We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Article

Co-delivery of doxorubicin and PEGylated C16-ceramide by nanoliposomes for enhanced therapy against multidrug resistance

    Xiao Su

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    Authors contributed equally

    Search for more papers by this author

    ,
    Hao Song

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    Centre for Stem Cell & Regenerative Medicine, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shangdong 252000, China

    Authors contributed equally

    Search for more papers by this author

    ,
    Fangfang Niu

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    Authors contributed equally

    Search for more papers by this author

    ,
    Kaixuan Yang

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    Authors contributed equally

    Search for more papers by this author

    ,
    Geng Kou

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    ,
    Xiaohang Wang

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

    ,
    Huaiwen Chen

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    ,
    Wei Li

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    ,
    Shangjing Guo

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    ,
    Jun Li

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    ,
    Bohua Li

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

    ,
    Si-shen Feng

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02–11, 4 Engineering Drive 4, Singapore 117576, Singapore

    Suzhou NanoStar Biopharm Inc Ltd, BioBay, Bld B2, Unit 604, 218 Xing-Hu Street, Suzhou Industrial Park, Suzhou 215123, China

    ,
    Jianxin Jiang

    Department of Hepatobiliary Surgery, Hubei Province Tumor Hospital, Wuhan, Hubei 430079, China

    ,
    Chuan Yin

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

    &
    Jie Gao

    ***Author for correspondence:

    E-mail Address: gaojiehighclea@163.com

    International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

    College of Pharmacy, Liaocheng University, 1 Hu'nan Road, Liaocheng, Shandong 25200, PR China

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

    Published Online:https://doi.org/10.2217/nnm.15.50

    Aim: To develop novel nanoliposomes (Lip-ADR-Cer) codelivering doxorubicin (ADR) and PEGylated C16 ceramide (PEG-ceramide C16) to overcome multidrug resistance. Materials & methods: The antitumor activity and mechanism of Lip-ADR-Cer were evaluated. Results & conclusion: The IC50 of Lip-ADR-Cer after 48-h treatment with the MCF-7/ADR and HL-60/ADR cancer cells, both being ADR resistant, was 2.2- and 1.4-fold effective respectively versus the general nanoliposomes with no PEG-ceramide C16 (Lip-ADR). The antitumor assay in mice bearing MCF-7/ADR or HL-60/ADR xenograft tumors confirmed the superior antitumor activity of Lip-ADR-Cer over Lip-ADR. We found that the improved therapeutic effect of Lip-ADR-Cer may be attributed to both of the cytotoxic effect of PEG-ceramide C16 and glucosylceramide synthase overexpression in multidrug resistance cells.

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

    References

    • 1 Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13(10), 714–726 (2013).•• Comprehensive review dealing with the evolving paradigm of cancer drug resistance.
    • 2 Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5(4), 275–284 (2005).
    • 3 Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist. Updat. 14(3), 150–163 (2011).•• Excellent review elucidating nanomedicine that overcomes cancer drug resistance.
    • 4 Gao J, Feng SS, Guo Y. Nanomedicine for treatment of cancer stem cells. Nanomedicine (Lond.) 9(2), 181–184 (2014).
    • 5 Stover TC, Kim YS, Lowe TL, Kester M. Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug. Biomaterials 29(3), 359–369 (2008).
    • 6 Liu YY, Han TY, Giuliano AE, Cabot MC. Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers doxorubicin resistance in human breast cancer cells. J. Biol. Chem. 274(2), 1140–1146 (1999).
    • 7 Lavie Y, Cao H, Bursten SL, Giuliano AE, Cabot MC. Accumulation of glucosylceramides in multidrug-resistant cancer cells. J. Biol. Chem. 271(32), 19530–19536 (1996).
    • 8 Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC. Modification of ceramide metabolism increases cancer cell sensitivity to cytotoxics. Int. J. Oncol. 15(3), 541–546 (1999).
    • 9 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).
    • 10 Dumitru CA, Carpinteiro A, Trarbach T, Hengge UR, Gulbins E. Doxorubicin enhances TRAIL-induced cell death via ceramide-enriched membrane platforms. Apoptosis 12(8), 1533–1541 (2007).
    • 11 Liu YY, Yu JY, Yin D et al. A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J. 22(7), 2541–2551 (2008).• Investigating the role of ceramide in driving cancer resistance.
    • 12 van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 67(10), 4843–4850 (2007).•• Utilizing nanoparticles to deliver ceramide to cells to overcome cancer resistance.
    • 13 Gouazé V, Yu JY, Bleicher RJ et al. Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol. Cancer Ther. 3(5), 633–639 (2004).
    • 14 Liu YY, Han TY, Giuliano AE, Cabot MC. Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J. 15(3), 719–730 (2001).
    • 15 van Lummel M, van Blitterswijk WJ, Vink SR et al. Enriching lipid nanovesicles with short-chain glucosylceramide improves doxorubicin delivery and efficacy in solid tumors. FASEB J. 25(1), 280–289 (2011).
    • 16 Veldman RJ, Koning GA, van Hell A et al. Coformulated N-octanoyl-glucosylceramide improves cellular delivery and cytotoxicity of liposomal doxorubicin. J. Pharmacol. Exp. Ther. 315(2), 704–710 (2005).
    • 17 Pedrosa LR, van Hell A, Süss R et al. Improving intracellular doxorubicin delivery through nanoliposomes equipped with selective tumor cell membrane permeabilizing short-chain sphingolipids. Pharm. Res. 30(7), 1883–1895 (2013).
    • 18 Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism – a strategy for overcoming drug resistance. J. Natl Cancer Inst. 93(5), 347–357 (2001).
    • 19 Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin. Cancer Res. 14(10), 3193–3203 (2008).
    • 20 Devalapally H, Duan Z, Seiden MV, Amiji MM. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int. J. Cancer 121(8), 1830–1838 (2007).•• Co-delivery of chemotherapy drug and ceramide to overcome cancer resistance.
    • 21 Fonseca NA, Gomes-da-Silva LC, Moura V, Simões S, Moreira JN. Simultaneous active intracellular delivery of doxorubicin and C6-ceramide shifts the additive/antagonistic drug interaction of non-encapsulated combination. J. Control. Release 196, 122–131 (2014).
    • 22 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).
    • 23 Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4(2), 145–160 (2005).
    • 24 Win KY, Feng SS. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 26(15), 2713–2722 (2005).
    • 25 Zhang S, Li J, Lykotrafitis G, Bao G, Suresh S. Size-dependent endocytosis of nanoparticles. Adv. Mater. 21, 419–424 (2009).
    • 26 Decuzzi P, Ferrari M. The role of specific and non-specific interactions in receptor-mediated endocytosis of nanoparticles. Biomaterials 28(18), 2915–2922 (2007).
    • 27 Veiga MP, Arrondo JL, Goñi FM, Alonso A. Ceramides in phospholipid membranes: effects on bilayer stability and transition to nonlamellar phases. Biophys. J. 76(1), 342–350 (1999).
    • 28 Khazanov E, Priev A, Shillemans JP, Barenholz Y. Physicochemical and biological characterization of ceramide-containing liposomes: paving the way to ceramide therapeutic application. Langmuir 24(13), 6965–6980 (2008).•• Elucidating how to use surfactant to stabilize ceramide in liposomes.
    • 29 Han L, Miyasaka K, Terasaki O, Che S. 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).
    • 30 Kumar VV. Complementary molecular shapes and additivity of the packing parameter of lipids. Proc. Natl Acad. Sci. USA 88(2), 444–448 (1991).
    • 31 Wheeler JJ, Palmer L, Ossanlou M et al. Stabilized plasmid-lipid particles: construction and characterization. Gene Ther. 6(2), 271–281 (1999).
    • 32 Zhang YP, Sekirov L, Saravolac EG et al. Stabilized plasmid-lipid particles for regional gene therapy: formulation and transfection properties. Gene Ther. 6(8), 1438–1447 (1999).
    • 33 Feng SS. Interpretation of mechanochemical properties of lipid monolayers at the air-water or oil-water interface and bilayer vesicles from equation of state or pressure-area measurement. Langmuir 15(4), 998–1010 (1999).
    • 34 Feng SS, MacDonald RC. Effects of chain unsaturation on equation of state for monolayers at the air-water interface. Biophys. J. 69(2), 460–469 (1995).
    • 35 Cao N, Feng SS. Doxorubicin conjugated to d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS): in vitro cytotoxicity, in vivo pharmacokinetics and biodistribution. Biomaterials 29(28), 3856–3865 (2008).
    • 36 Anbharasi V, Cao N, Feng SS. Targeted delivery of doxorubicin conjugated to folic acid and d-α-tocopheryl polyethylene glycol succinate (TPGS). J. Biomed. Mat. Res. A 94(3), 730–743 (2010).
    • 37 Gao J, Xia Y, Chen H et al. Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma. Nanomedicine (Lond.) 9(2), 279–293 (2014).
    • 38 Sapra P, Tyagi P, Allen TM. Ligand-targeted liposomes for cancer treatment. Curr. Drug Deliv. 2(4), 369–381 (2005).
    • 39 Sapra P, Allen TM. Improved outcome when B-cell lymphoma is treated with combinations of immunoliposomal anticancer drugs targeted to both the CD19 and CD20 epitopes. Clin. Cancer Res. 10(7), 2530–2537 (2004).
    • 40 Stewart JC. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal. Biochem. 104(1), 10–14 (1980).
    • 41 Gao J, Feng SS, Guo Y. Nanomedicine against multidrug resistance in cancer treatment. Nanomedicine (Lond.) 7(4), 465–468 (2012).•• Excellent editorial elucidating the advantages of nanomedicine in overcoming cancer resistance.
    • 42 Lasic DD, Woodle MC, Martin FJ, Valentincic T. Phase behavior of ‘stealth-lipid’ decithin mixtures. Period Biol. 93, 9287–9290 (1991).
    • 43 Watters RJ, Kester M, Tran MA, Loughran TP Jr, Liu X. Development and use of ceramide nanoliposomes in cancer. Methods Enzymol. 508, 89–108 (2012).