol. 104:1647–54. [Cross Ref]

            23. Wall DA, Hubbard AL. Galactose-specific recognition system of mammalian liver: Receptor distribution on the hepatocyte cell surface. J Cell Biol. 1981. Vol. 90:687–96. [Cross Ref]

            24. Shi B, Abrams M, Sepp-Lorenzino L. Expression of asialoglycoprotein receptor 1 in human hepatocellular carcinoma. J Histochem Cytochem. 2013. Vol. 61:901–9. [Cross Ref]

            25. Mu H, Lin KX, Zhao H, et al.. Identification of biomarkers for hepatocellular carcinoma by semiquantitative immunocytochemistry. World J Gastroentero. 2014. Vol. 20:5826–38. [Cross Ref]

            26. Trerè D, Fiume L, De Giorgi LB, et al.. The asialoglycoprotein receptor in human hepatocellular carcinomas: Its expression on proliferating cells. Br J Cancer. 1999. Vol. 81:404–8. [Cross Ref]

            27. Li T, Yu P, Chen Y, et al.. N-acetylgalactosamine-decorated nanoliposomes for targeted delivery of paclitaxel to hepatocellular carcinoma. Eur J Med Chem. 2021. Vol. 222:113605. [Cross Ref]

            28. D’Souza AA, Devarajan PV. Asialoglycoprotein receptor mediated hepatocyte targeting-strategies and applications. J Control Release. 2015. Vol. 203:126–39. [Cross Ref]

            29. Spiess M. The asialoglycoprotein receptor: A model for endocytic transport receptors. Biochem. 1990. Vol. 29:10009–18. [Cross Ref]

            30. Lou S, Gao S, Wang W, et al.. Galactose-functionalized multi-responsive nanogels for hepatoma-targeted drug delivery. Nanoscale. 2015. Vol. 7:3137–46. [Cross Ref]

            31. Li YL, Zhu XM, Liang H, et al.. Recent advances in asialoglycoprotein receptor and glycyrrhetinic acid receptor-mediated and/or pH-responsive hepatocellular carcinoma-targeted drug delivery. Curr Med Chem. 2021. Vol. 28:1508–1534. [Cross Ref]

            32. Xia Y, Zhong J, Zhao M, et al.. Galactose-modified selenium nanoparticles for targeted delivery of doxorubicin to hepatocellular carcinoma. Drug Deliv. 2019. Vol. 26:1–11. [Cross Ref]

            33. Hu X, Zhang J, Deng L, et al.. Galactose-modified pH-sensitive niosomes for controlled release and hepatocellular carcinoma target delivery of tanshinone IIA. AAPS Pharm Sci Tech. 2021. Vol. 22:96[Cross Ref]

            34. Huang KW, Lai YT, Chern GJ, et al.. Galactose derivative-modified nanoparticles for efficient siRNA delivery to hepatocellular carcinoma. Biomacromolecules. 2018. Vol. 19:2330–2339. [Cross Ref]

            35. Du Z, Mao Y, Zhang P, et al.. TPGS-galactose-modified polydopamine co-delivery nanoparticles of nitric oxide donor and doxorubicin for targeted chemo-photothermal therapy against drug-resistant hepatocellular carcinoma. ACS Appl Mater Interfaces. 2021. Vol. 13:35518–35532. [Cross Ref]

            36. Zhou F, Shang W, Yu X, et al.. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev. 2018. Vol. 38:741–767. [Cross Ref]

            37. Xia L, Teng Q, Chen Q, et al.. Preparation and characterization of anti-GPC3 nanobody against hepatocellular carcinoma. Int J Nanomed. 2020. Vol. 15:2197–2205. [Cross Ref]

            38. Sun B, Huang Z, Wang B, et al.. Significance of glypican-3 (GPC3) expression in hepatocellular cancer diagnosis. Med Sci Monit. 2017. Vol. 23:850–855. [Cross Ref]

            39. Shimizu Y, Suzuki T, Yoshikawa T, et al.. Next-generation cancer immunotherapy targeting glypican-3. Front Oncol. 2019. Vol. 9:248. [Cross Ref]

            40. Nishida T, Kataoka H. Glypican 3-targeted therapy in hepatocellular carcinoma. Cancers (Basel). 2019. Vol. 11:1339. [Cross Ref]

            41. Wang S, Chen N, Chen Y, et al.. Elevated GPC3 level promotes cell proliferation in liver cancer. Oncol Lett. 2018. Vol. 16:970–976. [Cross Ref]

            42. Hsu HC, Cheng W, Lai PL. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res. 1997. Vol. 57:5179–84

            43. Kolluri A, Ho M. The Role of glypican-3 in regulating Wnt, YAP, and hedgehog in liver cancer. Front Oncol. 2019. Vol. 9:708. [Cross Ref]

            44. Sha YL, Liu S, Yan WW, et al.. Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma. Biosci Rep. 2019. Vol. 39:BSR20192466. [Cross Ref]

            45. Yu M, Luo H, Fan M, et al.. Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma. Mol Ther. 2018. Vol. 26:366–378. [Cross Ref]

            46. Du K, Li Y, Liu J, et al.. A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC. Mol Ther. 2021. Vol. 29:1572–1584. [Cross Ref]

            47. Feng M, Ho M. Glypican-3 antibodies: A new therapeutic target for liver cancer. FEBS Lett. 2014. Vol. 588:377–82. [Cross Ref]

            48. Ishiguro T, Sugimoto M, Kinoshita Y, et al.. Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer. Cancer Res. 2008. Vol. 68:9832–8. [Cross Ref]

            49. Park JY, Chae JR, Cho YL, et al.. Targeted therapy of hepatocellular carcinoma using gemcitabine-incorporated GPC3 aptamer. Pharmaceutics. 2020. Vol. 12:985. [Cross Ref]

            50. Fu Y, Urban DJ, Nani RR, et al.. Glypican-3-specific antibody drug conjugates targeting hepatocellular carcinoma. Hepatology. 2019. Vol. 70:563–576. [Cross Ref]

            51. Li S, Zhang Y, Liu X, et al.. Smart NIR-II croconaine dye-peptide for enhanced photo-sonotheranostics of hepatocellular carcinoma. Theranostics. 2022. Vol. 12:76–86. [Cross Ref]

            52. Gammella E, Buratti P, Cairo G, et al.. The transferrin receptor: the cellular iron gate. Metallomic. 2017. Vol. 9:1367–1375. [Cross Ref]

            53. Aisen P. Entry of iron into cells: A new role for the transferrin receptor in modulating iron release from transferrin. Ann Neurol. 1992. Vol. 32:S62–8. [Cross Ref]

            54. Li H, Qian ZM. Transferrin/transferrin receptor-mediated drug delivery. Med Res Rev. 2002. Vol. 22:225–50. [Cross Ref]

            55. Daniels TR, Delgado T, Rodriguez JA, et al.. The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol. 2006. Vol. 121:144–58. [Cross Ref]

            56. Neckers LM. Regulation of transferrin receptor expression and control of cell growth. Pathobiology. 1991. Vol. 59:11–8. [Cross Ref]

            57. Qian ZM, Li H, Sun H, et al.. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev. 2002. Vol. 54:561–87. [Cross Ref]

            58. Pascale RM, De Miglio MR, Muroni MR, et al.. Transferrin and transferrin receptor gene expression and iron uptake in hepatocellular carcinoma in the rat. Hepatology. 1998. Vol. 27:452–61. [Cross Ref]

            59. Zhang X, Li J, Yan M. Targeted hepatocellular carcinoma therapy: transferrin modified, self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin. Drug Dev Ind Pharm. 2016. Vol. 42:1590–9. [Cross Ref]

            60. Wei Y, Gu X, Cheng L, et al.. Low-toxicity transferrin-guided polymersomal doxorubicin for potent chemotherapy of orthotopic hepatocellular carcinoma in vivo. Acta Biomater. 2019. Vol. 92:196–204. [Cross Ref]

            61. Malarvizhi GL, Retnakumari AP, Nair S, et al.. Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma. Nanomed. 2014. Vol. 10:1649–59. [Cross Ref]

            62. Zhang W, Peng F, Zhou T, et al.. Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes. Int J Nanomed. 2015. Vol. 10:4825–36. [Cross Ref]

            63. Varshosaz J, Farzan M. Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma. World J Gastroentero. 2015. Vol. 21:12022–41. [Cross Ref]

            64. Zhang H, Patel N, Ding S, et al.. Theranostics for hepatocellular carcinoma with Fe3O4@ZnO nanocomposites. Biomater Sci. 2016. Vol. 4:288–98. [Cross Ref]

            65. Negishi M, Irie A, Nagata N, et al.. Specific binding of glycyrrhetinic acid to the rat liver membrane. Biochim Biophys Acta. 1991. Vol. 1066:77–82. [Cross Ref]

            66. Roohbakhsh A, Iranshahy M, Iranshahi M. Glycyrrhetinic acid and its derivatives: Anti-cancer and cancer chemopreventive properties, mechanisms of action and structure-cytotoxic activity relationship. Curr Med Chem. 2016. Vol. 23:498–517. [Cross Ref]

            67. Tian Q, Wang X, Wang W, et al.. Insight into glycyrrhetinic acid: The role of the hydroxyl group on liver targeting. Int J Pharm. 2010. Vol. 400:153–7. [Cross Ref]

            68. Shi L, Tang C, Yin C. Glycyrrhizin-modified O-carboxymethyl chitosan nanoparticles as drug vehicles targeting hepatocellular carcinoma. Biomaterials. 2012. Vol. 33:7594–604. [Cross Ref]

            69. Lv Y, Li J, Chen H, et al.. Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier. Int J Nanomed. 2017. Vol. 12:4361–4370. [Cross Ref]

            70. Yan T, Cheng J, Liu Z, et al.. Acid-sensitive polymeric vector targeting to hepatocarcinoma cells via glycyrrhetinic acid receptor-mediated endocytosis. Mater Sci Eng C Mater Biol Appl. 2018. Vol. 87:32–40. [Cross Ref]

            71. Kim J, Lee S, Na K. Glycyrrhetinic acid-modified silicon phthalocyanine for liver cancer-targeted photodynamic therapy. Biomacromolecules. 2021. Vol. 22:811–822. [Cross Ref]

            72. Bhat SS, Mukherjee D, Sukharamwala P, et al.. Thiolated polymer nanocarrier reinforced with glycyrrhetinic acid for targeted delivery of 5-fluorouracil in hepatocellular carcinoma. Drug Deliv Transl Res. 2021. Vol. 11:2252–2269. [Cross Ref]

            73. Danhier F, Le Breton A, Préat V. RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis. Mol Pharm. 2012. Vol. 9:2961–73. [Cross Ref]

            74. Zitzmann S, Ehemann V, Schwab M. Arginine-glycine-aspartic acid (RGD)-peptide binds to both tumor and tumor-endothelial cells in vivo. Cancer Res. 2002. Vol. 62:5139–43

            75. Jiang X, Xin H, Gu J, et al.. Solid tumor penetration by integrin-mediated pegylated poly (trimethylene carbonate) nanoparticles loaded with paclitaxel. Biomaterials. 2013. Vol. 34:1739–46. [Cross Ref]

            76. Xiong XB, Huang Y, Lu WL, et al.. Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy: In vitro and in vivo. J Pharm Sci. 2005. Vol. 94:1782–93. [Cross Ref]

            77. Loyer P, Bedhouche W, Huang ZW, et al.. Degradable and biocompatible nanoparticles decorated with cyclic RGD peptide for efficient drug delivery to hepatoma cells in vitro. Int J Pharm. 2013. Vol. 454:727–37. [Cross Ref]

            78. Li H, Shi S, Wu M, et al.. iRGD peptide-mediated liposomal nanoparticles with photoacoustic/ultrasound dual-modality imaging for precision theranostics against hepatocellular carcinoma. Int J Nanomedicine. 2021. Vol. 16:6455–6475. [Cross Ref]

            79. Wu M, Zhong C, Zhang Q, et al.. pH-responsive delivery vehicle based on RGD-modified polydopamine-paclitaxel-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles for targeted therapy in hepatocellular carcinoma. J Nanobiotechnology. 2021. Vol. 19:39[Cross Ref]

            80. Ma C, Wei T, Hua Y, et al.. Effective antitumor of orally intestinal targeting penetrating peptide-loaded tyroserleutide/PLGA nanoparticles in hepatocellular carcinoma. Int J Nanomedicine. 2021. Vol. 16:4495–4513. [Cross Ref]

            81. Bakrania A, Zheng G, Bhat M. Nanomedicine in hepatocellular carcinoma: A new frontier in targeted cancer treatment. Pharmaceutics. 2021. Vol. 14:41. [Cross Ref]

            82. Zhang J, Wang X, Cheng L, et al.. SP94 peptide mediating highly specific and efficacious delivery of polymersomal doxorubicin hydrochloride to hepatocellular carcinoma in vivo. Colloids Surf B Biointerfaces. 2021. Vol. 197:111399. [Cross Ref]

            83. Sukumar UK, Rajendran JCB, Gambhir SS, et al.. SP94-targeted triblock copolymer nanoparticle delivers thymidine kinase-p53-nitroreductase triple therapeutic gene and restores anticancer function against hepatocellular carcinoma in vivo. ACS Appl Mater Interfaces. 2020. Vol. 12:11307–11319. [Cross Ref]

            84. Baig B, Halim SA, Farrukh A, et al.. Current status of nanomaterial-based treatment for hepatocellular carcinoma. Biomed Pharmacother. 2019. Vol. 116:108852. [Cross Ref]

            85. Kumar V, Rahman M, Gahtori P, et al.. Current status and future directions of hepatocellular carcinoma-targeted nanoparticles and nanomedicine. Expert Opin Drug Deliv. 2021. Vol. 18:673–694. [Cross Ref]

            86. Mohamed NK, Hamad MA, Hafez MZ, et al.. Nanomedicine in management of hepatocellular carcinoma: Challenges and opportunities. Int J Cancer. 2017. Vol. 140:1475–1484. [Cross Ref]

            87. Endo K, Terada T. Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival. J Hepatol. 2000. Vol. 32:78–84. [Cross Ref]

            88. Patel YC. Somatostatin and its receptor family. Front Neuroendocrin. 1999. Vol. 20:157–98. [Cross Ref]

            Author and article information

            Journal of Modern Nanotechnology
            Innovation Forever Publishing Group (China )
            07 June 2022
            : 2
            : 1
            [1 ]National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
            Author notes
            *Correspondence to: Guang Yang, PhD, Professor, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin 300060, China; Email: yangguang@ 123456tjmuch.com
            Copyright © 2022 The Author(s).

            This open-access article is licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution, and reproduction in any medium, provided the original work is properly cited.

            Page count
            Figures: 1, References: 88, Pages: 8

            Clinical chemistry,Chemistry,Physical chemistry,Batteries & Fuel cells,Polymer chemistry
            cell surface receptors,hepatocellular carcinoma,nanomaterial,ligands


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