Advertisement

AAPS PharmSciTech

, Volume 15, Issue 3, pp 694–708 | Cite as

Nanoemulsions in Translational Research—Opportunities and Challenges in Targeted Cancer Therapy

  • Srinivas Ganta
  • Meghna Talekar
  • Amit Singh
  • Timothy P. Coleman
  • Mansoor M. Amiji
Review Article Theme: Translational Application of Nano Delivery Systems: Emerging Cancer Therapy
Part of the following topical collections:
  1. Theme: Translational Application of Nano Delivery Systems: Emerging Cancer Therapy

Abstract

Nanoemulsion dosage form serves as a vehicle for the delivery of active pharmaceutical ingredients and has attracted great attention in drug delivery and pharmacotherapy. In particular, nanoemulsions act as an excellent vehicle for poorly aqueous soluble drugs, which are otherwise difficult to formulate in conventional dosage forms. Nanoemulsions are submicron emulsions composed of generally regarded as safe grade excipients. Particle size at the nanoscale and larger surface area lead to some very interesting physical properties that can be exploited to overcome anatomical and physiological barriers associated in drug delivery to the complex diseases such as cancer. Along these lines, nanoemulsions have been engineered with specific attributes such as size, surface charge, prolonged blood circulation, target specific binding ability, and imaging capability. These attributes can be tuned to assist in delivering drug/imaging agents to the specific site of interest, based on active and passive targeting mechanisms. This review focuses on the current state of nanoemulsions in the translational research and its role in targeted cancer therapy. In addition, the production, physico-chemical characterization, and regulatory aspects of nanoemulsion are addressed.

KEY WORDS

cancer homogenization microenvironment microfluidization nanoemulsion size distribution targeted delivery 

Notes

ACKNOWLEDGEMENTS

The authors are thankful to the support by the National Cancer Institute of the National Institutes of Health grant U54-CA151881.

REFERENCES

  1. 1.
    Sareen S, Mathew G, Joseph L. Improvement in solubility of poor water-soluble drugs by solid dispersion. Int J Pharm Investig. 2012;2(1):12.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Ganta S, Paxton JW, Baguley BC, Garg S. Pharmacokinetics and pharmacodynamics of chlorambucil delivered in parenteral emulsion. Int J Pharm. 2008;360(1–2):115–21.PubMedGoogle Scholar
  3. 3.
    Ganta S, Amiji M. Coadministration of paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Mol Pharm. 2009;6(3):928–39.PubMedGoogle Scholar
  4. 4.
    Ganta S, Devalapally H, Amiji M. Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation. J Pharm Sci. 2010;99(11):4630–41.PubMedGoogle Scholar
  5. 5.
    Ganta S, Sharma P, Paxton JW, Baguley BC, Garg S. Pharmacokinetics and pharmacodynamics of chlorambucil delivered in long-circulating nanoemulsion. J Drug Target. 2010;18(2):125–33.PubMedGoogle Scholar
  6. 6.
    Dehelean CA, Feflea S, Ganta S, Amiji M. Anti-angiogenic effects of betulinic acid administered in nanoemulsion formulation using chorioallantoic membrane assay. J Biomed Nanotechnol. 2011;7(2):317–24.PubMedGoogle Scholar
  7. 7.
    Talekar M, Ganta S, Singh A, Amiji M, Kendall J, Denny WA, et al. Phosphatidylinositol 3-kinase inhibitor (PIK75) containing surface functionalized nanoemulsion for enhanced drug delivery, cytotoxicity and pro-apoptotic activity in ovarian cancer cells. Pharm Res. 2012;29(10):2874–86.PubMedGoogle Scholar
  8. 8.
    Dehelean CA, Feflea S, Gheorgheosu D, Ganta S, Cimpean AM, Muntean D, et al. Anti-angiogenic and anti-cancer evaluation of betulin nanoemulsion in chicken chorioallantoic membrane and skin carcinoma in Balb/c mice. J Biomed Nanotechnol. 2013;9(4):577–89.PubMedGoogle Scholar
  9. 9.
    Ganta S, Devalapally H, Baguley BC, Garg S, Amiji M. Microfluidic preparation of chlorambucil nanoemulsion formulations and evaluation of cytotoxicity and pro-apoptotic activity in tumor cells. J Biomed Nanotechnol. 2008;4(2):165–73.Google Scholar
  10. 10.
    Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2007;66(2):227–43.Google Scholar
  11. 11.
    Khandavilli S, Panchagnula R. Nanoemulsions as versatile formulations for paclitaxel delivery: peroral and dermal delivery studies in rats. J Investig Dermatol. 2007;127(1):154–62.PubMedGoogle Scholar
  12. 12.
    Patlolla RR, Vobalaboina V. Pharmacokinetics and tissue distribution of etoposide delivered in parenteral emulsion. J Pharm Sci. 2005;94(2):437–45.PubMedGoogle Scholar
  13. 13.
    Tiwari S, Tan Y-M, Amiji M. Preparation and in vitro characterization of multifunctional nanoemulsions for simultaneous MR imaging and targeted drug delivery. J Biomed Nanotechnol. 2006;2(3–4):3–4.Google Scholar
  14. 14.
    Gallarate M, Chirio D, Bussano R, Peira E, Battaglia L, Baratta F, et al. Development of O/W nanoemulsions for ophthalmic administration of timolol. Int J Pharm. 2013;440(2):126–34.PubMedGoogle Scholar
  15. 15.
    Nesamony J, Shah IS, Kalra A, Jung R. Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development, physico-chemical characterization and in vitro evaluation. Drug Dev Ind Pharm. 2013. doi: 10.3109/03639045.2013.814065.
  16. 16.
    Hippalgaonkar K, Majumdar S, Kansara V. Injectable lipid emulsions-advancements, opportunities and challenges. AAPS PharmSciTech. 2010;11(4):1526–40.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Cockshott ID. Propofol ('Diprivan') pharmacokinetics and metabolism—an overview. Postgrad Med J. 1985;61 Suppl 3:45–50.PubMedGoogle Scholar
  18. 18.
    Tibell A, Larsson M, Alvestrand A. Dissolving intravenous cyclosporin A in a fat emulsion carrier prevents acute renal side effects in the rat. Transplant Int Off J Eur Soc Organ Transplant. 1993;6(2):69–72.Google Scholar
  19. 19.
    Gianella A, Jarzyna PA, Mani V, Ramachandran S, Calcagno C, Tang J, et al. Multifunctional nanoemulsion platform for imaging guided therapy evaluated in experimental cancer. ACS Nano. 2011;5(6):4422–33.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer. 2005;5(3):161–71.PubMedGoogle Scholar
  21. 21.
    Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev. 2006;58(14):1532–55.PubMedGoogle Scholar
  22. 22.
    Kim KY. Nanotechnology platforms and physiological challenges for cancer therapeutics. Nanomedicine Nanotechnol Biol Med. 2007;3(2):103–10.Google Scholar
  23. 23.
    Ganta S, Deshpande D, Korde A, Amiji M. A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers. Mol Membr Biol. 2010;27(7):260–73.PubMedGoogle Scholar
  24. 24.
    3Lawler J. Editorial foreword: introduction to the tumour microenvironment review series. J Cell Mol Med. 2009;13(8 A):1403–4.PubMedGoogle Scholar
  25. 25.
    Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135–46.PubMedGoogle Scholar
  26. 26.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedGoogle Scholar
  27. 27.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96(12):1788–95.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Winter PM, Schmieder, Anne H, Caruthers, Shelton D, Keene, et al. Minute dosages of ανβ3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits. FASEB J. 2008;22(8):2758–67.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Shen Y, Jin E, Zhang B, Murphy CJ, Sui M, Zhao J, et al. Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery. J Am Chem Soc. 2010;132(12):4259–65.PubMedGoogle Scholar
  30. 30.
    Devalapally H, Shenoy, Dinesh, Little, Steven, Langer, et al. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model. Cancer Chemother Pharmacol. 2007;59(4):477–84.PubMedGoogle Scholar
  31. 31.
    Shenoy D, Little, Steven, Langer, Robert, Amiji, et al. Poly(ethylene oxide)-modified poly(β-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 2. In vivo distribution and tumor localization studies. Pharm Res. 2005;22(12):2107–14.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Na K, Bae YH. Self-assembled hydrogel nanoparticles responsive to tumor extracellular pH from pullulan derivative/sulfonamide conjugate: characterization, aggregation, and adriamycin release in vitro. Pharm Res. 2002;19(5):681–8.PubMedGoogle Scholar
  33. 33.
    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.PubMedGoogle Scholar
  34. 34.
    Caron WP, Lay JC, Fong AM, La-Beck NM, Kumar P, Newman SE, et al. Translational studies of phenotypic probes for the mononuclear phagocyte system and liposomal pharmacology. J Pharm Exp Ther. 2013. doi: 10.1124/jpet.113.208801.
  35. 35.
    Gabizon A, Shmeeda, Hilary, Barenholz, Yechezkel. Pharmacokinetics of pegylated liposomal doxorubicin. Clin Pharmacokinet. 2003;42(5):419–36.PubMedGoogle Scholar
  36. 36.
    Allen TM, Martin FJ. Advantages of liposomal delivery systems for anthracyclines. Semin Oncol. 2004;31(Supplement 13(0)):5–15.PubMedGoogle Scholar
  37. 37.
    Wang X, Wang Y-W, Huang Q. Enhancing stability and oral bioavailability of polyphenols using nanoemulsions. Micro/Nanoencapsulation Act Food Ingredients: Am Chem Soc. 2009. p 198–212.Google Scholar
  38. 38.
    Tagne J-B, Kakumanu S, Ortiz D, Shea T, Nicolosi RJ. A nanoemulsion formulation of tamoxifen increases its efficacy in a breast cancer cell line. Mol Pharm. 2008;5(2):280–6.PubMedGoogle Scholar
  39. 39.
    Huynh NT, Passirani C, Saulnier P, Benoit JP. Lipid nanocapsules: a new platform for nanomedicine. Int J Pharm. 2009;379(2):201–9.PubMedGoogle Scholar
  40. 40.
    Hoarau D, Delmas P, David S, phanie, Roux E, Leroux J-C. Novel long-circulating lipid nanocapsules. Pharm Res. 2004;21(10):1783–9.PubMedGoogle Scholar
  41. 41.
    Khalid M, Simard P, Hoarau D, Dragomir A, Leroux J-C. Long circulating poly(ethylene glycol)-decorated lipid nanocapsules deliver docetaxel to solid tumors. Pharm Res. 2006;23(4):752–8.PubMedGoogle Scholar
  42. 42.
    Mulik RS, Monkkonen J, Juvonen RO, Mahadik KR, Paradkar AR. Transferrin mediated solid lipid nanoparticles containing curcumin: enhanced in vitro anticancer activity by induction of apoptosis. Int J Pharm. 2010;398(1–2):190–203.PubMedGoogle Scholar
  43. 43.
    Milane L, Duan Z, Amiji M. Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm. 2011;8(1):185–203.PubMedGoogle Scholar
  44. 44.
    Dimova I, Zaharieva B, Raitcheva S, Dimitrov R, Doganov N, Toncheva D. Tissue microarray analysis of EGFR and erbB2 copy number changes in ovarian tumors. Int J Gynecol Cancer. 2006;16(1):145–51.PubMedGoogle Scholar
  45. 45.
    Lin CK, Chao TK, Yu CP, Yu MH, Jin JS. The expression of six biomarkers in the four most common ovarian cancers: correlation with clinicopathological parameters. APMIS. 2009;117(3):162–75.PubMedGoogle Scholar
  46. 46.
    Acharya S, Dilnawaz F, Sahoo SK. Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials. 2009;30(29):5737–50.PubMedGoogle Scholar
  47. 47.
    Zhang Y, Li J, Lang M, Tang X, Li L, Shen X. Folate-functionalized nanoparticles for controlled 5-fluorouracil delivery. J Colloid Interface Sci. 2011;354(1):202–9.PubMedGoogle Scholar
  48. 48.
    Zhang C, Zhao LQ, Dong YF, Zhang XY, Lin J, Chen Z. Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery. Eur J Pharm Biopharm. 2010;76(1):10–6.PubMedGoogle Scholar
  49. 49.
    Esmaeili FGM, Ostad S, Atyabi F, Seyedabadi M, Malekshahi M, Amini M, et al. Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate. J Drug Target. 2008;16(5):415–23.PubMedGoogle Scholar
  50. 50.
    Zhang HLX, Gao F, Liu L, Zhou Z, Zhang Q. Preparation of folate-modified pullulan acetate nanoparticles for tumor-targeted drug delivery. Drug Deliv. 2010;17(1):48–57.PubMedGoogle Scholar
  51. 51.
    Rapoport N, Gao Z, Kennedy A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst. 2007;99(14):1095–106.PubMedGoogle Scholar
  52. 52.
    Kaneda M, Caruthers S, Lanza GM, Wickline SA. Perfluorocarbon nanoemulsions for quantitative molecular imaging and targeted therapeutics. Ann Biomed Eng. 2009;37(10):1922–33.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Rapoport NY, Kennedy AM, Shea JE, Scaife CL, Nam K-H. Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. J Control Release. 2009;138(3):268–76.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Gao Z, Kennedy AM, Christensen DA, Rapoport NY. Drug-loaded nano/microbubbles for combining ultrasonography and targeted chemotherapy. Ultrasonics. 2008;48(4):260–70.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Bae P, Jung J, Lim SJ, Kim D, Kim S-K, Chung BH. Bimodal perfluorocarbon nanoemulsions for nasopharyngeal carcinoma targeting. Mol Imaging Biol. 2013;15(4):401–10.PubMedGoogle Scholar
  56. 56.
    Almeida CP, Vital CG, Contente TC, Maria DA, Maranhao RC. Modification of composition of a nanoemulsion with different cholesteryl ester molecular species: effects on stability, peroxidation, and cell uptake. Int J Nanomedicine. 2010;5:679–86.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Wooster TJ, Golding M, Sanguansri P. Impact of oil type on nanoemulsion formation and Ostwald ripening stability. Langmuir. 2008;24(22):12758–65.PubMedGoogle Scholar
  58. 58.
    Capek I. Degradation of kinetically-stable o/w emulsions. Adv Colloid Interface Sci. 2004;107(2–3):125–55.PubMedGoogle Scholar
  59. 59.
    McClements DJ. Edible nanoemulsions: fabrication, properties, and functional performance. Soft Matter. 2011;7(6):2297–316.Google Scholar
  60. 60.
    Donsi F, Annunziata M, Vincensi M, Ferrari G. Design of nanoemulsion-based delivery systems of natural antimicrobials: effect of the emulsifier. J Biotechnol. 2012;159(4):342–50.PubMedGoogle Scholar
  61. 61.
    Ohguchi Y, Kawano K, Hattori Y, Maitani Y. Selective delivery of folate-PEG-linked, nanoemulsion-loaded aclacinomycin A to KB nasopharyngeal cells and xenograft: effect of chain length and amount of folate-PEG linker. J Drug Target. 2008;16(9):660–7.PubMedGoogle Scholar
  62. 62.
    Chanamai R, McClements DJ. Impact of weighting agents and sucrose on gravitational separation of beverage emulsions. J Agric Food Chem. 2000;48(11):5561–5.PubMedGoogle Scholar
  63. 63.
    McClements DJ. Emulsion design to improve the delivery of functional lipophilic components. Annu Rev Food Sci Technol. 2010;1:241–69.PubMedGoogle Scholar
  64. 64.
    Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release Off J Control Release Soc. 2008;126(3):187–204.Google Scholar
  65. 65.
    Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release. 2008;126(3):187–204.PubMedGoogle Scholar
  66. 66.
    Anyarambhatla GR, Needham D. Enhancement of the phase transition permeability of DPPC liposomes by incorporation of MPPC: a new temperature-sensitive liposome for use with mild hyperthermia. J Liposome Res. 1999;9(4):491–506.Google Scholar
  67. 67.
    Dromi S, Frenkel V, Luk A, Traughber B, Angstadt M, Bur M, et al. Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect. Clin Cancer Res. 2007;13(9):2722–7.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Paasonen L, Laaksonen T, Johans C, Yliperttula M, Kontturi K, Urtti A. Gold nanoparticles enable selective light-induced contents release from liposomes. J Control Release. 2007;122(1):86–93.PubMedGoogle Scholar
  69. 69.
    Manzoor AA, Lindner LH, Landon CD, Park JY, Simnick AJ, Dreher MR, et al. Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors. Cancer Res. 2012;72(21):5566–75.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Pradhan P, Giri J, Rieken F, Koch C, Mykhaylyk O, Doblinger M, et al. Targeted temperature sensitive magnetic liposomes for thermo-chemotherapy. J Control Release. 2010;142(1):108–21.PubMedGoogle Scholar
  71. 71.
    Landon CD, Park JY, Needham D, Dewhirst MW. Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. Open Nanomed J. 2011;3:38–64.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Yarmolenko PS, Zhao Y, Landon C, Spasojevic I, Yuan F, Needham D, et al. Comparative effects of thermosensitive doxorubicin-containing liposomes and hyperthermia in human and murine tumours. Int J Hyperthermia. 2010;26(5):485–98.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Hauck ML, LaRue SM, Petros WP, Poulson JM, Yu D, Spasojevic I, et al. Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors. Clin Cancer Res. 2006;12(13):4004–10.PubMedGoogle Scholar
  74. 74.
    Kong G, Anyarambhatla G, Petros WP, Braun RD, Colvin OM, Needham D, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 2000;60(24):6950–7.PubMedGoogle Scholar
  75. 75.
    Matteucci ML, Anyarambhatla G, Rosner G, Azuma C, Fisher PE, Dewhirst MW, et al. Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas. Clin Cancer Res. 2000;6(9):3748–55.PubMedGoogle Scholar
  76. 76.
    Wang CY, Huang L. pH-sensitive immunoliposomes mediate target-cell-specific delivery and controlled expression of a foreign gene in mouse. Proc Natl Acad Sci U S A. 1987;84(22):7851–5.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Connor J, Huang L. pH-sensitive immunoliposomes as an efficient and target-specific carrier for antitumor drugs. Cancer Res. 1986;46(7):3431–5.PubMedGoogle Scholar
  78. 78.
    Negrini R, Mezzenga R. pH-responsive lyotropic liquid crystals for controlled drug delivery. Langmuir. 2011;27(9):5296–303.PubMedGoogle Scholar
  79. 79.
    Mo R, Sun Q, Xue J, Li N, Li W, Zhang C, et al. Multistage pH-responsive liposomes for mitochondrial-targeted anticancer drug delivery. Adv Mater. 2012;24(27):3659–65.PubMedGoogle Scholar
  80. 80.
    Obata Y, Tajima S, Takeoka S. Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo. J Control Release. 2010;142(2):267–76.PubMedGoogle Scholar
  81. 81.
    Qian C, McClements DJ. Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: factors affecting particle size. Food Hydrocoll. 2011;25(5):1000–8.Google Scholar
  82. 82.
    Lovelyn C, Attama AA. Current state of nanoemulsions in drug delivery. J Biomater Nanobiotechnol. 2011;2(5):626–39.Google Scholar
  83. 83.
    Solans C, Izquierdo P, Nolla J, Azemar N, Garcia-Celma MJ. Nano-emulsions. Curr Opin Colloid Interface Sci. 2005;10(3–4):102–10.Google Scholar
  84. 84.
    Han J, Washington C. Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability. Int J Pharm. 2005;288(2):263–71.PubMedGoogle Scholar
  85. 85.
    Junghanns J-U, Buttle I, Müller R, Araujo I, Silva A, Egito E, et al. SolEmuls® technology: a way to overcome the drawback of parenteral administration of insoluble drugs. Pharm Dev Technol. 2007;12(5):437–45.PubMedGoogle Scholar
  86. 86.
    Singh M, Ravin LJ. Parenteral emulsions as drug carrier systems. J Parenter Sci Technol Publ Parenter Drug Assoc. 1986;40(1):34–41.Google Scholar
  87. 87.
    Hatanaka J, Chikamori H, Sato H, Uchida S, Debari K, Onoue S, et al. Physicochemical and pharmacological characterization of alpha-tocopherol-loaded nano-emulsion system. Int J Pharm. 2010;396(1–2):188–93.PubMedGoogle Scholar
  88. 88.
    Klang V, Matsko NB, Valenta C, Hofer F. Electron microscopy of nanoemulsions: an essential tool for characterisation and stability assessment. Micron. 2012;43(2–3):85–103.PubMedGoogle Scholar
  89. 89.
    Kuntsche J, Horst JC, Bunjes H. Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems. Int J Pharm. 2011;417(1–2):120–37.PubMedGoogle Scholar
  90. 90.
    Jiang SP, He SN, Li YL, Feng DL, Lu XY, Du YZ, et al. Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin. Int J Nanomedicine. 2013;8:3141–50.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Shakeel F, Ramadan W, Ahmed MA. Investigation of true nanoemulsions for transdermal potential of indomethacin: characterization, rheological characteristics, and ex vivo skin permeation studies. J Drug Target. 2009;17(6):435–41.PubMedGoogle Scholar
  92. 92.
    Shafiq S, Shakeel F. Enhanced stability of ramipril in nanoemulsion containing Cremophor-EL: a technical note. AAPS PharmSciTech. 2008;9(4):1097–101.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Qian C, Decker EA, Xiao H, McClements DJ. Physical and chemical stability of Œ≤-carotene-enriched nanoemulsions: influence of pH, ionic strength, temperature, and emulsifier type. Food Chem. 2012;132(3):1221–9.Google Scholar
  94. 94.
    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.PubMedGoogle Scholar
  95. 95.
    Barzegar-Jalali M, Adibkia K, Valizadeh H, Shadbad MR, Nokhodchi A, Omidi Y, et al. Kinetic analysis of drug release from nanoparticles. J Pharm Pharm Sci. 2008;11(1):167–77.PubMedGoogle Scholar
  96. 96.
    Modi S, Anderson BD. Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method. Mol Pharm. 2013;10(8):3076–89.PubMedGoogle Scholar
  97. 97.
    Desai N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 2012;14(2):282–95.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Fukui H, Koike T, Nakagawa T, Saheki A, Sonoke S, Tomii Y, et al. Comparison of LNS-AmB, a novel low-dose formulation of amphotericin B with lipid nano-sphere (LNS), with commercial lipid-based formulations. Int J Pharm. 2003;267(1–2):101–12.PubMedGoogle Scholar
  99. 99.
    Wehrung D, Geldenhuys WJ, Oyewumi MO. Effects of gelucire content on stability, macrophage interaction and blood circulation of nanoparticles engineered from nanoemulsions. Colloids Surf B: Biointerfaces. 2012;94:259–65.PubMedGoogle Scholar
  100. 100.
    Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 2003;42(6):463–78.PubMedGoogle Scholar
  101. 101.
    Szebeni J, Alving CR, Rosivall L, Bunger R, Baranyi L, Bedocs P, et al. Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J Liposome Res. 2007;17(2):107–17.PubMedGoogle Scholar
  102. 102.
    Zahr AS, Davis CA, Pishko MV. Macrophage uptake of core-shell nanoparticles surface modified with poly(ethylene glycol). Langmuir ACS J Surf Colloids. 2006;22(19):8178–85.Google Scholar
  103. 103.
    Stolnik S, Daudali B, Arien A, Whetstone J, Heald CR, Garnett MC, et al. The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers. Biochim et Biophys Acta. 2001;1514(2):261–79.Google Scholar
  104. 104.
    Alvarez-Lorenzo C, Rey-Rico A, Sosnik A, Taboada P, Concheiro A. Poloxamine-based nanomaterials for drug delivery. Frontiers Biosci (Elite edition). 2010;2:424–40.Google Scholar
  105. 105.
    Maranhao RC, Tavares ER, Padoveze AF, Valduga CJ, Rodrigues DG, Pereira MD. Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerosis regression in the rabbit. Atherosclerosis. 2008;197(2):959–66.PubMedGoogle Scholar
  106. 106.
    Rodrigues DG, Maria DA, Fernandes DC, Valduga CJ, Couto RD, Ibañez OCM, et al. Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies. Cancer Chemother Pharmacol. 2005;55(6):565–76.PubMedGoogle Scholar
  107. 107.
    Valduga CJ, Fernandes DC, Lo Prete AC, Azevedo CHM, Rodrigues DG, Maranhão RC. Use of a cholesterol-rich microemulsion that binds to low-density lipoprotein receptors as vehicle for etoposide. J Pharm Pharmacol. 2003;55(12):1615–22.PubMedGoogle Scholar
  108. 108.
    Maranhao RC, Roland IA, Toffoletto O, Ramires JA, Goncalves RP, Mesquita CH, et al. Plasma kinetic behavior in hyperlipidemic subjects of a lipidic microemulsion that binds to low density lipoprotein receptors. Lipids. 1997;32(6):627–33.PubMedGoogle Scholar
  109. 109.
    Pinheiro KV, Hungria VT, Ficker ES, Valduga CJ, Mesquita CH, Maranhao RC. Plasma kinetics of a cholesterol-rich microemulsion (LDE) in patients with Hodgkin's and non-Hodgkin's lymphoma and a preliminary study on the toxicity of etoposide associated with LDE. Cancer Chemother Pharmacol. 2006;57(5):624–30.PubMedGoogle Scholar
  110. 110.
    Maranhão RC, Graziani SR, Yamaguchi N, Melo RF, Latrilha MC, Rodrigues DG, et al. Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients. Cancer Chemother Pharmacol. 2002;49(6):487–98.PubMedGoogle Scholar
  111. 111.
    Béduneau A, Saulnier P, Hindré F, Clavreul A, Leroux J-C, Benoit J-P. Design of targeted lipid nanocapsules by conjugation of whole antibodies and antibody Fab’ fragments. Biomaterials. 2007;28(33):4978–90.PubMedGoogle Scholar
  112. 112.
    Remmer H. The role of the liver in drug metabolism. Am J Med. 1970;49(5):617–29.PubMedGoogle Scholar
  113. 113.
    Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (London, England). 2008;3(5):703–17.Google Scholar
  114. 114.
    Soo Choi H, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, et al. Renal clearance of quantum dots. Nat Biotechnol. 2007;25(10):1165–70.Google Scholar
  115. 115.
    FDA. Q8(R1) Pharmaceutical development revision 1. International Conference on Harmonisation (ICH) Q8 Guideline 2008.Google Scholar
  116. 116.
    FDA. Guidance for Industry Q9 Quality Risk management. International Conference on Harmonisation (ICH) Q9 Guideline. 2006. http://www.fda.gov/.
  117. 117.
    FDA. Guidance for Industry Q10 Pharmaceutical Quality System. International Conference on Harmonisation (ICH) Q10 Guideline 2009. http://www.fda.gov/.

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Srinivas Ganta
    • 1
  • Meghna Talekar
    • 2
  • Amit Singh
    • 2
  • Timothy P. Coleman
    • 1
  • Mansoor M. Amiji
    • 2
  1. 1.Nemucore Medical Innovations, Inc.WorcesterUSA
  2. 2.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA

Personalised recommendations