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Research Article

Therapeutic PEG-ceramide nanomicelles synergize with salinomycin to target both liver cancer cells and cancer stem cells

    Meiping Wang

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    Authors contributed equally

    Search for more papers by this author

    ,
    Fangyuan Xie

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China

    Authors contributed equally

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    ,
    Xikai Wen

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    Authors contributed equally

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    ,
    Han Chen

    Department of General Surgery, 411 Hospital of Chinese People's Liberation Army, 15 East Jiangwan Road, Shanghai 200081, China

    Authors contributed equally

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    ,
    Hai Zhang

    Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China

    ,
    Junjie Liu

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    He Zhang

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    Hao Zou

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    Yuan Yu

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    Yan Chen

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    Zhiguo Sun

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    ,
    Xinxia Wang

    Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China

    ,
    Guoqing Zhang

    Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai 200438, China

    ,
    Chuan Yin

    Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China

    ,
    Duxin Sun

    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Jie Gao

    ****Author for correspondence:

    E-mail Address: gaojie@smmu.edu.cn

    ;

    E-mail Address: gaojiehighclea@163.com

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA

    ,
    Beige Jiang

    ***Author for correspondence:

    E-mail Address: jiang_beige@aliyun.com

    Third Department of HepaticSurgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China

    ,
    Yanqiang Zhong

    **Author for correspondence:

    E-mail Address: yqzhong68@163.com

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    &
    Ying Lu

    *Author for correspondence:

    E-mail Address: acuace@163.com

    Department of Pharmaceutical Sciences, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China

    Published Online:https://doi.org/10.2217/nnm-2016-0408

    Aim: Salinomycin (SAL)-loaded PEG-ceramide nanomicelles (SCM) were prepared to target both liver cancer cells and cancer stem cells. Materials & methods: The synergistic ratio of SAL/PEG-ceramide was evaluated to prepare SCM, and the antitumor activity of SCM was examined both in vitro and in vivo. Results: SAL/PEG-ceramide molar ratio of 1:4 was chosen as the synergistic ratio, and SCM showed superior cytotoxic effect and increased apoptosis-inducing activity in both liver cancer cells and cancer stem cells. In vivo, SCM showed the best tumor inhibitory effect with a safety profile. Conclusion: Thus, PEG-ceramide nanomicelles could serve as an effective and safe therapeutic drug carrier to deliver SAL into liver cancer, opening up the avenue of using PEG-ceramide as therapeutic drug carriers.

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

    References

    • 1 Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science 303(5665), 1818–1822 (2004).
    • 2 Banzato A, Bobisse S, Rondina M et al. A paclitaxel-hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity. Clin. Cancer. Res. 14(11), 3598–3606 (2008).
    • 3 Chung JE, Tan S, Gao SJ et al. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nat. Nanotechnol. 9(11), 907–912 (2014). •• An excellent article suggesting that therapeutic drug carriers can solve the issue of the use of high quantities of carriers.
    • 4 Saddoughi SA, Ogretmen B. Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res. 117, 37–58 (2013).
    • 5 Jayadev S, Liu B, Bielawska AE et al. Role for ceramide in cell cycle arrest. J. Biol. Chem. 270(5), 2047–2052 (1995).
    • 6 Kitatani K, Usui T, Sriraman SK et al. Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35(21), 2801–2812 (2016).
    • 7 Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science 274(5294), 1855–1859 (1996).
    • 8 Kitatani K, Sheldon K, Anelli V et al. Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid. J. Biol. Chem. 284(19), 12979–12988 (2009).
    • 9 Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism-a strategy for overcoming drug resistance. J. Natl Cancer Inst. 93(5), 347–357 (2001).
    • 10 Rath G, Schneider C, Langlois B et al. De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int. J. Biochem. Cell. Biol. 41(5), 1165–1172 (2009).
    • 11 Li F, Zhang N. Ceramide: therapeutic potential in combination therapy for cancer treatment. Curr. Drug. Metab. 17(1), 37–51 (2015).
    • 12 Feng LX, Li M, Liu YJ et al. Synergistic enhancement of cancer therapy using a combination of ceramide and docetaxel. Int. J. Mol. Sci. 15(3), 4201–4220 (2014).
    • 13 Su X, Song H, Niu F et al. Co-delivery of doxorubicin and PEGylated C16-ceramide by nanoliposomes for enhanced therapy against multidrug resistance. Nanomedicine (Lond.) 10(13), 2033–2050 (2015).
    • 14 Han L, Miyasaka K, Terasaki O et al. Evolution of packing parameters in the structural changes of silica mesoporous crystals: cage-type, 2D cylindrical, bicontinuous diamond and gyroid, and lamellar. J. Am. Chem. Soc. 133(30), 11524–11533 (2011).
    • 15 Khazanov E, Priev A, Shillemans JP et al. Physicochemical and biological characterization of ceramide containing liposomes: paving the way to ceramide therapeutic application. Langmuir 24(13), 6965–6980 (2008).
    • 16 Mao X, Liu J, Gong Z et al. iRGD-conjugated DSPE-PEG2000 nanomicelles for targeted delivery of salinomycin for treatment of both liver cancer cells and cancer stem cells. Nanomedicine (Lond.) 10(17), 2677–2695 (2015).
    • 17 Ashok B, Arleth L, Hjelm RP et al. In vitro characterization of PEGylated phospholipid micelles for improved drug solubilization: effects of PEG chain length and PC incorporation. J. Pharm. Sci. 93(10), 2476–2487 (2004).
    • 18 Zhao BJ, Ke XY, Huang Y et al. The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats. J. Drug. Target. 19(5), 382–390 (2011).
    • 19 Wang AT, Liang DS, Liu YJ et al. Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors. Biomaterials 53, 160–172 (2015).
    • 20 Xie F, Zhang S, Liu J et al. Codelivery of salinomycin and chloroquine by liposomes enables synergistic antitumor activity in vitro. Nanomedicine (Lond.) 11(14), 1831–1846 (2016).
    • 21 Gong Z, Chen D, Xie F et al. Codelivery of salinomycin and doxorubicin using nanoliposomes for targeting both liver cancer cells and cancer stem cells. Nanomedicine (Lond.) 11(19), 2565–2579 (2016).
    • 22 Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J. Biomed. Biotechnol. 2012, 950658 (2012). •• An excellent article elucidating salinomycin is a potent drug in killing cancer stem cells (CSCs).
    • 23 Boehmerle W, Endres M. Salinomycin induces calpain and cytochrome c-mediated neuronal cell death. Cell. Death Dis. 2, e168 (2011).
    • 24 Liboiron BD, Mayer LD. Nanoscale particulate systems for multidrug delivery: towards improved combination chemotherapy. Ther. Deliv. 5(2), 149–171 (2014).
    • 25 Song H, Su X, Yang K et al. CD20 antibody-conjugated immunoliposomes for targeted chemotherapy of melanoma cancer initiating cells. J. Biomed. Nanotechnol. 11(11), 1927–1946 (2015).
    • 26 Yang K, Lu Y, Xie F et al. Cationic liposomes induce cell necrosis through lysosomal dysfunction and late-stage autophagic flux inhibition. Nanomedicine (Lond.) 11(23), 3117–3137 (2016).
    • 27 Gao J, Chen H, Yu Y et al. Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials 34(38), 10084–10098 (2013).
    • 28 Ren J, Shen S, Wang D et al. The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2. Biomaterials 33(11), 3324–3333 (2012).
    • 29 Chou TC, Talaly P. A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems. J. Biol. Chem. 252(18), 6438–6442 (1977).
    • 30 Huang J, Zhang H, Yu Y et al. Biodegradable self-assembled nanoparticles of poly(D,L-lactide-co-glycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer. Biomaterials 35(1), 550–566 (2014).
    • 31 Li W, Li J, Gao J et al. The fine-tuning of thermosensitive and degradable polymer micelles for enhancing intracellular uptake and drug release in tumors. Biomaterials 32(15), 3832–3844 (2011).
    • 32 Tong Z, Luo W, Wang Y et al. Tumor tissue-derived formaldehyde and acidic microenvironment synergistically induce bone cancer pain. PLoS ONE 5(4), e10234 (2010).
    • 33 Wei T, Liu J, Ma H et al. Functionalized nanoscale micelles improve drug delivery for cancer therapy in vitro and in vivo. Nano Lett. 13(6), 2528–2534 (2013).
    • 34 Gupta PB, Onder TT, Jiang G et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138(4), 645–659 (2009). •• An excellent article elucidating salinomycin is a potent drug in killing CSCs.
    • 35 Lu W, Wan J, She Z et al. Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle. J. Control. Release 118(1), 38–53 (2007).
    • 36 Musacchio T, Torchilin VP. Recent developments in lipid-based pharmaceutical nanocarriers. Front. Biosci. 16, 1388–1412 (2011).
    • 37 Duncan R. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2(5), 347–360 (2003).
    • 38 Jia T, Sun Z, Lu Y et al. A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1–42-injected mice. Int. J. Nanomedicine 11, 3765–3775 (2016).
    • 39 Yin C, Lin Y, Zhang X et al. Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology 48(5), 1528–1539 (2008).
    • 40 Yin C, Wang PQ, Xu WP et al. Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region. Hepatology 58(6), 1964–1976 (2013).
    • 41 Chiba T, Kita K, Zheng YW et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell like properties. Hepatology 44(1), 240–251 (2006).
    • 42 Yin C, Xie WF. Differentiation therapy with transcription factors might present as an ideal strategy for the treatment of cancer. Hepatology 50(6), 2046–2047 (2009).
    • 43 Yin C, Xie WF. Hepatocellular carcinoma: basic and transitional research. Gastrointest. Tumors 1(2), 76–83 (2014).
    • 44 Zeng X, Lin Y, Yin C et al. Recombinant adenovirus carrying the hepatocyte nuclear factor-1α gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 54(6), 2036–2047 (2011).
    • 45 Chaffer CL, Brueckmann I, Scheel C et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108(19), 7950–7955 (2011). •• An excellent article elucidating non-CSCs in the tumor can spontaneously and stochastically turn into CSCs de novo.
    • 46 Xie FY, Xu WH, Yin C et al. Nanomedicine strategies for sustained, controlled, and targeted treatment of cancer stem cells of the digestive system. World J. Gastrointest. Oncol. 8(10), 735–744 (2016).
    • 47 Gao J, Feng SS, Guo Y. Nanomedicine for treatment of cancer stem cells. Nanomedicine (Lond.) 9(2), 181–184 (2014).
    • 48 Abraham SA, McKenzie C, Masin D et al. In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading. Clin. Cancer. Res. 10(2), 728–738 (2004).
    • 49 Zucker D, Barenholz Y. Optimization of vincristine-topotecan combination-paving the way for improved chemotherapy regimens by nanoliposomes. J. Control. Release 146(3), 326–333 (2010).