Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, typically diagnosed in advanced stages. Chemotherapy is necessary for treating advanced liver cancer; however, several challenges affect its effectiveness. These challenges include low specificity, high dosage requirements, high systemic toxicity and severe side effects, which significantly limit the efficacy of chemotherapy. These limitations can hinder the treatment of HCC. This review focuses on the prevalence of HCC, different types of liver cancer and the staging of the disease, along with available treatment methods. Additionally, explores recent and relevant studies on smart drug- and gene-delivery systems specifically designed for HCC. These systems include targeted endogenous and exogenous stimuli-responsive platforms.

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Liver cancer is the third leading cause of cancer deaths in the world that is usually diagnosed in the last stages. Chemotherapy is commonly used to treat advanced liver cancer, but it faces several challenges that reduce its effectiveness. These challenges include low specificity (not targeting cancer cells specifically), high dosage requirements and side effects that can affect anywhere in the body. As a result, the efficacy of chemotherapy is significantly limited, making it difficult to treat liver cancer. This review discusses the prevalence of liver cancer, different types of liver cancer and how the disease is staged. It also explores various treatment methods available for liver cancer. Furthermore, the article explores recent and relevant studies on smart drug- and gene-delivery systems that are specifically designed to target liver cancer. These systems include platforms that respond to targeted and internal or external stimuli. They aim to improve the effectiveness of treatment for liver cancer.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Mahmoud K, Swidan S, El-Nabarawi M, Teaima M. Lipid based nanoparticles as a novel treatment modality for hepatocellular carcinoma: a comprehensive review on targeting and recent advances. J. Nanobiotechnol. 20(1), 1–42 (2022).
MedlineGoogle Scholar
2. International Agency for research on cancer. Global cancer observatory (1965). www.gco.iarc.fr/today/online-analysis-pie (Accessed 19 January 2023).
Google Scholar
3. American Cancer Society. About liver cancer (1913). www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics (Accessed 19 January 2023).
Google Scholar
4. Cancer Research UK. About cancer (2002). www.cancerresearchuk.org/about-cancer/liver-cancer/about-liver-cancer (Accessed 19 January 2023).
Google Scholar
5. Mohamed NK, Hamad MA, Hafez MZE, Wooley KL, Elsabahy M. Nanomedicine in management of hepatocellular carcinoma: challenges and opportunities. Int. J. Cancer 140(7), 1475–1484 (2017).
Medline CASGoogle Scholar
6. Elnaggar MH, Abushouk AI, Hassan AHE et al. Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma. Semin. Cancer Biol. 69, 91–99 (2019). •• This review article offers valuable insights into the treatment approaches for hepatocellular carcinoma (HCC), as well as the receptors linked to this particular cancer type.
MedlineGoogle Scholar
7. American Cancer Society. Treating liver cancer (1913). www.cancer.org/cancer/liver-cancer/treating/chemotherapy (Accessed 19 January 2023).
Google Scholar
8. American Cancer Society. Treating liver cancer (1913). www.cancer.org/cancer/liver-cancer/treating/targeted-therapy (Accessed 19 January 2023).
Google Scholar
9. Fathi M, Dalir Abdolahinia E, Barar J, Omidi Y. Smart stimuli-responsive biopolymeric nanomedicines for targeted therapy of solid tumors. Nanomedicine 15(22), 2171–2200 (2020).
CASGoogle Scholar
10. van der Meel R, Sulheim E, Shi Y, Kiessling F, Mulder WJM. Smart cancer nanomedicine. Nat. Nanotechnol. 14(11), 1007–1017 (2019). •• In this article, various aspects of nano-smart therapy have been well discussed.
MedlineGoogle Scholar
11. Mossenta M, Busato D, Bo MD, Macor P. Novel nanotechnology approaches to overcome drug resistance in the treatment of hepatocellular carcinoma: glypican 3 as a useful target for innovative therapies. Int. J. Mol. Sci. 23(17), 10038 (2022).
Medline CASGoogle Scholar
12. Zhou Q, Sun X, Zeng L, Liu J, Zhang Z. A randomized multicenter phase II clinical trial of mitoxantrone-loaded nanoparticles in the treatment of 108 patients with unresected hepatocellular carcinoma. Nanomed. Nanotechnol. Biol. Med. 5(4), 419–423 (2009).
CASGoogle Scholar
13. U.S. National Institutes of Health. U.S. National Library of Medicine (1887). https://clinicaltrials.gov/ct2/results/LiverCancer/NCT01655693 (Accessed 19 January 2023).
Google Scholar
14. ONXEO (1997). www.onxeo.com/onxeo-completes-enrollment-phase-iii-study-livatag-treatment-hepatocellular-carcinoma/ (Accessed 19 January 2023).
Google Scholar
15. D'Souza AA, Devarajan PV. Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications. J. Control. Rel. 203, 126–139 (2015).
MedlineGoogle Scholar
16. Alonso S. Exploiting the bioengineering versatility of lactobionic acid in targeted nanosystems and biomaterials. J. Control. Rel. 287, 216–234 (2018).
Medline CASGoogle Scholar
17. Lee J, Choi M, Song I. Recent advances in doxorubicin formulation to enhance pharmacokinetics and tumor targeting. Pharmaceuticals 16(6), 802 (2023).
Medline CASGoogle Scholar
18. Li F, Qin Y, Lee J et al. Stimuli-responsive nano-assemblies for remotely controlled drug delivery. J. Control. Rel. 322, 566–592 (2020).
Medline CASGoogle Scholar
19. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12(11), 991–1003 (2013).
Medline CASGoogle Scholar
20. Alsawaftah NM, Awad NS, Pitt WG. pH-responsive nanocarriers in cancer therapy. Polymers 14(5), 936 (2022).
Medline CASGoogle Scholar
21. Kumari R, Sunil D, Ningthoujam RS. Hypoxia-responsive nanoparticle based drug delivery systems in cancer therapy: an up-to-date review. J. Control. Rel. 319, 135–156 (2020).
Medline CASGoogle Scholar
22. Li M, Zhao G, Su W, Shuai Q. Enzyme-responsive nanoparticles for anti-tumor drug delivery. Front. Chem. 8, 647 (2020).
Medline CASGoogle Scholar
23. Liu Z, Jiang W, Nam J, Moon JJ, Kim BYS. Immuno-modulating nanomedicine for cancer therapy. Nano Lett. 18(11), 6655–6659 (2018).
Medline CASGoogle Scholar
24. Thakur N, Thakur S, Chatterjee S, Das J. Nanoparticles as smart carriers for enhanced cancer immunotherapy. Front. Chem. 8, 597806 (2020).
Medline CASGoogle Scholar
25. Gindy ME, Prud'homme RK. Multifunctional nanoparticles for imaging, delivery and targeting in cancer therapy. Expert. Opin. Drug Deliv. 6(8), 865–878 (2009).
Medline CASGoogle Scholar
26. Wang J, Zhang Z, Ai Y, Liu F, Chen MM, Liu D. Lactobionic acid-modified thymine-chitosan nanoparticles as potential carriers for methotrexate delivery. Carbohydr. Res. 501, 108275 (2021).
Medline CASGoogle Scholar
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. 222, 113605 (2021).
Medline CASGoogle Scholar
28. Ganguly S, Dewanjee S, Sen R, Chattopadhyay D. Apigenin-loaded galactose tailored PLGA nanoparticles: a possible strategy for liver targeting to treat hepatocellular carcinoma. Colloids Surf. B. 204, 111778 (2021).
Medline CASGoogle Scholar
29. Cai Y, Xu Y, Chan HF, Fang X, He C, Chen M. Glycyrrhetinic acid mediated drug delivery carriers for hepatocellular carcinoma therapy. Mol. Pharm. 13(3), 699–709 (2016).
Medline CASGoogle Scholar
30. 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. 9, 2265–2275 (2015).
Medline CASGoogle Scholar
31. Yan G, Chen Q, Xu L, Wei H, Ma C, Sun Y. Preparation and evaluation of liver-targeting micelles loaded with oxaliplatin. Artif. Cells Nanomed. Biotechnol. 44(2), 491–496 (2016).
Medline CASGoogle Scholar
32. Lv Y, Li J, Chen H, Bai Y, Zhang L. Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier. Int. J. Nanomed. 12, 4361–4370 (2017).
Medline CASGoogle Scholar
33. Hu J, Zheng Y, Wen Z et al. Construction of redox-sensitive liposomes modified by glycyrrhetinic acid and evaluation of anti-hepatocellular carcinoma activity. Chem. Phys. Lipids 252, 105292 (2023). •• An example of dual targeted and stimuli responsive drug-delivery system against hepatocellular carcinoma.
Medline CASGoogle Scholar
34. Kong L, Sui G, Guo R et al. A multi-strategy liposome targeting hepatocellular carcinoma cells and stem cells enhances the chemotherapy effect of doxorubicin in hepatocellular carcinoma. J. Drug Deliv. Sci. Technol. 81, 104188 (2023).
CASGoogle Scholar
35. Nisha R, Kumar P, Kumar U et al. Assessment of hyaluronic acid-modified imatinib mesylate cubosomes through CD44 targeted drug delivery in NDEA-induced hepatic carcinoma. Int. J. Pharm. 622, 121848 (2022).
Medline CASGoogle Scholar
36. Saadat M, Mostafaei F, Mahdinloo S et al. Drug delivery of pH-sensitive nanoparticles into the liver cancer cells. J. Drug Deliv. Sci. Technol. 63, 102557 (2021).
CASGoogle Scholar
37. Bian Y, Guo D. Targeted therapy for hepatocellular carcinoma: co-delivery of sorafenib and curcumin using lactosylated ph-responsive nanoparticles. Drug Des. Devel. Ther. 14, 647–659 (2020).
Medline CASGoogle Scholar
38. Li XX, Chen J, Shen JM et al. pH-sensitive nanoparticles as smart carriers for selective intracellular drug delivery to tumor. Int. J. Pharm. 545(1–2), 274–285 (2018).
Medline CASGoogle Scholar
39. Zhang YQ, Shen Y, Liao MM et al. Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms. Nanomed.: Nanotechnol. Biol. Med. 15(1), 86–97 (2019).
CASGoogle Scholar
40. Zha Q, Wang X, Cheng X et al. Acid–degradable carboxymethyl chitosan nanogels via an ortho ester linkage mediated improved penetration and growth inhibition of 3D tumor spheroids in vitro. Mater. Sci. Eng. C 78, 246–257 (2017).
Medline CASGoogle Scholar
41. Mojarad-Jabali S, Farshbaf M, Walker PR et al. An update on actively targeted liposomes in advanced drug delivery to glioma. Int. J. Pharm. 602, 120645 (2021).
Medline CASGoogle Scholar
42. Zahednezhad F, Saadat M, Valizadeh H, Zakeri-Milani P, Baradaran B. Liposome and immune system interplay: challenges and potentials. J. Control. Rel. 305, 194–209 (2019).
Medline CASGoogle Scholar
43. Wang Y, Ding R, Zhang Z, Zhong C, Wang J, Wang M. Curcumin-loaded liposomes with the hepatic and lysosomal dual-targeted effects for therapy of hepatocellular carcinoma. Int. J. Pharm. 602, 120628 (2021).
Medline CASGoogle Scholar
44. Hu X, Zhang J, Deng L, Hu H, Hu J, Zheng G. Galactose-modified pH-sensitive niosomes for controlled release and hepatocellular carcinoma target delivery of Tanshinone IIA. AAPS PharmSciTech 22(3), 1–14 (2021).
Google Scholar
45. Mahdinloo S, Hemmati S, Valizadeh H et al. Synthesis and preparation of vitamin A coupled butein-loaded solid lipid nanoparticles for liver fibrosis therapy in rats. Int. J. Pharm. 625, 122063 (2022).
Medline CASGoogle Scholar
46. Mahmoudian M, Valizadeh H, Löbenberg R, Zakeri-Milani P. Bortezomib-loaded lipidic-nano drug delivery systems; formulation, therapeutic efficacy, and pharmacokinetics. J. Microencapsul. 38(3), 192–202 (2021).
Medline CASGoogle Scholar
47. Chuang CH, Wu PC, Tsai TH et al. Development of pH-sensitive cationic PEGylated solid lipid nanoparticles for selective cancer-targeted therapy. J. Biomed. Nanotechnol. 13(2), 192–203 (2017).
Medline CASGoogle Scholar
48. Li Y, Miao Y, Chen M et al. Stepwise targeting and responsive lipid-coated nanoparticles for enhanced tumor cell sensitivity and hepatocellular carcinoma therapy. Theranostics 10(8), 3722–3736 (2020).
Medline CASGoogle Scholar
49. Fouladi F, Steffen KJ, Mallik S. Enzyme-responsive liposomes for the delivery of anticancer drugs. Bioconjug. Chem. 28(4), 857–868 (2017).
Medline CASGoogle Scholar
50. Kuruvilla SP, Tiruchinapally G, Crouch AC, ElSayed MEH, Greve JM. Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model. PLOS ONE 12(8), e0181944 (2017).
MedlineGoogle Scholar
51. Liu Y, Ding X, Li J et al. Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo. Nanotechnology 26(14), 145102 (2015).
MedlineGoogle Scholar
52. Ruan J, Zheng H, Rong X et al. Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients. Mol. Cancer 15(1), 1–13 (2016).
MedlineGoogle Scholar
53. Lee S, Song SJ, Lee J, Ha TH, Choi JS. Cathepsin b-responsive liposomes for controlled anticancer drug delivery in Hep G2 cells. Pharmaceutics 12(9), 1–12 (2020).
Google Scholar
54. Gilbert HF. Thiol/disulfide exchange equilibria and disulfidebond stability. Methods Enzymol. 251, 8–28 (1995).
Medline CASGoogle Scholar
55. Mirhadi E, Mashreghi M, Faal Maleki M et al. Redox-sensitive nanoscale drug delivery systems for cancer treatment. Int. J. Pharm. 589, 119882 (2020).
Medline CASGoogle Scholar
56. Li J, Huo M, Wang J et al. Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials 33(7), 2310–2320 (2012).
Medline CASGoogle Scholar
57. Kuppusamy P, Li H, Ilangovan G et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res. 62(1), 307–312 (2002).
Medline CASGoogle Scholar
58. Torchilin VP. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13(11), 813–827 (2014).
Medline CASGoogle Scholar
59. Cai M, Li B, Lin L et al. A reduction and pH dual-sensitive nanodrug for targeted theranostics in hepatocellular carcinoma. Biomater. Sci. 8(12), 3485–3499 (2020). • An example of reduction and pH dual-sensitive nanotheranostics drug-delivery system modified with anti GPC3 Ab.
Medline CASGoogle Scholar
60. Alsawaftah N, Pitt WG, Husseini GA. Dual-targeting and stimuli-triggered liposomal drug delivery in cancer treatment. ACS Pharmacol. Transl. Sci. 4(3), 1028–1049 (2021).
Medline CASGoogle Scholar
61. Depalo N, Iacobazzi RM, Valente G et al. Sorafenib delivery nanoplatform based on superparamagnetic iron oxide nanoparticles magnetically targets hepatocellular carcinoma. Nano Res. 10(7), 2431–2448 (2017).
CASGoogle Scholar
62. Liao S, Liu C, Lin F, Wu KC. Functionalized magnetic iron oxide / alginate core-shell nanoparticles for targeting hyperthermia. Int. J. Nanomed. 3315–3328 (2015).
MedlineGoogle Scholar
63. Yang S, Cai C, Wang H et al. Drug delivery strategy in hepatocellular carcinoma therapy. Cell Commun. Signal. 20(1), 1–14 (2022).
MedlineGoogle Scholar
64. Boissenot T, Bordat A, Fattal E, Tsapis N. Ultrasound-triggered drug delivery for cancer treatment using drug delivery systems: from theoretical considerations to practical applications. J. Control. Rel. 241, 144–163 (2016).
Medline CASGoogle Scholar
65. Wang J, Xia Y, Liu H et al. Poly(lactobionamidoethyl methacrylate)-based amphiphiles with ultrasound-labile components in manufacture of drug delivery nanoparticulates for augmented cytotoxic efficacy to hepatocellular carcinoma. J. Colloid Interface Sci. 551, 1–9 (2019).
Medline CASGoogle Scholar
66. Xu J, Cheng X, Tan L et al. Microwave responsive nanoplatform via p-selectin mediated drug delivery for treatment of hepatocellular carcinoma with distant metastasis. Nano Lett. 19(5), 2914–2927 (2019).
Medline CASGoogle Scholar
67. Liu L, Zong Z, Liu Q et al. A novel galactose-PEG-conjugated biodegradable copolymer is an efficient gene delivery vector for immunotherapy of hepatocellular carcinoma. Biomaterials 184, 20–30 (2018).
Medline CASGoogle Scholar
68. Böttger R, Chao P, Al Fayez N, Hohenwarter L, Li S. Lipid-based nanoparticle technologies for liver targeting. Adv. Drug Deliv. Rev. 154, 79–101 (2020). •• This review article thoroughly discusses lipid nanoparticles for targeting different liver diseases and reviews the formulations that are currently in clinical trials for treating liver diseases, including hepatocellular carcinoma.
MedlineGoogle Scholar
69. Rana A, Adhikary M, Singh PK, Das BC, Bhatnagar S. Smart drug delivery: a window to future of translational medicine. Front. Chem. 10, 1095598 (2023).
MedlineGoogle Scholar
70. Liu C, Yang M, Zhang D, Chen M, Zhu D. Clinical cancer immunotherapy: current progress and prospects. Front. Immunol. 13, 961805 (2022).
Medline CASGoogle Scholar
71. Xia Y, Guo M, Xu T et al. siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy. Int. J. Nanomed. 1539–1552 (2018).
MedlineGoogle Scholar
72. Perrone F, Craparo EF, Cemazar M et al. Targeted delivery of siRNAs against hepatocellular carcinoma-related genes by a galactosylated polyaspartamide copolymer. J. Control. Rel. 330, 1132–1151 (2021). • In this article, a new copolymer called galactosylated polyaspartamide was used as a nonviral vector for gene therapy against hepatocellular carcinoma.
Medline CASGoogle Scholar
73. Journal AI, Yao Y, Wang T, Liu Y, Zhang N. Co-delivery of sorafenib and VEGF-siRNA via pH-sensitive liposomes for the synergistic treatment of hepatocellular carcinoma. Artif. Cells. Nanomed. Biotechnol. 47(1), 1374–1383 (2019). • In this article, the codelivery of drug and gene by pH-sensitive liposomes was investigated to increase the therapeutic effect of sorafenib against hepatocellular carcinoma.
MedlineGoogle Scholar
74. Dika IE, Lim HY, Yong WP et al. An open-label, multicenter, Phase I, dose escalation study with Phase II expansion cohort to determine the safety, pharmacokinetics, and preliminary antitumor activity of intravenous TKM-080301 in subjects with advanced hepatocellular carcinoma. Oncologist 24(6), 747–e218 (2019).
MedlineGoogle Scholar
75. Dou Y, Hynynen K, Allen C. To heat or not to heat: challenges with clinical translation of thermosensitive liposomes. J. Control. Rel. 249, 63–73 (2017).
Medline CASGoogle Scholar
76. Tak WY, Lin S, Wang Y et al. Phase III heat study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin. Cancer Res. 24(1), 73–83 (2018).
Medline CASGoogle Scholar
77. Wood BJ, Poon RT, Locklin JK et al. Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. J. Vasc. Interv. Radiol. 23(2), 248–255 (2012).
MedlineGoogle Scholar
78. U.S. National Institutes of Health. U.S. National Library of Medicine (1877). https://classic.clinicaltrials.gov/ct2/show/record/NCT04331743 (Accessed 6 September 2023).
Google Scholar
79. U.S. National Institutes of Health. U.S. National Library of Medicine (1887). https://classic.clinicaltrials.gov/ct2/show/NCT05497453 (Accessed 6 September 2023).
Google Scholar

Vol. 18, No. 25

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Received 23 July 2023

Accepted 4 October 2023

Published online 22 November 2023

Published in print October 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0196

Author contributions

P Zakeri-Milani and F Mostafaei designed the work. F Mostafaei, S Mahdinloo and M Abdi collected data and wrote the manuscript. S Hemmati, H Valizadeh, M Sarfraz, B Baradaran and P Zakeri-Milani checked and revised the article. All of the authors have read and approved the final manuscript.

Acknowledgments

We gratefully thank the support of Tabriz University of Medical Science. This article is based on a PhD thesis (No. 62886) submitted by F Mostafaei in the Faculty of Pharmacy, Tabriz University of Medical Sciences, Iran.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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No writing assistance was utilized in the production of this manuscript.

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An update review of smart nanotherapeutics and liver cancer: opportunities and challenges

Abstract

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References