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

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.

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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

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.

    CAS  Google Scholar 

  2. 2.

    Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–44.

    CAS  Google 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.

    CAS  PubMed  Google 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.

    PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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.

    Google 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.

    CAS  PubMed  Google 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.

    CAS  Google 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.

    CAS  PubMed  Google 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.

    Google 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.

    CAS  Google 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.

    CAS  Google 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.

    CAS  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  37. 37.

    Wills ED. Mechanisms of lipid peroxide formation in animal tissues. Biochem J. 1966;99(3):667–76.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  43. 43.

    Bowers LD, Wong ET. Kinetic serum creatinine assays. II. A critical evaluation and review. Clin Chem. 1980;26(5):555–61.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  47. 47.

    Chan YH. Biostatistics 102: quantitative data—parametric & non-parametric tests. Singap Med J. 2003;44(8):391–6.

    CAS  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.

    Google 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.

    CAS  PubMed  Google Scholar 

  51. 51.

    Solanki SS, Sarkar B, Dhanwani RK. Microemulsion drug delivery system: for bioavailability enhancement of ampelopsin. ISRN Pharmaceutics. 2012;2012:4.

    Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google 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).

  56. 56.

    Riedel G, Platt B, Micheau J. Glutamate receptor function in learning and memory. Behav Brain Res. 2003;140(1–2):1–47.

    CAS  PubMed  Google 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.

    CAS  Google 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.

    Google 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.

    CAS  PubMed  Google 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.

    CAS  Google 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.

    CAS  PubMed  Google Scholar 

  63. 63.

    Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367–79.

    PubMed  PubMed Central  Google 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.

    CAS  Google 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.

    CAS  PubMed  Google 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.

    CAS  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google Scholar 

  75. 75.

    Roberson MR, Harrell LE. Cholinergic activity and amyloid precursor protein metabolism. Brain Res Rev. 1997;25(1):50–69.

    CAS  PubMed  Google 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.

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    De Jong WH, Borm PJA. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133–49.

    PubMed  PubMed Central  Google 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.

    Google Scholar 

  79. 79.

    Singh A, Bhat TK, Sharma OP. Clinical biochemistry of hepatotoxicity. J Clinic Toxicology. 2011;S4:001.

  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.

    Google 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.

    CAS  PubMed  Google Scholar 

  82. 82.

    Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther. 2012;20(3):268–72.

    CAS  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google Scholar 

  88. 88.

    Yildirimer L, Thanh NTK, Loizidou M, Seifalian AM. Toxicology and clinical potential of nanoparticles. Nano Today. 2011;6(6):585–607.

    CAS  PubMed  PubMed Central  Google 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.

    CAS  PubMed  Google Scholar 

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Etman, S.M., Elnaggar, Y.S.R., Abdelmonsif, D.A. et al. Oral Brain-Targeted Microemulsion for Enhanced Piperine Delivery in Alzheimer’s Disease Therapy: In Vitro Appraisal, In Vivo Activity, and Nanotoxicity. AAPS PharmSciTech 19, 3698–3711 (2018). https://doi.org/10.1208/s12249-018-1180-3

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KEY WORDS

  • piperine
  • Alzheimer’s disease
  • microemulsion
  • nanotoxicology
  • brain targeting