Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

Online
ISSN
1437-4315
See all formats and pricing
More options …
Volume 396, Issue 6-7

Issues

Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic

Mark Kester
  • Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
  • Keystone Nano, Inc, 1981 Pine Hall Road, State College, PA 16803, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jocelyn Bassler / Todd E. Fox
  • Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Carly J. Carter / Jeff A. Davidson / Mylisa R. Parette
Published Online: 2015-04-01 | DOI: https://doi.org/10.1515/hsz-2015-0129

Abstract

Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC).

Keywords: ceramide; liposome; preclinical; sphingolipid; therapeutic

References

  • Adan-Gokbulut, A., Kartal-Yandim, M., Iskender, G., and Baran, Y. (2013). Novel agents targeting bioactive sphingolipids for the treatment of cancer. Curr. Med. Chem. 20, 108–122.Google Scholar

  • Adiseshaiah, P.P., Clogston, J.D., McLeland, C.B., Rodriguez, J., Potter, T.M., Neun, B.W., Skoczen, S.L., Shanmugavelandy, S.S., Kester, M, Stern, S.T., et al. (2013). Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models. Cancer Lett. 337, 254–265.Google Scholar

  • Avella, D.M., Li, G., Schell, T.D., Liu, D., Zhang, S.S., Lou, X., Berg, A., Kimchi, E.T., Tagaram, H.R., Yang, Q., et al. (2012). Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. Hepatology 55, 141–152.Google Scholar

  • Barth, B.M., Cabot, M.C., and Kester M. (2011). Ceramide-based therapeutics for the treatment of cancer. Anticancer Agents Med. Chem. 11, 911–919.Google Scholar

  • Bieberich, E., Kawaguchi, T., and Yu, R.K. (2000). N-acylated serinol is a novel ceramide mimic inducing apoptosis in neuroblastoma cells. J. Biol. Chem. 275, 177–181.Google Scholar

  • Bieberich, E., Silva, J. Wang G., Krishnamurthy, K., and Condie, B.G. (2004). Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J. Cell Biol. 167, 723–734.Google Scholar

  • Bikman, B.T. and Summers, S.A. (2011). Ceramides as modulators of cellular and whole-body metabolism. J. Clin. Invest. 121, 4222–4230.Google Scholar

  • Bourbon, N.A., Sandirasegarane, L., and Kester, M. (2002). Ceramide-induced inhibition of Akt is mediated through protein kinase Cζ: implications for growth arrest. J. Biol. Chem. 277, 3286–3292.Google Scholar

  • Bourbon, N.A., Yun, J. Berkey D., Wang, Y., and Kester, M. (2001). Inhibitory actions of ceramide upon PKC-ε/ERK interactions. Am. J. Physiol. Cell Physiol. 280, C1403–C1411.Google Scholar

  • Coroneos, E., Wang, Y., Panuska, J.R., Templeton, D.J., and Kester, M. (1996). Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades. Biochem. J. 316, 13–17.Google Scholar

  • Crawford, K.W., Bittman, R., Chun, J., Byun, H.S., and Bowen, W.D. (2003). Novel ceramide analogues display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells. Cell. Mol. Biol. (Noisy-le-Grand) 49, 1017–1023.Google Scholar

  • Desai, A., Vyas, T., and Amiji, M. (2008). Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of paclitaxel and ceramide in nanoemulsion formulations. J. Pharm. Sci. 97, 2745–2756.Google Scholar

  • Devalapally, H., Duan, Z., Seiden, M.V., and Amiji, M.M. (2007). Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int. J. Cancer 121, 1830–1838.Google Scholar

  • Dickson, M.A., Carvajal, R.D., Merrill, A.H., Jr, Gonen, M., Cane, L.M., and Schwartz, G.K. (2011). A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin. Cancer Res. 17, 2484–2492.PubMedCrossrefGoogle Scholar

  • FDA. (1995). Guidance for Industry – Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products. C. f. D. E. a. R. C. C. f. B. E. a. R. (CBER), US Department of Health and Human Services.Google Scholar

  • FDA. (2002). Guidance for Industry – Liposome Drug Products (Draft). C. f. D. E. a. R. (CDER), US Department of Health and Human Services.Google Scholar

  • FDA. (2005). CDER. Pharmacology Review for NDA 21–923, Nexavar (Sorafenib Tosylate).Google Scholar

  • FDA. (2010). Guidance for Industry – Nonclinical Evaluation for Anticancer Pharmaceuticals. (CBER), US Department of Health and Human Services.Google Scholar

  • Fox, T.E., Houck, K.L., O’Neill, S.M., Nagarajan, M., Stover, T.C., Pomianowski, P.T., Unal, O, Yun, J.K., Naides, S.J., and Kester, M. (2007). Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J. Biol. Chem. 282, 12450–12457.Google Scholar

  • Hankins, J.L., Doshi, U.A., Haakenson, J.K., Young, M.M., Barth, B.M., and Kester, M. (2013). The therapeutic potential of nanoscale sphingolipid technologies. Handb. Exp. Pharmacol. 215, 197–210.Google Scholar

  • Hannun, Y.A. and Luberto, C. (2000). Ceramide in the eukaryotic stress response. Trends Cell Biol. 10, 73–80.PubMedCrossrefGoogle Scholar

  • Hou, Q., Jin, J., Zhou, H., Novgorodov, S.A., Bielawska, A., Szulc, Z.M., Hannun, Y.A., Obeid, L.M., and Hsu, Y.T. (2011). Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J. Lipid. Res. 52, 278–288.Google Scholar

  • Jiang, Y., DiVittore, N.A., Kaiser, J.M., Shanmugavelandy, S.S., Fritz, J.L., Heakal, Y., Tagaram, H.R., Cheng, H., Cabot, M.C., Staveley-O’Carroll, K.F., et al. (2011). Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol. Ther. 12, 574–585.CrossrefPubMedGoogle Scholar

  • Kester, M., Heakal, Y., Fox, T., Sharma, A., Robertson, G.P., Morgan, T.T., Altinoğlu, E.I., Tabaković, A., Parette, M.R., Rouse, S.M., et al. (2008). Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapeutic drug delivery to cancer cells. Nano Lett. 8, 4116–4121.Google Scholar

  • Kolesnick, R.N., Goni, F.M., and Alonso, A. (2000). Compartmentalization of ceramide signaling: physical foundations and biological effects. J. Cell Physiol. 184, 285–300.Google Scholar

  • Liu, J., Antoon, J.W., Ponnapakkam, A., Beckman, B.S., and Foroozesh, M. (2010a). Novel anti-viability ceramide analogs: design, synthesis, and structure-activity relationship studies of substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides. Bioorg. Med. Chem. 18, 5316–5322.Google Scholar

  • Liu, X., Ryland, L., Yang, J., Liao, A., Aliaga, C., Watts, R., Tan, S.F., Kaiser, J., Shanmugavelandy, S.S., Rogers, A., et al. (2010b). Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116, 4192–4201.Google Scholar

  • Llovet, J.M., Ricci, S. Mazzaferro V., Hilgard, P., Gane, E., Blanc, J-F., Cosme de Oliveira, A., Santoro, A., Raoul, J-L., Forner, A., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390.Google Scholar

  • Macchia, M., Barontini, S., Bertini, S., Di Bussolo, V., Fogli, S., Giovannetti, E., Grossi, E., Minutolo, F., and Danesi, R. (2001). Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues. J. Med. Chem. 44, 3994–4000.Google Scholar

  • Muschick, P., Wehrmann, D., Schuhmann-Giampieri, G., and Krause, W. (1995). Cardiac and hemodynamic tolerability of iodinated contrast media in the anesthetized rat. Invest. Radiol. 30, 745–753.Google Scholar

  • NCL (2007). Ceramide Liposomes for Penn State University. Nanotechnology Characterization Laboratory, N.C. Institute.Google Scholar

  • Novgorodov, S.A., Szulc, Z.M., Luberto, C., Jones, J.A., Bielawski, J., Bielawska, A., Hannun, Y.A., and Obeid, L.M. (2005). Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J. Biol. Chem. 280, 16096–16105.Google Scholar

  • Ogretmen, B. and Hannun, Y.A. (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604–616.CrossrefPubMedGoogle Scholar

  • Raichur, S., Wang, S.T., Chan, P.W., Li, Y., Ching, J., Chaurasia, B., Dogra, S., Öhman, M.K., Takeda, K., Sugii, S., et al. (2014). CerS2 haploinsufficiency inhibits beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695.Google Scholar

  • Ruvolo, P.P. (2001). Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15, 1153–1160.CrossrefPubMedGoogle Scholar

  • Ryland, L.K., Fox, T.E., Liu, X., Loughran, T.P., and Kester, M. (2011). Dysregulation of sphingolipid metabolism in cancer. Cancer Biol. Ther. 11, 138–149.CrossrefPubMedGoogle Scholar

  • Ryland, L.K., Doshi, U.A., Shanmugavelandy, S.S., Fox, T.E., Aliaga, C., Broeg, K., Baab, K.T., Young, M., Khan, O., Haakenson, J.K., et al. (2013). C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia. PLoS One 8, e84648.Google Scholar

  • Senkal, C.E., Ponnusamy, S., Rossi, M.J., Sundararaj, K., Szulc, Z., Bielawski, J., Bielawska A., Meyer M., Cobanoglu, B., Koybasi, S., et al. (2006). Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J. Pharmacol. Exp. Ther. 317, 1188–1199.Google Scholar

  • Sharma, S., Mathur, A.G., Pradhan, S., Singh, D.B., and Sparsh Gupta. (2011). Fingolimod (FTY720): first approved oral therapy for multiple sclerosis. J. Pharmacol. Pharmacother. 2, 49–51.Google Scholar

  • Stover, T. and Kester, M. (2003). Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J. Pharmacol. Exp. Ther. 307, 468–475.Google Scholar

  • Stover, T.C., Sharma, A., Robertson, G.P., and Kester, M. (2005). Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin. Cancer Res. 11, 3465–3474.CrossrefPubMedGoogle Scholar

  • Stover, T.C., Kim, Y.S., Lowe, T.L., and Kester, M. (2008). Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug. Biomaterials 29, 359–369.Google Scholar

  • Struckhoff, A.P., Bittman, R., Burow, M.E., Clejan, S., Elliott, S., Hammond, T., Tang, Y., and Beckman, B.S. (2004). Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J. Pharmacol. Exp. Ther. 309, 523–532.Google Scholar

  • Symolon, H., Bushnev, A., Peng, Q., Ramaraju, H., Mays, S.G., Allegood, J.C., Pruett, S.T., Sullards, M.C., Dillehay, D.L., Liotta, D.C., et al. (2011). Enigmol: a novel sphingolipid analogue with anticancer activity against cancer cell lines and, models for intestinal and prostate cancer. Mol. Cancer Ther. 10, 648–657.Google Scholar

  • Szebeni, J., Alving, C.R., Rosivall, L., Bünger, R., Baranyi, L., Bedöcs, P., Tóth, M., and Barenholz, Y. (2007). Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J. Liposome Res. 17, 107–117.Google Scholar

  • Tagaram, H.R., Divittore, N.A., Barth, B.M., Kaiser, J.M., Avella, D., Kimchi, E.T., Jiang, Y., Isom, H.C., Kester, M., and Staveley-O’Carroll, K.F. (2011). Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 60, 695–701.Google Scholar

  • Tan, K.B., Ling, L.U., Bunte, R.M., Chng, W.J., and Chiu, G.N. (2012). In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia. J. Control Release 160, 290–298.Google Scholar

  • Tran, M.A., Smith, C.D., Kester, M., and Robertson, G.P. (2008). Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin. Cancer Res. 14, 3571–3581.CrossrefPubMedGoogle Scholar

  • Truman, J.P., Garcia-Barros, M., Obeid, L.M., and Hannun, Y.A. (2014). Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim. Biophys. Acta 1841, 1174–1788.Google Scholar

  • Turpin, S.M., Nicholls, H.T., Willmes, D.M., Mourier, A., Brodesser, S., Wunderlich, C.M., Mauer, J., Xu, E., Hammerschmidt, P., Brönneke, H.S., et al. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686.Google Scholar

  • van Vlerken, L.E., Duan, Z., Seiden, M.V., and Amiji, M.M. (2007). Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 67, 4843–4850.Google Scholar

  • Verheij, M., van Blitterswijk, W.J., and Bartelink, H. (1998). Radiation-induced apoptosis--the ceramide-SAPK signaling pathway and clinical aspects. Acta Oncol. 37, 575–581.Google Scholar

  • Wang, Y.M., Seibenhener, M.L., Vandenplas, M.L., and Wooten M.W. (1999). Atypical PKCζ is activated by ceramide, resulting in coactivation of NF-κB/JNK kinase and cell survival. J. Neurosci. Res. 55, 293–302.Google Scholar

  • Zolnik, B.S., Stern, S.T., Kaiser, J.M., Heakal, Y., Clogston, J.D., Kester, M., and McNeil, S.E. (2008). Rapid distribution of liposomal short-chain ceramide in vitro and in vivo. Drug Metab. Dispos. 36, 1709–1715.Google Scholar

About the article

Mark Kester

Mark Kester, Chief Medical Officer and co-founder of Keystone Nano, earned his PhD from the State University of New York at Buffalo. He has held faculty positions at Case Western Reserve University, Penn State University and currently serves as a Professor of Pharmacology and the Director of the NanoSTAR Institute at the University of Virginia. His research in the field of sphingolipids and nano-drug delivery systems led to the invention of the Ceramide NanoLiposome in his laboratory at Penn State University.

Jocelyn Bassler

Jocelyn Bassler received her BS in Biology from Virginia Polytechnic Institute and State University and worked with Southern Research Institute for 7 years before joining Keystone Nano as a Biological Researcher. She specializes in liposome formulation development and synthesis as well as cell-based assays.

Todd E. Fox

Todd E. Fox is an Assistant Professor of Pharmacology at the University of Virginia. He is the Director of the UVA Cancer Center’s Metabolomic and Lipidomic Core Facility. He is an expert in the utilization of mass spectrometry to quantify sphingolipid metabolites.

Carly J. Carter

Carly J. Carter received her BS in Chemistry from Penn State University in 2003 and her PhD in Chemistry and Biochemistry from the University of Colorado in 2010. Dr. Carter’s research background includes utilizing the interactions between biological molecules and materials to develop nanoparticle therapeutics. Dr. Carter is the Research Leader at Keystone Nano.

Jeff A. Davidson

Jeff A. Davidson holds a BS in Chemical Engineering from Purdue University and an MBA from the University of Minnesota. His 27 years of experience in industry and academia include serving as the Executive Director of the Penn State Bioprocessing Resource Center; founder and Executive Director of the Pennsylvania Biotechnology Association; publisher of Your World, a biotechnology applications magazine; founder of the Biotechnology Institute, a national biotechnology education nonprofit and founder of BioSciEd, Inc. Mr. Davidson co-founded Keystone Nano and has served as its CEO for the past 10 years.

Mylisa R. Parette

Mylisa R. Parette received her BS in Biology and Chemistry from Towson University, a MAT degree from Brown University and her PhD in Biochemistry, Microbiology and Molecular Biology from Penn State University. Dr. Parette has served as Research Manager at Keystone Nano for the past 9 years, leading the development of NanoLiposome and calcium phosphate NanoJacket programs from the bench to IND stage.


Corresponding author: Mylisa R. Parette, Keystone Nano, Inc, 1981 Pine Hall Road, State College, PA 16803, USA, e-mail:


Received: 2015-02-17

Accepted: 2015-03-21

Published Online: 2015-04-01

Published in Print: 2015-06-01


Citation Information: Biological Chemistry, Volume 396, Issue 6-7, Pages 737–747, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2015-0129.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Yanyan Zhu, Chaojie Wang, Yun Zhou, Ning Ma, and Jianwei Zhou
Journal of Cellular Physiology, 2018
[2]
Guangfu Li, Dai Liu, Eric T. Kimchi, Jussuf T. Kaifi, Xiaoqiang Qi, Yariswamy Manjunath, Xinjian Liu, Tye Deering, Todd Fox, Don C. Rockey, Todd D. Schell, Mark Kester, and Kevin F. Staveley-O’Carroll
Gastroenterology, 2018
[3]
Ushma A Doshi, Jeremy Shaw, Todd E Fox, David F Claxton, Thomas P Loughran, and Mark Kester
Signal Transduction and Targeted Therapy, 2017, Volume 2, Page 17051
[4]
E. Ramsay Camp, Logan D. Patterson, Mark Kester, and Christina Voelkel-Johnson
Cancer Biology & Therapy, 2017, Page 1
[5]
Samy A. F. Morad, Terence E. Ryan, P. Darrell Neufer, Tonya N. Zeczycki, Traci S. Davis, Matthew R. MacDougall, Todd E. Fox, Su-Fern Tan, David J. Feith, Thomas P. Loughran, Mark Kester, David F. Claxton, Brian M. Barth, Tye G. Deering, and Myles C. Cabot
Journal of Lipid Research, 2016, Volume 57, Number 7, Page 1231
[6]
Huiqing Lv, Zhongmin Zhang, Xiaoyu Wu, Yaoxia Wang, Chenglin Li, Weihong Gong, Liang Gui, Xin Wang, and Diego Calvisi
PLOS ONE, 2016, Volume 11, Number 1, Page e0145195
[7]
Fangzhen Jiang, Kai Jin, Shenyu Huang, Qi Bao, Zheren Shao, Xueqing Hu, Juan Ye, and Houhui Xia
PLOS ONE, 2016, Volume 11, Number 9, Page e0159849
[8]
Edward H. Schuchman
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2016, Volume 1862, Number 9, Page 1459
[9]
Elliot M. Epner, Bikramajit Singh Saroya, Zainul S. Hasanali, and Thomas P. Loughran
Experimental Hematology, 2016, Volume 44, Number 3, Page 157

Comments (0)

Please log in or register to comment.
Log in