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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Targeted Therapy for Hepatocellular Carcinoma: Co-Delivery of Sorafenib and Curcumin Using Lactosylated pH-Responsive Nanoparticles

      research-article
      Author(s): 1 , 2
      Publication date (Electronic):
      Journal: Drug Design, Development and Therapy
      Publisher: Dove
      Keywords: hepatocellular carcinoma, nanoparticles, pH-responsive, sorafenib, curcumin

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          Abstract

          Purpose

          Hepatocellular carcinoma (HCC) is a leading cancer worldwide. In the present investigation, sorafenib (SFN) and curcumin (CCM) were co-delivered using pH-sensitive lactosylated nanoparticles (LAC-NPs) for targeted HCC treatment.

          Methods

          pH-responsive lactosylated materials were synthesized. SFN and CCM co-delivered, pH-responsive lactosylated nanoparticles (LAC-SFN/CCM-NPs) were self-assembled by using the nanoprecipitation technique. The nanoparticles were characterized in terms of particle size, charge and drug release profile. The anti-cancer effects of the nanoparticles were evaluated in human hepatic carcinoma cells (HepG2) cells and HCC tumor xenograft models.

          Results

          LAC-SFN/CCM-NPs are spherical particles with light coats on the surface. The size and zeta potential of LAC-SFN/CCM-NPs were 115.5 ± 3.6 nm and −34.6 ± 2.4, respectively. The drug release of LAC-SFN/CCM-NPs in pH 5.5 was more efficient than in pH 7.4. LAC-SFN/CCM-NPs group exhibited the smallest tumor volume (239 ± 14 mm 3), and the inhibition rate of LAC-SFN/CCM-NPs was 77.4%.

          Conclusion

          In summary, LAC-SFN/CCM-NPs was proved to be a promising system for targeted HCC therapy.

          Most cited references53

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          The diagnosis and treatment of hepatocellular carcinoma.

          Justin Hartke, Matthew W. Johnson, Marwan Ghabril (2017)
          Hepatocellular carcinoma is a leading cancer worldwide. Its incidence is increasing, and is closely related to advanced liver disease. Cirrhosis represents the greatest risk factor for this malignancy, and is the main indication for screening and surveillance. The diagnosis of hepatocellular carcinoma can frequently, and uniquely, be made on characteristic multiphase contrast based cross-sectional imaging rather than strict need for tissue sampling. Despite advances in medical, locoregional and surgical therapies, hepatocellular carcinoma remains one of the most common causes of cancer-related death globally. In this review, current approaches to management of hepatocellular carcinoma are discussed, which incorporate both tumor and patient factors. The salient considerations in surgical (resection, liver transplantation), locoregional (ablation and embolic therapies) and medical therapies are highlighted.
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            Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors

            Carolina Méndez-Blanco, Flavia Fondevila, Andrés García-Palomo … (2018)
            Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and sorafenib resistance, suggesting that targeting HIFs is a promising way to increase the efficiency of treatment.
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              Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles.

              Shaobo Ruan, Mingqing Yuan, Li-Li Zhang … (2015)
              Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An-PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid-responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of -19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX-AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX-AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX-AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX-AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma-bearing mice.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): DDDT
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 18 February 2020
                Publication date Collection: 2020
                Volume: 14
                Pages: 647-659
                Affiliations
                [1 ]Department of Pharmacy, Affiliated Hospital of Jiangnan University, The Fourth People’s Hospital of Wuxi City , WuXi 214000, Jiangsu Province, People’s Republic of China
                [2 ]Affiliated Hospital of Jiangnan University, The Fourth People’s Hospital of Wuxi City , Wuxi 214000, Jiangsu Province, People’s Republic of China
                Author notes
                Correspondence: Dong Guo Affiliated Hospital of Jiangnan University, The Fourth People’s Hospital of Wuxi City , No. 200 Hui He Road, Wuxi214000, Jiangsu Province, People’s Republic of China Email bianyunjnu@163.com
                Article
                Publisher ID: 238955
                DOI: 10.2147/DDDT.S238955
                PMC ID: 7035906
                SO-VID: a0b0f0b6-57c7-44db-84fb-d855551c8946
                Copyright © © 2020 Bian and Guo.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 17 November 2019
                Date accepted : 11 January 2020
                Page count
                Figures: 9, Tables: 1, References: 62, Pages: 13
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: hepatocellular carcinoma,nanoparticles,ph-responsive,sorafenib,curcumin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: hepatocellular carcinoma, nanoparticles, ph-responsive, sorafenib, curcumin

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