Pharmaceutical Research

, 35:91 | Cite as

Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Naïve and Tumor-Bearing Mice

  • Gulzar Ahmad
  • Florence Gattacecca
  • Rana El Sadda
  • Galina Botchkina
  • Iwao Ojima
  • James Egan
  • Mansoor Amiji
Research Paper



The main purpose of this study was to formulate an oil-in-water nanoemulsion of a next generation taxoid DHA-SBT-1214 and evaluate its biodistribution and pharmacokinetics.


DHA-SBT-1214 was encapsulated in a fish oil containing nanoemulsion using a high pressure homogenization method. Following morphological characterization of the nanoemulsions, qualitative and quantitative biodistribution was evaluated in naïve and cancer stem cell-enriched PPT-2 human prostate tumor bearing mice.


DHA-SBT-1214 was successfully encapsulated up to 20 mg/ml in the nanoemulsion formulation and had an average oil droplet size of 200 nm. Using a DiR near infra-red dye encapsulated nanoemulsion, we have shown the delivery of nanoemulsion to mouse tumor region. By quantitative analysis, DHA-SBT-1214 encapsulated nanoemulsion demonstrated improved pharmacokinetic properties in plasma and different tissues as compared to its solution form. Furthermore, the nanoemulsions were stable and had slower in vitro drug release compared to its solution form.


The results from this study demonstrated effective encapsulation of the drug in a nanoemulsion and this nanoemulsion showed sustained plasma levels and enhanced tumor delivery relative to the solution form.

Key words

biodistribution and pharmacokinetic nanoemulsion formulation prostate tumor taxoid 



Area under curve




Cancer Stem Cells


Docosahexaenoic acid


1, 2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]


High Performance Liquid Chromatography


Institutional Animal Care and Use Committee


Limulus Amebocyte Lysate


Limit of Detection


Limit of Quantification


Multi Drug Resistance


Mean residence time


Mesenchymal Stem Cell Growth Media


Poly Ethylene Glycol


Polydispersity index


Prostate cancer




Sodium Lauryl Sulfate


Terminal half-life


Transmission Electron Microscopy


Trifluoroacetic acid


Tumor Initiating Cells


Volume of distribution at steady state


Acknowledgments and Disclosures

Financial support was provided by the National Cancer Institute of the National Institutes of Health through grants and contract R21-CA150085 (to GB), R01-CA103314 and R44-CA132396 (to IO), HHSN261201500018C (to JE) and U01-CA151452 and R21-CA179652 (to MA). Additionally, transmission electron microscopy of the nanoemulsion samples was performed by Mr. William Fowle at the Electron Microscopy Center, Northeastern University (Boston, MA).


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhou CK, Check DP, Lortet-Tieulent J, Laversanne M, Jemal A, Ferlay J, et al. Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group. Int J Cancer. 2016;138(6):1388–400.CrossRefPubMedGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea--a paradigm shift. Cancer Res. 2006;66(4):1883–90. discussion 95–6CrossRefPubMedGoogle Scholar
  6. 6.
    Clarke MF, Fuller M. Stem cells and cancer: two faces of eve. Cell. 2006;124(6):1111–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Semenas J, Allegrucci C, Boorjian SA, Mongan NP, Persson JL. Overcoming drug resistance and treating advanced prostate cancer. Curr Drug Targets. 2012;13(10):1308–23.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ni J, Cozzi P, Hao J, Duan W, Graham P, Kearsley J, et al. Cancer stem cells in prostate cancer chemoresistance. Curr Cancer Drug Targets. 2014;14(3):225–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Hutchinson L, Kirk R. High drug attrition rates--where are we going wrong? Nat Rev Clin Oncol. 2011;8(4):189–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. 2009;457(7229):603–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Gillet JP, Calcagno AM, Varma S, Marino M, Green LJ, Vora MI, et al. Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance. Proc Natl Acad Sci U S A. 2011;108(46):18,708–13.CrossRefGoogle Scholar
  12. 12.
    Botchkina GI, Zuniga ES, Rowehl RH, Park R, Bhalla R, Bialkowska AB, et al. Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24. PLoS One. 2013;8(9):e69884.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vredenburg MR, Ojima I, Veith J, Pera P, Kee K, Cabral F, et al. Effects of orally active taxanes on P-glycoprotein modulation and colon and breast carcinoma drug resistance. J Natl Cancer Inst. 2001;93(16):1234–45.CrossRefPubMedGoogle Scholar
  14. 14.
    Ojima I, Wang T, Miller ML, Lin S, Borella CP, Geng X, et al. Synthesis and structure-activity relationships of new second-generation taxoids. Bioorg Med Chem Lett. 1999;9(24):3423–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Ojima I, Slater JC, Michaud E, Kuduk SD, Bounaud PY, Vrignaud P, et al. Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells. J Med Chem. 1996;39(20):3889–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Ojima I, Chen J, Sun L, Borella CP, Wang T, Miller ML, et al. Design, synthesis, and biological evaluation of new-generation taxoids. J Med Chem. 2008;51(11):3203–21.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Botchkina GI, Zuniga ES, Das M, Wang Y, Wang H, Zhu S, et al. New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells. Mol Cancer. 2010;9:192.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Das M, Zuniga E, Ojima I. Novel taxoid-based tumor-targeting drug conjugates. Chim Oggi. 2009;27(6):54–6.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Sauer LA, Dauchy RT. The effect of omega-6 and omega-3 fatty acids on 3H-thymidine incorporation in hepatoma 7288CTC perfused in situ. Br J Cancer. 1992;66(2):297–303.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jones RJ, Hawkins RE, Eatock MM, Ferry DR, Eskens FA, Wilke H, et al. A phase II open-label study of DHA-paclitaxel (Taxoprexin) by 2-h intravenous infusion in previously untreated patients with locally advanced or metastatic gastric or oesophageal adenocarcinoma. Cancer Chemother Pharmacol. 2008;61(3):435–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Harries M, O’Donnell A, Scurr M, Reade S, Cole C, Judson I, et al. Phase I/II study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours. British J Cancer. 2004;91(9):1651–5.CrossRefGoogle Scholar
  22. 22.
    Hennenfent KL, Govindan R. Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncol. 2006;17(5):735–49.CrossRefPubMedGoogle Scholar
  23. 23.
    Kuznetsova L, Chen J, Sun L, Wu X, Pepe A, Veith JM, et al. Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents. Bioorg Med Chem Lett. 2006;16(4):974–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm. 2008;358(1–2):285–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Mehta SB, Lewus R, Bee JS, Randolph TW, Carpenter JF. Gelation of a monoclonal antibody at the silicone oil-water interface and subsequent rupture of the interfacial gel results in aggregation and particle formation. J Pharm Sci. 2015;104(4):1282–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–84.CrossRefPubMedGoogle Scholar
  27. 27.
    Maeda H, Fang J, Inutsuka T, Kitamoto Y. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol. 2003;3(3):319–28.CrossRefPubMedGoogle Scholar
  28. 28.
    Maeda H. Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(3):53–71.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 2007;67(10):4843–50.CrossRefPubMedGoogle Scholar
  30. 30.
    Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7(9):771–82.CrossRefPubMedGoogle Scholar
  31. 31.
    Shah L, Gattacceca F, Amiji MM. CNS delivery and pharmacokinetic evaluations of DALDA analgesic peptide analog administered in Nano-sized oil-in-water emulsion formulation. Pharm Res. 2014;31(5):1315–24.CrossRefPubMedGoogle Scholar
  32. 32.
    Kadakia E, Shah L, Amiji MM. Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers. Pharm Res. 2017;34(7):1416–27.CrossRefPubMedGoogle Scholar
  33. 33.
    Ganta S, Singh A, Rawal Y, Cacaccio J, Patel NR, Kulkarni P, et al. Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer. Drug Deliv. 2016;23(3):968–80.PubMedGoogle Scholar
  34. 34.
    Pawar VK, Panchal SB, Singh Y, Meher JG, Sharma K, Singh P, et al. Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response. J Control Release. 2014;196:295–306.CrossRefPubMedGoogle Scholar
  35. 35.
    Sarker DK. Engineering of nanoemulsions for drug delivery. Curr Drug Deliv. 2005;2(4):297–310.CrossRefPubMedGoogle Scholar
  36. 36.
    Mehta SB, Carpenter JF, Randolph TW. Colloidal Instability Fosters Agglomeration of Subvisible Particles Created by Rupture of Gels of a Monoclonal Antibody Formed at Silicone Oil-Water Interfaces. J Pharm Sci. 2016;105(8):2338–48.CrossRefPubMedGoogle Scholar
  37. 37.
    Mu L, Feng SS. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. J Control Release. 2003;86(1):33–48.CrossRefPubMedGoogle Scholar
  38. 38.
    Ali MS, Pandit V, Jain M, Dhar KL. Mucoadhesive microparticulate drug delivery system of curcumin against Helicobacter pylori infection: Design, development and optimization. J Adv Pharm Technol Res. 2014;5(1):48–56.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhu RR, Qin LL, Wang M, Wu SM, Wang SL, Zhang R, et al. Preparation, characterization, and anti-tumor property of podophyllotoxin-loaded solid lipid nanoparticles. Nanotechnology. 2009;20(5):055702.CrossRefPubMedGoogle Scholar
  40. 40.
    Chen CC, Tsai TH, Huang ZR, Fang JY. Effects of lipophilic emulsifiers on the oral administration of lovastatin from nanostructured lipid carriers: physicochemical characterization and pharmacokinetics. Eur J Pharm Biopharm. 2010;74(3):474–82.CrossRefPubMedGoogle Scholar
  41. 41.
    Rossi J, Giasson S, Khalid MN, Delmas P, Allen C, Leroux JC. Long-circulating poly(ethylene glycol)-coated emulsions to target solid tumors. Eur J Pharm Biopharm. 2007;67(2):329–38.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Gulzar Ahmad
    • 1
  • Florence Gattacecca
    • 2
  • Rana El Sadda
    • 3
  • Galina Botchkina
    • 3
    • 4
  • Iwao Ojima
    • 3
    • 5
  • James Egan
    • 6
  • Mansoor Amiji
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Institut de Recherche en Cancérologie de Montpellier IRCM, INSERM U1194, ICMUniversité de MontpellierMontpellierFrance
  3. 3.Institute of Chemical Biology and Drug DiscoveryStony Brook UniversityStony BrookUSA
  4. 4.Department of Pathology, School of MedicineStony Brook UniversityStony BrookUSA
  5. 5.Department of ChemistryStony Brook UniversityStony BrookUSA
  6. 6.Targagenix, Inc.Stony BrookUSA

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