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CardioVascular and Interventional Radiology

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12.04.2024 | Laboratory Investigation

Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma

verfasst von: Miltiadis Krokidis, Danae Fakitsa, Katerina Malagari, Theodoros Karampelas, Demosthenes Fokas, Constantin Tamvakopoulos, Achilles Chatziioannou

Erschienen in: CardioVascular and Interventional Radiology | Ausgabe 5/2024

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Abstract

Purpose

Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the first-line treatment for intermediate HCC. The two types of drugs have not been combined for intraarterial delivery yet. The loading and release dynamics and the in vitro effect of their combination are tested in this experimental study.

Materials and Methods

Drug-eluting beads were loaded with doxorubicin, sunitinib and sunitinib analogue piperazine (SAP) alone and with their combinations. Diameter change, loading, release, and effect in cellular proliferation were assessed.

Results

The average microsphere diameter after loading was 473.7 µm (μm) for Doxorubicin, 388.4 μm for Sunitinib, 515.5 μm for SAP, 414.8 μm for the combination Doxorubicin/Sunitinib and 468.8 μm for the combination Doxorubicin /SAP. Drug release in 0.9% NaCl was 10% for Doxorubicin, 49% for Sunitinib, 25% for SAP, 20%/18% for the combination Doxorubicin/Sunitinib, and 18%/23% for the combination Doxorubicin/SAP whereas in human plasma it was 56%, 27%, 13%, 76%/63% and 62%/15%, respectively. The mean concentration of Doxorubicin that led to inhibition of 50% of cellular proliferation in an HCC Huh7 cell line was 163.1 nM (nM), for Sunitinib 10.3 micromolar (μΜ), for SAP 16.7 μΜ, for Doxorubicin/Sunitinib 222.4 nM and for Doxorubicin/SAP 275 nM.

Conclusions

Doxorubicin may be combined with antiangiogenic drugs with satisfactory in vitro loading and release outcomes and effect on cellular lines.

Graphical Abstract

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Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.CrossRefPubMed

European Association for Study of Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Eur J Cancer. 2012;48(5):599–641.CrossRef

Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681–93. https://doi.org/10.1016/j.jhep.2021.11.018.CrossRefPubMed

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019.CrossRef

Llovet JM, Real MI, Montaña X, et al. Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–9.CrossRefPubMed

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37(2):429–42.CrossRefPubMed

Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–81.CrossRefPubMed

Lencioni R, de Baere T, Burrel M, et al. Transcatheter treatment of hepatocellular carcinoma with Doxorubicin-loaded DC bead (DEBDOX): technical recommendations. Cardiovasc Interv Radiol. 2012;35(5):980–5.CrossRef

Xie ZB, Wang XB, Peng YC, et al. Systematic review comparing the safety and efficacy of conventional and drug-eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma. Hepatol Res. 2015;45:190–200.CrossRefPubMed

10.

Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol JVIR. 2011;22:1545–52.CrossRefPubMed

11.

Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer. 2014;111:255–64.CrossRefPubMedPubMedCentral

12.

Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Interv Radiol. 2012;35:1119–28.CrossRef

13.

Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Interv Radiol. 2010;33:41–52.CrossRef

14.

Cersosimo RJ. Systemic targeted and immunotherapy for advanced hepatocellular carcinoma. Am J Health Syst Pharm. 2021;78:187–202.CrossRefPubMed

15.

Contratto M, Wu J. Targeted therapy or immunotherapy? Optimal treatment in hepatocellular carcinoma. World J Gastrointest Oncol. 2018;10:108–14.CrossRefPubMedPubMedCentral

16.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.CrossRefPubMed

17.

Yau T, Park W, Finn RS, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874-V875. https://doi.org/10.1093/annonc/mdz394.029.CrossRef

18.

Finn S, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed

19.

A Global Study to Evaluate Transarterial Chemoembolization (TACE) in Combination With Durvalumab and Bevacizumab Therapy in Patients With Locoregional Hepatocellular Carcinoma (EMERALD-1). https://clinicaltrials.gov/ct2/show/NCT03778957.

20.

Nivolumab in combination with TACE/TAE for patients with intermediate stage HCC (TACE-3). https://clinicaltrials.gov/ct2/show/NCT04268888.

21.

Safety and efficacy of Lenvatinib (E7080/MK-7902) With Pembrolizumab (MK-3475) in combination with transarterial chemoembolization (TACE) in participants with incurable/non-metastatic hepatocellular carcinoma (MK-7902-012/E7080-G000-318/LEAP-012). https://clinicaltrials.gov/ct2/show/NCT04246177.

22.

Fuchs K, Bize PE, Dormond O, et al. Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model. J Vasc Interv Radiol. 2014;25(3):379–87.CrossRefPubMed

23.

Argyros O, Karampelas T, Varela A, et al. Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule. Oncotarget. 2017;8(23):37250–62.CrossRefPubMedPubMedCentral

24.

Jordan O, Denys A, De Baere T, Boulens N, Doelker E. Comparative study of chemoembolization loadable beads: in vitro drug release and physical properties of DC bead and hepasphere loaded with doxorubicin and irinotecan. J Vasc Interv Radiol. 2010;21(7):1084–90.CrossRefPubMed

25.

Raoul J-L, Forner A, Bolondi L, et al. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence. Cancer Treat Rev. 2019;72:28–36.CrossRefPubMed

26.

Kang YJ, Lee BC, Kim JK, Yim NY, Kim HO, Cho SB, Jeong YY. Conventional versus small doxorubicin-eluting bead transcatheter arterial chemoembolization for treating barcelona clinic liver cancer stage 0/A hepatocellular carcinoma. Cardiovasc Interv Radiol. 2020;43(1):55–64.CrossRef

27.

Lewis AL, Gonzalez MV, Lloyd AW, et al. DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol. 2006;17(2 Pt 1):335–42.CrossRefPubMed

28.

Abdekhodaie MJ, Wu XY. Drug loading onto ion-exchange microspheres: modeling study and experimental verification. Biomaterials. 2006;27(19):3652–62.PubMed

29.

Gonzalez MV, Tang Y, Phillips GJ, et al. Doxorubicin eluting beads-2: methods for evaluating drug elution and in-vitro:in-vivo correlation. J Mater Sci Mater Med. 2008;19(2):767–75.CrossRefPubMed

30.

Al-Abd AM, Aljehani ZK, Gazzaz RW, Fakhri SH, Jabbad AH, Alahdal AM, Torchilin VP. Pharmacokinetic strategies to improve drug penetration and entrapment within solid tumors. J Control Release. 2015;10(219):269–77.CrossRef

31.

Forster RE, Tang Y, Bowyer C, et al. Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies. Anticancer Drugs. 2012;23(4):355–69.CrossRefPubMed

32.

Ranieri G, Ammendola M, Marech I, et al. Vascular endothelial growth factor and tryptase changes after chemoembolization in hepatocarcinoma patients. World J Gastroenterol. 2015;21(19):6018–25.CrossRefPubMedPubMedCentral

33.

Liang B, Zheng CS, Feng GS, et al. Correlation of hypoxia-inducible factor 1alpha with angiogenesis in liver tumors after transcatheter arterial embolization in an animal model. Cardiovasc Interv Radiol. 2010;33(4):806–12.CrossRef

34.

Gupta S, Kobayashi S, Phongkitkarun S, Broemeling LD, Kan Z. Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model. Invest Radiol. 2006;41(6):516–21.CrossRefPubMed

35.

Rhee TK, Young JY, Larson AC, et al. Effect of transcatheter arterial embolization on levels of hypoxia-inducible factor-1alpha in rabbit VX2 liver tumors. J Vasc Interv Radiol. 2007;18(5):639–45.CrossRefPubMed

36.

Deudero JJ, Caramelo C, Castellanos MC, et al. Induction of hypoxia-inducible factor-1alpha gene expression by vascular endothelial growth factor. J Biol Chem. 2008;283(17):11435–44.CrossRefPubMed

37.

Chung YH, Han G, Yoon JH, et al. Interim analysis of START: study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int J Cancer. 2013;132(10):2448–58.CrossRefPubMed

38.

Fuchs K, Bize PE, Denys A, Borchard G, Jordan O. Sunitinib-eluting beads for chemoembolization: methods for in vitro evaluation of drug release. Int J Pharm. 2015;482(1–2):68–74.CrossRefPubMed

39.

Hagan A, Phillips GJ, Macfarlane WM, Lloyd AW, Czuczman P, Lewis AL. Preparation and characterisation of vandetanib-eluting radiopaque beads for locoregional treatment of hepatic malignancies. Eur J Pharm Sci. 2017;1(101):22–30.CrossRef

40.

Lee KH, Liapi EA, Cornell C, et al. Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer. Cardiovasc Interv Radiol. 2010;33(3):576–82.CrossRef

41.

Benjamin RS, Riggs CE Jr, Bachur NR. Plasma pharmacokinetics of adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res. 1977;37(5):1416–20.PubMed

42.

Laubrock N, Hempel G, Schulze-Westhoff P, et al. The stability of doxorubicin and ldarubicin in plasma and whole blood. Chromatographia. 2000;52:9–13.CrossRef

43.

Riss TL, Moravec RA, Niles AL, et al. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004.

44.

Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 1982;42(9):3858–63.PubMed

Titel: Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma
verfasst von: Miltiadis Krokidis
Danae Fakitsa
Katerina Malagari
Theodoros Karampelas
Demosthenes Fokas
Constantin Tamvakopoulos
Achilles Chatziioannou
Publikationsdatum: 12.04.2024
Verlag: Springer US
Erschienen in: CardioVascular and Interventional Radiology / Ausgabe 5/2024
Print ISSN: 0174-1551
Elektronische ISSN: 1432-086X
DOI: https://doi.org/10.1007/s00270-024-03714-z

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Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma