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

      1 , 2

      Drug Design, Development and Therapy

      Dove

      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.

          Related collections

          Most cited references 53

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          The diagnosis and treatment of hepatocellular carcinoma.

          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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            Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt.

            Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. The mechanism by which curcumin initiates apoptosis remains poorly understood. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human renal Caki cells. Treatment of Caki cells with 50 microM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-gamma1 and DNA fragmentation. Curcumin-induced apoptosis is mediated through the activation of caspase, which is specifically inhibited by the caspase inhibitor, benzyloxycarbony-Val-Ala-Asp-fluoromethyl ketone. Curcumin causes dose-dependent apoptosis and DNA fragmentation of Caki cells, which is preceded by the sequential dephosphorylation of Akt, down-regulation of the anti-apoptotic Bcl-2, Bcl-XL and IAP proteins, release of cytochrome c and activation of caspase 3. Cyclosporin A, as well as caspase inhibitor, specifically inhibit curcumin-induced apoptosis in Caki cells. Pre-treatment with N-acetyl-cysteine, markedly prevented dephosphorylation of Akt, and cytochrome c release, and cell death, suggesting a role for reactive oxygen species in this process. The data indicate that curcumin can cause cell damage by inactivating the Akt-related cell survival pathway and release of cytochrome c, providing a new mechanism for curcumin-induced cytotoxicity.
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              Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles.

              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
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                18 February 2020
                2020
                : 14
                : 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
                238955
                10.2147/DDDT.S238955
                7035906
                © 2020 Bian and Guo.

                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).

                Page count
                Figures: 9, Tables: 1, References: 62, Pages: 13
                Categories
                Original Research

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