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AAPS PharmSciTech

, Volume 19, Issue 8, pp 3698–3711 | Cite as

Oral Brain-Targeted Microemulsion for Enhanced Piperine Delivery in Alzheimer’s Disease Therapy: In Vitro Appraisal, In Vivo Activity, and Nanotoxicity

  • Samar M. Etman
  • Yosra S. R. Elnaggar
  • Doaa A. Abdelmonsif
  • Ossama Y. Abdallah
Research Article
  • 146 Downloads

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that has no cure till now. Piperine (PIP) is an alkaloid characterized by memory-enhancing properties but challenging oral delivery obstacles. The objectives of this study are as follows: preparation of microemulsion (ME) as a proposed oral PIP nanocarrier for treatment of Alzheimer’s disease and testing its safety on the brain and other internal organs. This study employs bioactive surfactants in the common safe doses to improve PIP targeting to the brain. Selected ME systems encompassed Caproyl 90 (oil)/Tween 80/Cremophor RH 40 (surfactant) and Transcutol HP (co-surfactant). The particle size of the prepared formulations was less than 150 nm with negative zeta potential. The in vivo results showed a superior effect of ME over free PIP. Colchicine-induced brain toxicity results showed the safety of ME on brain cells. Nevertheless, toxicological results showed a potential ME nephrotoxicity. Oral microemulsion increased PIP efficacy and enhanced its delivery to the brain resulting in better therapeutic outcome compared to the free drug. However, the toxicity of this nanosystem should be carefully taken into consideration on chronic use.

KEY WORDS

piperine Alzheimer’s disease microemulsion nanotoxicology brain targeting 

Abbreviations

AD

Alzheimer’s disease

ME

Microemulsion

PIP

Piperine

BE

Bioactive excipient

HLB

Hydrophilic lipophilic balance

TEM

Transmission electron microscope

ICV

Intracerebroventricular

SDAT

Sporadic dementia of Alzheimer’s type

TNF-α

Tumor necrosis factor-α

ZP

Zeta potential

PDI

Polydispersity index

TAC

Total antioxidant capacity

MDA

Malondialdehyde

SOD

Superoxide dismutase activity

AChE

Acetylcholine esterase

LD

Lethal dose

BBB

Blood-brain barrier

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12249_2018_1180_MOESM1_ESM.jpg (46 kb)
Supplementary figure 1 (JPG 46 kb)
12249_2018_1180_MOESM2_ESM.docx (15 kb)
Supplementary Table 1 (DOCX 14 kb)

References

  1. 1.
    Brambilla D, Le Droumaguet B, Nicolas J, Hashemi SH, Wu LP, Moghimi SM, et al. Nanotechnologies for Alzheimer’s disease: diagnosis, therapy, and safety issues. Nanomed. 2011;7(5):521–40.CrossRefGoogle Scholar
  2. 2.
    Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Sahni JK, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C. Neurotherapeutic applications of nanoparticles in Alzheimer’s disease. J Control Release. 2011;152(2):208–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: are they effective? Pharm Ther. 2010;35(4):208–11.Google Scholar
  5. 5.
    Freag MS, Elnaggar YS, Abdallah OY. Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation. Int J Nanomedicine. 2013;8:2385–97.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Peng S, Hung WL, Peng YS, Chu IM. Oligoalanine-modified Pluronic-F127 nanocarriers for the delivery of curcumin with enhanced entrapment efficiency. J Biomater Sci Polym Ed. 2014;25(12):1225–39.CrossRefPubMedGoogle Scholar
  7. 7.
    Chonpathompikunlert P, Wattanathorn J, Muchimapura S. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer’s disease. Food Chem Toxicol. 2010;48(3):798–802.CrossRefPubMedGoogle Scholar
  8. 8.
    Elnaggar YS, Etman SM, Abdelmonsif DA, Abdallah OY. Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer’s disease: optimization, biological efficacy, and potential toxicity. J Pharm Sci. 2015;104(10):3544–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Wu Z-J, Xia X-J, Huang X-S. Determination of equilibrium solubility and apparent oil/water partition coefficient of piperine. J Jinan Uni Natl Sci Med. 2012;5(33):473–6.Google Scholar
  10. 10.
    Sahu PK, Sharma A, Rayees S, Kour G, Singh A, Khullar M, et al. Pharmacokinetic study of Piperine in Wistar rats after oral and intravenous administration. Int J Drug Deliver. 2014;6(1):82–8.Google Scholar
  11. 11.
    Yusuf M, Khan M, Khan RA, Ahmed B. Preparation, characterization, in vivo and biochemical evaluation of brain targeted piperine solid lipid nanoparticles in an experimentally induced Alzheimer’s disease model. J Drug Target. 2013;21(3):300–11.CrossRefGoogle Scholar
  12. 12.
    Shao B, Cui C, Ji H, Tang J, Wang Z, Liu H, et al. Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro, in vivo and in situ intestinal permeability studies. Drug Deliv. 2015;22(6):740–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Elnaggar YSR, Etman SM, Abdelmonsif DA, Abdallah OY. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies. Int J Nanomedicine. 2015;10:5459–73.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Li H, Tong Y, Bai L, Ye L, Zhong L, Duan X, et al. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int J Biol Macromol. 2018;107(Pt A):204–11.CrossRefPubMedGoogle Scholar
  15. 15.
    Patel SK, Gajbhiye V, Jain NK. Synthesis, characterization and brain targeting potential of paclitaxel loaded thiamine-PPI nanoconjugates. J Drug Target. 2012;20(10):841–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen W, Zuo H, Zhang E, Li L, Henrich-Noack P, Cooper H, et al. Brain targeting delivery facilitated by ligand-functionalized layered double hydroxide nanoparticles. ACS Appl Mater Interfaces. 2018;10(24):20326–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Loureiro Joana A, Gomes B, Coelho MAN, Md CP, Rocha S. Targeting nanoparticles across the blood–brain barrier with monoclonal antibodies. Nanomedicine. 2014;9(5):709–22.CrossRefPubMedGoogle Scholar
  18. 18.
    Monaco I, Camorani S, Colecchia D, Locatelli E, Calandro P, Oudin A, et al. Aptamer functionalization of nanosystems for glioblastoma targeting through the blood–brain barrier. J Med Chem. 2017;60(10):4510–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Elnaggar YS, El-Massik MA, Abdallah OY. Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles. Int J Nanomedicine. 2011;6:3195–205.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Elnaggar YS, El-Massik MA, Abdallah OY. Self-nanoemulsifying drug delivery systems of tamoxifen citrate: design and optimization. Int J Pharm. 2009;380(1–2):133–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Elsheikh MA, Elnaggar YS, Gohar EY, Abdallah OY. Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal. Int J Nanomedicine. 2012;7:3787–802.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Prabhakar K, Afzal SM, Surender G, Kishan V. Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain. Acta Pharma Sinica B. 2013;3(5):345–53.CrossRefGoogle Scholar
  23. 23.
    Rao Z, Si L, Guan Y, Pan H, Qiu J, Li G. Inhibitive effect of Cremophor RH40 or Tween 80-based self-microemulsiflying drug delivery system on cytochrome P450 3A enzymes in murine hepatocytes. J Huazhong Univ Sci Technolog Med Sci. 2010;30(5):562–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu Y, Zhang J, Zheng Q, Wang M, Deng W, Li Q, et al. In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability. J Sci Food Agric. 2015;95(13):2678–85.CrossRefPubMedGoogle Scholar
  25. 25.
    Lu GW, Gao P. Chapter 3—emulsions and microemulsions for topical and transdermal drug delivery. In: Kulkarni VS, editor. Handbook of non-invasive drug delivery systems. Boston: William Andrew; 2010. p. 59–94.CrossRefGoogle Scholar
  26. 26.
    Gotch AJ, Loar GW, Reeder AJ, Glista EE. Formation of single-phase microemulsions in toluene/water/nonionic surfactant systems. Langmuir. 2008;24(9):4485–93.CrossRefPubMedGoogle Scholar
  27. 27.
    Shah B, Khunt D, Misra M, Padh H. Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: formulation, physicochemical and pharmacokinetic consideration. Euro J Pharm Sci. 2016;91:196–207.CrossRefGoogle Scholar
  28. 28.
    Shah BM, Misra M, Shishoo CJ, Padh H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv. 2015;22(7):918–30.CrossRefPubMedGoogle Scholar
  29. 29.
    Rajshree LS, Anil BJ, Padma VD. Microemulsions and nanoemulsions for targeted drug delivery to the brain. Curr Nanosci. 2011;7(1):119–33.CrossRefGoogle Scholar
  30. 30.
    Elnaggar YS, El-Massik MA, Abdallah OY. Sildenafil citrate nanoemulsion vs. self-nanoemulsifying delivery systems: rational development and transdermal permeation. Intl J Nanotech. 2011;8(8):749–63.CrossRefGoogle Scholar
  31. 31.
    Rajpal V. Piper nigrum. Standardization of botanicals. 2nd ed. New Delhi: Eastern Publications; 2002. p. 258–67.Google Scholar
  32. 32.
    Aboofazeli R, Lawrence MJ. Investigations into the formation and characterization of phospholipid microemulsions. I. Pseudo-ternary phase diagrams of systems containing water-lecithin-alcohol-isopropyl myristate. Int J Pharm. 1993;93(1–3):161–75.CrossRefGoogle Scholar
  33. 33.
    Sakr FM, Gado AMI, Mohammed HR, Adam ANI. Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology: a pilot study. Drug Des, Dev Ther. 2013;7:413–23.CrossRefGoogle Scholar
  34. 34.
    D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001;36(1):60–90.CrossRefGoogle Scholar
  35. 35.
    Ganguly R, Guha D. Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer’s disease & protection by Moringa oleifera. Indian J Med Res. 2008;128(6):744–51.PubMedGoogle Scholar
  36. 36.
    Monleon S, Urquiza A, Carmen Arenas M, Vinader-Caerols C, Parra A. Chronic administration of fluoxetine impairs inhibitory avoidance in male but not female mice. Behav Brain Res. 2002;136(2):483–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Wills ED. Mechanisms of lipid peroxide formation in animal tissues. Biochem J. 1966;99(3):667–76.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol. 2001;54(5):356–61.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kono Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. 1978;186(1):189–95.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7:88–95.CrossRefGoogle Scholar
  41. 41.
    Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 1957;28(1):56–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Tabacco A, Meiattini F, Moda E, Tarli P. Simplified enzymic/colorimetric serum urea nitrogen determination. Clin Chem. 1979;25(2):336–7.PubMedGoogle Scholar
  43. 43.
    Bowers LD, Wong ET. Kinetic serum creatinine assays. II. A critical evaluation and review. Clin Chem. 1980;26(5):555–61.PubMedGoogle Scholar
  44. 44.
    Casciola-Rosen L, Nicholson DW, Chong T, Rowan KR, Thornberry NA, Miller DK, et al. Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death. J Exp Med. 1996;183(5):1957–64.CrossRefPubMedGoogle Scholar
  45. 45.
    Tiwari V, Chopra K. Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain. J Neurochem. 2011;117(4):678–90.PubMedGoogle Scholar
  46. 46.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.PubMedGoogle Scholar
  47. 47.
    Chan YH. Biostatistics 102: quantitative data—parametric & non-parametric tests. Singap Med J. 2003;44(8):391–6.Google Scholar
  48. 48.
    Kotz SBN, Read CB, Vidakovic B. Encyclopedia of statistical sciences. Hoboken (NJ): Wiley; 2006.Google Scholar
  49. 49.
    Elsheikh MA, Elnaggar YS, Abdallah OY. Rationale employment of cell culture versus conventional techniques in pharmaceutical appraisal of nanocarriers. J Control Release. 2014;194C:92–102.CrossRefGoogle Scholar
  50. 50.
    Pestel S, Martin H-J, Maier G-M, Guth B. Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats. J Pharmacol Toxicol Methods. 2006;54(2):200–14.CrossRefPubMedGoogle Scholar
  51. 51.
    Solanki SS, Sarkar B, Dhanwani RK. Microemulsion drug delivery system: for bioavailability enhancement of ampelopsin. ISRN Pharmaceutics. 2012;2012:4.CrossRefGoogle Scholar
  52. 52.
    Bhat BG, Chandrasekhara N. Studies on the metabolism of piperine: absorption, tissue distribution and excretion of urinary conjugates in rats. Toxicology. 1986;40(1):83–92.CrossRefPubMedGoogle Scholar
  53. 53.
    Li S, Wang C, Wang M, Li W, Matsumoto K, Tang Y. Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci. 2007;80(15):1373–81.CrossRefPubMedGoogle Scholar
  54. 54.
    D’Hooge R, Pei YQ, Raes A, Lebrun P, van Bogaert PP, de Deyn PP. Anticonvulsant activity of piperine on seizures induced by excitatory amino acid receptor agonists. Arzneimittelforschung. 1996;46(6):557–60.PubMedGoogle Scholar
  55. 55.
    Ogren SO, Stone WS, Altman HJ. Evidence for a functional interaction between serotoninergic and cholinergic mechanisms in memory retrieval. Soc Neurosci Abstract. 1985;11(256).Google Scholar
  56. 56.
    Riedel G, Platt B, Micheau J. Glutamate receptor function in learning and memory. Behav Brain Res. 2003;140(1–2):1–47.CrossRefPubMedGoogle Scholar
  57. 57.
    Priprem A, Chonpathompikunlert P, Sutthiparinyanont S, Wattanathorn J. Antidepressant and cognitive activities of intranasal piperine-encapsulated liposomes. Adv Bioscience Biotechnology. 2011;2(02):108.CrossRefGoogle Scholar
  58. 58.
    Barbagallo M, Marotta F, Dominguez LJ. Oxidative stress in patients with Alzheimer’s disease: effect of extracts of fermented papaya powder. Mediat Inflamm. 2015;2015:6.CrossRefGoogle Scholar
  59. 59.
    Yemparala V, Damre AA, Manohar V, Sharan Singh K, Mahajan GB, Sawant SN, et al. Effect of the excipient concentration on the pharmacokinetics of PM181104, a novel antimicrobial thiazolyl cyclic peptide antibiotic, following intravenous administration to mice. Res Pharm Sci. 2014;4:34–41.Google Scholar
  60. 60.
    Ren S, Park MJ, Sah H, Lee BJ. Effect of pharmaceutical excipients on aqueous stability of rabeprazole sodium. Int J Pharm. 2008;350(1–2):197–204.CrossRefPubMedGoogle Scholar
  61. 61.
    Gad SC, Cassidy CD, Aubert N, Spainhour B, Robbe H. Nonclinical vehicle use in studies by multiple routes in multiple species. Intl J Toxicol. 2006;25(6):499–521.CrossRefGoogle Scholar
  62. 62.
    Varma RK, Kaushal R, Junnarkar AY, Thomas GP, Naidu MU, Singh PP, et al. Polysorbate 80: a pharmacological study. Arzneimittelforschung. 1985;35(5):804–8.PubMedGoogle Scholar
  63. 63.
    Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367–79.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Egbuonu A, Obidoa O, Ezeokonkwo C, Ejikeme P, Ezeanyika L. Some biochemical effects of sub-acute oral administration of L-arginine on monosodium glutamate-fed Wistar albino rats 1: body weight changes, serum cholesterol, creatinine, and sodium ion concentrations. Toxicol Environ Chem. 2010;92(7):1331–7.CrossRefGoogle Scholar
  65. 65.
    Liu Z, Gastard M, Verina T, Bora S, Mouton PR, Koliatsos VE. Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus. J Comp Neurol. 2001;441(1):1–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Kumar A, Seghal N, Padi SV, Naidu PS. Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats. Euro J Pharmacol. 2006;551(1):58–66.CrossRefGoogle Scholar
  67. 67.
    Wilson B, Samanta MK, Santhi K, Kumar KP, Paramakrishnan N, Suresh B. Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 2008;70(1):75–84.CrossRefPubMedGoogle Scholar
  68. 68.
    Gulyaev AE, Gelperina SE, Skidan IN, Antropov AS, Kivman GY, Kreuter J. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm Res. 1999;16(10):1564–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Liu W, Sun D, Li C, Liu Q, Xu J. Formation and stability of paraffin oil-in-water nano-emulsions prepared by the emulsion inversion point method. J Colloid Interface Sci. 2006;303(2):557–63.CrossRefPubMedGoogle Scholar
  70. 70.
    Cheng MB, Wang JC, Li YH, Liu XY, Zhang X, Chen DW, et al. Characterization of water-in-oil microemulsion for oral delivery of earthworm fibrinolytic enzyme. J Control Release. 2008;129(1):41–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Yang R, Huang X, Dou J, Zhai G, Su L. Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid: design and evaluation. Int J Nanomedicine. 2013;8:2917–26.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA, et al. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology. 2005;64(7):1152–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Kheradmand E, Hajizadeh Moghaddam A, Zare M. Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer’s disease. Biomed Pharmacother. 2018;97:1096–101.CrossRefPubMedGoogle Scholar
  74. 74.
    Prado VF, Martins-Silva C, de Castro BM, Lima RF, Barros DM, Amaral E, et al. Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron. 2006;51(5):601–12.CrossRefPubMedGoogle Scholar
  75. 75.
    Roberson MR, Harrell LE. Cholinergic activity and amyloid precursor protein metabolism. Brain Res Rev. 1997;25(1):50–69.CrossRefPubMedGoogle Scholar
  76. 76.
    Ismail MF, ElMeshad AN, Salem NA-H. Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer’s disease. Int J Nanomedicine. 2013;8:393–406.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    De Jong WH, Borm PJA. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133–49.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Séralini G-E, Clair E, Mesnage R, Gress S, Defarge N, Malatesta M, et al. Republished study: long-term toxicity of a roundup herbicide and a roundup-tolerant genetically modified maize. Environ Sci Euro. 2014;26(1):14.CrossRefGoogle Scholar
  79. 79.
    Singh A, Bhat TK, Sharma OP. Clinical biochemistry of hepatotoxicity. J Clinic Toxicology. 2011;S4:001.Google Scholar
  80. 80.
    Dhillon A, Steadman RH. Chapter 5—liver diseases. In: Fleisher LA, editor. Anesthesia and uncommon diseases (Sixth edition). Philadelphia: W.B. Saunders; 2012. p. 162–214.CrossRefGoogle Scholar
  81. 81.
    Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245(3):194–205.CrossRefPubMedGoogle Scholar
  82. 82.
    Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther. 2012;20(3):268–72.CrossRefGoogle Scholar
  83. 83.
    Xie Y, Williams NG, Tolic A, Chrisler WB, Teeguarden JG, Maddux BLS, et al. Aerosolized ZnO nanoparticles induce toxicity in alveolar type II epithelial cells at the air-liquid Interface. Toxicol Sci. 2012;125(2):450–61.CrossRefPubMedGoogle Scholar
  84. 84.
    Nogueira DR, Carmen Morán M, Mitjans M, Pérez L, Ramos D, Lapuente J, et al. Lysine-based surfactants in nanovesicle formulations: the role of cationic charge position and hydrophobicity in in vitro cytotoxicity and intracellular delivery. Nanotoxicology. 2014;8(4):404–21.CrossRefPubMedGoogle Scholar
  85. 85.
    Wang R, Hughes T, Beck S, Vakil S, Li S, Pantano P, et al. Generation of toxic degradation products by sonication of Pluronic® dispersants: implications for nanotoxicity testing. Nanotoxicol. 2012;7(7):1272–81.CrossRefGoogle Scholar
  86. 86.
    Zhang X-Q, Xu X, Bertrand N, Pridgen E, Swami A, Farokhzad OC. Interactions of nanomaterials and biological systems: implications to personalized nanomedicine. Adv Drug Deliv Rev. 2012;64(13):1363–84.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Besarab A, Jarrell BE, Hirsch S, Carabasi RA, Cressman MD, Green P. Use of the isolated perfused kidney model to assess the acute pharmacologic effects of cyclosporin and its vehicle Cremophor EL. Transplantation. 1987;44(2):195–201.CrossRefPubMedGoogle Scholar
  88. 88.
    Yildirimer L, Thanh NTK, Loizidou M, Seifalian AM. Toxicology and clinical potential of nanoparticles. Nano Today. 2011;6(6):585–607.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Trickler WJ, Lantz SM, Murdock RC, Schrand AM, Robinson BL, Newport GD, et al. Silver nanoparticle induced blood-brain barrier inflammation and increased permeability in primary rat brain microvessel endothelial cells. Toxicol Sci. 2010;118(1):160–70.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Samar M. Etman
    • 1
  • Yosra S. R. Elnaggar
    • 1
    • 2
  • Doaa A. Abdelmonsif
    • 3
  • Ossama Y. Abdallah
    • 1
  1. 1.Department of Pharmaceutics, Faculty of PharmacyAlexandria UniversityAlexandriaEgypt
  2. 2.Department of Pharmaceutics, Faculty of Pharmacy and Drug ManufacturingPharos University of AlexandriaAlexandriaEgypt
  3. 3.Department of Medical Biochemistry, Faculty of MedicineAlexandria UniversityAlexandriaEgypt

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