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The AAPS Journal

, 21:57 | Cite as

Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence

  • Ana Cláudia SantosEmail author
  • Irina Pereira
  • Mariana Magalhães
  • Miguel Pereira-Silva
  • Mariana Caldas
  • Laura Ferreira
  • Ana Figueiras
  • António J. Ribeiro
  • Francisco Veiga
Review Article

Abstract

Resveratrol (RSV) is a polyphenol endowed with potential therapeutic effects in chronic diseases, particularly in cancer, the second leading cause of death worldwide in the twenty-first century. The advent of nanotechnology application in the field of drug delivery allows to overcome the constrains associated with the conventional anticancer treatments, in particular chemotherapy, reducing its adverse side effects, off target risks and surpassing cancer multidrug chemoresistance. Moreover, the use of nanotechnology-based carriers in the delivery of plant-derived anticancer agents, such as RSV, has already demonstrated to surpass the poor water solubility, instability and reduced bioavailability associated with phytochemicals, improving their therapeutic activity, thus prompting pharmaceutical developments. This review highlights the in vivo anticancer potential of RSV achieved by nanotherapeutic approaches. First, RSV physicochemical, stability and pharmacokinetic features are described. Thereupon, the chemotherapeutic and chemopreventive properties of RSV are underlined, emphasizing the RSV numerous cancer molecular targets. Lastly, a comprehensive analysis of the RSV-loaded nanoparticles (RSV-NPs) developed and administered in different in vivo cancer models to date is presented. Nanoparticles (NPs) have shown to improve RSV solubility, stability, pharmacokinetics and biodistribution in cancer tissues, enhancing markedly its in vivo anticancer activity. RSV-NPs are, thus, considered a potential nanomedicine-based strategy to fight cancer; however, further studies are still necessary to allow RSV-NP clinical translation.

KEY WORDS

anticancer activity in vivo administration molecular targets nanoparticles resveratrol 

Abbreviations

18F FDG

18f-Fluorodexoyglucose

ABC

ATP-binding cassette

AL

Alkali lignin

ALL

Acute lymphoblastic leukemia

AP-1

Activator protein-1

BBB

Blood-brain barrier

BCS

Biopharmaceutical Classification System

BSA

Bovine serum albumin

BTB

Blood-tumor barrier

CAS

Chemical Abstracts Service

c-IAP

Anti-cellular inhibitor of apoptosis protein

CNS

Central nervous system

COX

Cyclooxygenase

CUR

Curcumin

DH

Doxorubicin hydrochloride

dihRSV

Dihydroresveratrol

DL

Drug loading

DMBA

7,12-Dimethylbenz(a)anthracene

DMSO

Dimethyl sulfoxide

DSC

Differential scanning calorimetry

EE

Encapsulation efficiency

EGCG

Epigallocatechin-3-gallate

EPR

Enhanced permeability and retention

FOXO3a

Forkhead box O3 protein

HIF-1α

Hypoxia-inducible factor-1α

HRG-β1

Heregulin-beta 1

HSA

Human serum albumin

HSP

Heat shock protein

IC50

Half maximal inhibitory concentration

i.p.

Intraperitoneal

i.v.

Intravenous

IAP

Inhibitor of apoptosis protein

LDL

Low-density lipoprotein

LLC

Lewis lung carcinoma

LNC

Lipid-core nanocapsule

log Po/w

1-Octanol/water partition coefficient

MAPK

Mitogen-activated protein kinases

MIC-1

Macrophage inhibitory cytokine-1

MMP-2

Matrix metalloproteinase-2

mPEG

Methoxy polyethylene glycol

MPS

Mononuclear phagocytic system

mTOR

Mammalian target of rapamycin

NF-κB

Nuclear factor kappa B

NLC

Nanostructured lipid carrier

NOD/SCID

Non-obese diabetic/severe combined immunodeficient

NP

Nanoparticle

NSCLC

Non-small cell lung cancer

PARP

Poly (ADP-ribose) polymerase

PBS

Phosphate-buffered saline

PCL

Poly-ε-caprolactone

PEG

Polyethylene glycol

PI

Propidium iodide

PI3K

Phosphatidylinositol-3-kinase

PKG-I

Protein kinase I

PLA

Polylactic acid

PVA

Polyvinyl alcohol

RES

Reticuloendothelial system

RGD

Arginine-glycine-aspartate

ROCK

Rho-associated kinase

ROS

Reactive oxygen species

RSV

Resveratrol

SLN

Solid lipid nanoparticle

t1/2

Apparent terminal elimination half-life

T/B

Tumor-to-background

Tem

Temozolomide

Tf

Transferrin

TG/DTG-DSC

Simultaneous thermogravimetry and differential scanning calorimetry

THDHP

2,4,6-Trihydroxydihydrophenanthrene

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labeling

UV

Ultraviolet

VEGF

Vascular endothelial growth factor

WHO

World Health Organization

XIAP

X-linked inhibitor of apoptosis protein

ZP

Zeta potential

Notes

Funding Information

This work was funded from Portugal National Funds (FCT/MEC, Fundação para a Ciência e a Tecnologia/Ministério da Educação e Ciência) through project UID/QUI/50006/2013, co-financed by European Union (FEDER under the Partnership Agreement PT2020). It was supported as well by the grants FCT PTDC/CTM-BIO/1518/2014 and FCT PTDC/BTM-MAT/30255/2017 from the Portuguese Foundation for Science and Technology (FCT) and the European Community Fund (FEDER) through the COMPETE2020 program. The authors wish to acknowledge Fundação para a Ciência e a Tecnologia (FCT), the Portuguese Agency for Scientific Research, for financial support through the Research Project POCI-01-0145-FEDER-016642, and through the individual doctoral grant attributed to Irina Pereira, together with the Programa Operacional Capital Humano (POCH), with the reference SFRH/BD/136892/2018.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. 1.
    Mileo AM, Miccadei S. Polyphenols as modulator of oxidative stress in cancer disease: new therapeutic strategies. Oxidative Med Cell Longev. 2016;2016:6475624.Google Scholar
  2. 2.
    Tsai H-Y, Ho C-T, Chen Y-K. Biological actions and molecular effects of resveratrol, pterostilbene, and 3′-hydroxypterostilbene. J Food Drug Anal. 2017;25(1):134–47.PubMedGoogle Scholar
  3. 3.
    Gambini J, Inglés M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, et al. Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Med Cell Longev. 2015;2015:1–13.Google Scholar
  4. 4.
    Aluyen JK, Ton QN, Tran T, Yang AE, Gottlieb HB, Bellanger RA. Resveratrol: potential as anticancer agent. J Diet Suppl. 2012;9(1):45–56.PubMedGoogle Scholar
  5. 5.
    Jang M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218–20.PubMedGoogle Scholar
  6. 6.
    Kundu JK, Surh Y-J. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett. 2008;269(2):243–61.PubMedGoogle Scholar
  7. 7.
    Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16(3):225–38.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16(1):20–33.PubMedGoogle Scholar
  9. 9.
    Jones PA, Issa J-PJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–41.PubMedGoogle Scholar
  10. 10.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedGoogle Scholar
  11. 11.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.PubMedGoogle Scholar
  12. 12.
    Siemann DW, Horsman MR. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol Ther. 2015;153:107–24.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK, et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 2015;35:S224–S43.PubMedPubMedCentralGoogle Scholar
  14. 14.
    van Elk M, Murphy BP, Eufrásio-da-Silva T, O’Reilly DP, Vermonden T, Hennink WE, et al. Nanomedicines for advanced cancer treatments: transitioning towards responsive systems. Int J Pharm. 2016;515(1–2):132–64.PubMedGoogle Scholar
  15. 15.
    Mi P, Wang F, Nishiyama N, Cabral H. Molecular cancer imaging with polymeric nanoassemblies: from tumor detection to theranostics. Macromol Biosci. 2017;17:1600305.Google Scholar
  16. 16.
    Parhi P, Suklabaidya S, Sahoo SK. Enhanced anti-metastatic and anti-tumorigenic efficacy of berbamine-loaded lipid nanoparticles in vivo. Sci Rep. 2017;7(1):5806.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2–25.PubMedGoogle Scholar
  18. 18.
    Frank D, Tyagi C, Tomar L, Choonara YE, du Toit LC, Kumar P, et al. Overview of the role of nanotechnological innovations in the detection and treatment of solid tumors. Int J Nanomedicine. 2014;9:589.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Movassaghian S, Merkel OM, Torchilin VP. Applications of polymer micelles for imaging and drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7(5):691–707.PubMedGoogle Scholar
  20. 20.
    Hare JI, Lammers T, Ashford MB, Puri S, Storm G, Barry ST. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliv Rev. 2017;108:25–38.PubMedGoogle Scholar
  21. 21.
    Siddiqui IA, Sanna V, Ahmad N, Sechi M, Mukhtar H. Resveratrol nanoformulation for cancer prevention and therapy. Ann N Y Acad Sci. 2015;1348(1):20–31.PubMedGoogle Scholar
  22. 22.
    Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47.PubMedGoogle Scholar
  23. 23.
    Jahan ST, Sadat S, Walliser M, Haddadi A. Targeted therapeutic nanoparticles: an immense promise to fight against cancer. J Drug Deliv. 2017;2017:1–24.Google Scholar
  24. 24.
    Bonferoni MC, Rossi S, Sandri G, Ferrari F. Nanoparticle formulations to enhance tumor targeting of poorly soluble polyphenols with potential anticancer properties. Semin Cancer Biol. 2017;46:205–14.PubMedGoogle Scholar
  25. 25.
    Salas G, Costo R, del Puerto Morales M. Synthesis of inorganic nanoparticles. In: de la Fuente JM, Grazu V, editors. Nanobiotechnology: inorganic nanoparticles vs organic nanoparticles. Amsterdam: Elsevier; 2012. p. 35–79.Google Scholar
  26. 26.
    Berry CC. Applications of inorganic nanoparticles for biotechnology. In: de la Fuente JM, Grazu V, editors. Nanobiotechnology: inorganic nanoparticles vs organic nanoparticles. Amsterdam: Elsevier; 2012. p. 159–80.Google Scholar
  27. 27.
    Zu Y, Zhang Y, Wang W, Zhao X, Han X, Wang K, et al. Preparation and in vitro/in vivo evaluation of resveratrol-loaded carboxymethyl chitosan nanoparticles. Drug Deliv. 2016;23(3):981–91.PubMedGoogle Scholar
  28. 28.
    Feracci H, Gutierrez BS, Hempel W, Gil IS. Organic nanoparticles. In: de la Fuente JM, Grazu V, editors. Nanobiotechnology: inorganic nanoparticles vs organic nanoparticles. Amsterdam: Elsevier; 2012. p. 197–230.Google Scholar
  29. 29.
    Romero G, Moya SE. Synthesis of organic nanoparticles. In: de la Fuente JM, Grazu V, editors. Nanobiotechnology: inorganic nanoparticles vs organic nanoparticles. Amsterdam: Elsevier; 2012. p. 115–41.Google Scholar
  30. 30.
    Šoltys M, Kovačík P, Dammer O, Beránek J, Štěpánek F. Effect of solvent selection on drug loading and amorphisation in mesoporous silica particles. Int J Pharm. 2019;555:19–27.PubMedGoogle Scholar
  31. 31.
    Kobayashi K, Wei J, Iida R, Ijiro K, Niikura K. Surface engineering of nanoparticles for therapeutic applications. Polym J. 2014;46(8):460–8.Google Scholar
  32. 32.
    Navarro G, Pan J, Torchilin VP. Micelle-like nanoparticles as carriers for DNA and siRNA. Mol Pharm. 2015;12(2):301–13.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Toporkiewicz M, Meissner J, Matusewicz L, Czogalla A, Sikorski AF. Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges. Int J Nanomedicine. 2015;10:1399.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Mura S, Couvreur P. Nanotheranostics for personalized medicine. Adv Drug Deliv Rev. 2012;64(13):1394–416.PubMedGoogle Scholar
  35. 35.
    Bi Y, Hao F, Yan G, Teng L, Lee RJ, Xie J. Actively targeted nanoparticles for drug delivery to tumor. Curr Drug Metab. 2016;17(8):763–82.PubMedGoogle Scholar
  36. 36.
    Caballero D, Blackburn SM, de Pablo M, Samitier J, Albertazzi L. Tumour-vessel-on-a-chip models for drug delivery. Lab Chip. 2017;17(22):3760–71.PubMedGoogle Scholar
  37. 37.
    Summerlin N, Soo E, Thakur S, Qu Z, Jambhrunkar S, Popat A. Resveratrol nanoformulations: challenges and opportunities. Int J Pharm. 2015;479(2):282–90.PubMedGoogle Scholar
  38. 38.
    Tyagi N, De R, Begun J, Popat A. Cancer therapeutics with epigallocatechin-3-gallate encapsulated in biopolymeric nanoparticles. Int J Pharm. 2017;518(1–2):220–7.PubMedGoogle Scholar
  39. 39.
    Juère E, Florek J, Bouchoucha M, Jambhrunkar S, Wong KY, Popat A, et al. In vitro dissolution, cellular membrane permeability, and anti-inflammatory response of resveratrol-encapsulated mesoporous silica nanoparticles. Mol Pharm. 2017;14(12):4431–41.PubMedGoogle Scholar
  40. 40.
    Liu Y, Fan Y, Gao L, Zhang Y, Yi J. Enhanced pH and thermal stability, solubility and antioxidant activity of resveratrol by nanocomplexation with α-lactalbumin. Food Funct. 2018;9(9):4781–90.PubMedGoogle Scholar
  41. 41.
    Nawaz W, Zhou Z, Deng S, Ma X, Ma X, Li C, et al. Therapeutic versatility of resveratrol derivatives. Nutrients. 2017;9(11):1188.PubMedCentralGoogle Scholar
  42. 42.
    Sako M, Hosokawa H, Ito T, Iinuma M. Regioselective oxidative coupling of 4-hydroxystilbenes: synthesis of resveratrol and ε-viniferin (E)-dehydrodimers. J Organomet Chem. 2004;69(7):2598–600.Google Scholar
  43. 43.
    Pujara N, Jambhrunkar S, Wong KY, McGuckin M, Popat A. Enhanced colloidal stability, solubility and rapid dissolution of resveratrol by nanocomplexation with soy protein isolate. J Colloid Interface Sci. 2017;488:303–8.PubMedGoogle Scholar
  44. 44.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.PubMedGoogle Scholar
  45. 45.
    Catalgol B, Batirel S, Taga Y, Ozer N. Resveratrol: French paradox revisited. Front Pharmacol. 2012;3:141.Google Scholar
  46. 46.
    Lephart ED, Andrus MB. Human skin gene expression: natural (trans) resveratrol versus five resveratrol analogs for dermal applications. Exp Biol Med (Maywood). 2017;242(15):1482–9.Google Scholar
  47. 47.
    Pangeni R, Sahni JK, Ali J, Sharma S, Baboota S. Resveratrol: review on therapeutic potential and recent advances in drug delivery. Expert Opin Drug Deliv. 2014;11(8):1285–98.PubMedGoogle Scholar
  48. 48.
    Neves AR, Lucio M, Lima JL, Reis S. Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions. Curr Med Chem. 2012;19(11):1663–81.PubMedGoogle Scholar
  49. 49.
    Lephart ED. Resveratrol, 4′ acetoxy resveratrol, R-equol, racemic equol or S-equol as cosmeceuticals to improve dermal health. Int J Mol Sci. 2017;18(6):1193.PubMedCentralGoogle Scholar
  50. 50.
    Tsai M-J, Lu IJ, Fu Y-S, Fang Y-P, Huang Y-B, Wu P-C. Nanocarriers enhance the transdermal bioavailability of resveratrol: in vitro and in vivo study. Colloids Surf B: Biointerfaces. 2016;148:650–6.PubMedGoogle Scholar
  51. 51.
    Wahab A, Gao K, Jia C, Zhang F, Tian G, Murtaza G, et al. Significance of resveratrol in clinical management of chronic diseases. Molecules. 2017;22(8):1329.PubMedCentralGoogle Scholar
  52. 52.
    Amri A, Chaumeil JC, Sfar S, Charrueau C. Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release. 2012;158(2):182–93.PubMedGoogle Scholar
  53. 53.
    Silva RC, Teixeira JA, Nunes WDG, Zangaro GAC, Pivatto M, Caires FJ, et al. Resveratrol: a thermoanalytical study. Food Chem. 2017;237:561–5.PubMedGoogle Scholar
  54. 54.
    Robinson K, Mock C, Liang D. Pre-formulation studies of resveratrol. Drug Dev Ind Pharm. 2015;41(9):1464–9.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Francioso A, Mastromarino P, Masci A, d’Erme M, Mosca L. Chemistry, stability and bioavailability of resveratrol. Med Chem. 2014;10(3):237–45.PubMedGoogle Scholar
  56. 56.
    Varoni EM, Lo Faro AF, Sharifi-Rad J, Iriti M. Anticancer molecular mechanisms of resveratrol. Front Nutr. 2016;3:8.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Delmas D, Aires V, Limagne E, Dutartre P, Mazué F, Ghiringhelli F, et al. Transport, stability, and biological activity of resveratrol. Ann N Y Acad Sci. 2011;1215(1):48–59.PubMedGoogle Scholar
  58. 58.
    Zupančič Š, Lavrič Z, Kristl J. Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature. Eur J Pharm Biopharm. 2015;93:196–204.PubMedGoogle Scholar
  59. 59.
    Santos AC, Veiga F, Ribeiro AJ. New delivery systems to improve the bioavailability of resveratrol. Expert Opin Drug Deliv. 2011;8(8):973–90.PubMedGoogle Scholar
  60. 60.
    Chen J, Wei N, Lopez-Garcia M, Ambrose D, Lee J, Annelin C, et al. Development and evaluation of resveratrol, vitamin E, and epigallocatechin gallate loaded lipid nanoparticles for skin care applications. Eur J Pharm Biopharm. 2017;117:286–91.PubMedGoogle Scholar
  61. 61.
    Howells LM, Berry DP, Elliott PJ, Jacobson EW, Hoffmann E, Hegarty B, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res (Phila). 2011;4(9):1419–25.Google Scholar
  62. 62.
    Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011;68(3):593–601.PubMedGoogle Scholar
  63. 63.
    Rotches-Ribalta M, Andres-Lacueva C, Estruch R, Escribano E, Urpì-Sardà M. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol Res. 2012;66(5):375–82.PubMedGoogle Scholar
  64. 64.
    Marier J-F, Vachon P, Gritsas A, Zhang J, Moreau J-P, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302(1):369–73.PubMedGoogle Scholar
  65. 65.
    Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005;49(5):472–81.PubMedGoogle Scholar
  66. 66.
    Boocock DJ, Faust GES, Patel KR, Schinas AM, Brown VA, Ducharme MP, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomark Prev. 2007;16(6):1246–52.Google Scholar
  67. 67.
    Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32(12):1377–82.PubMedGoogle Scholar
  68. 68.
    Ortuño J, Covas M-I, Farre M, Pujadas M, Fito M, Khymenets O, et al. Matrix effects on the bioavailability of resveratrol in humans. Food Chem. 2010;120(4):1123–30.Google Scholar
  69. 69.
    Urpí-Sardà M, Jáuregui O, Lamuela-Raventós RM, Jaeger W, Miksits M, Covas M-I, et al. Uptake of diet resveratrol into the human low-density lipoprotein. Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry. Anal Chem. 2005;77(10):3149–55.PubMedGoogle Scholar
  70. 70.
    Burkon A, Somoza V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides—two novel resveratrol metabolites in human plasma. Mol Nutr Food Res. 2008;52(5):549–57.PubMedGoogle Scholar
  71. 71.
    Singh G, Pai RS. Optimized PLGA nanoparticle platform for orally dosed trans-resveratrol with enhanced bioavailability potential. Expert Opin Drug Deliv. 2014;11(5):647–59.PubMedGoogle Scholar
  72. 72.
    Urpí-Sardà M, Zamora-Ros R, Lamuela-Raventos R, Cherubini A, Jauregui O, De La Torre R, et al. HPLC–tandem mass spectrometric method to characterize resveratrol metabolism in humans. Clin Chem. 2007;53(2):292–9.PubMedGoogle Scholar
  73. 73.
    Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi PP, et al. Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res. 2005;49(5):495–504.PubMedGoogle Scholar
  74. 74.
    Sergides C, Chirilă M, Silvestro L, Pitta D, Pittas A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp Ther Med. 2016;11(1):164–70.PubMedGoogle Scholar
  75. 75.
    Zamora-Ros R. Resveratrol: marcador dietètic i biològic del consum de vi: Universitat de Barcelona. Departament de Nutrició i Bromatologia; 2008. Doctoral thesis.Google Scholar
  76. 76.
    Wenzel E, Soldo T, Erbersdobler H, Somoza V. Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res. 2005;49(5):482–94.PubMedGoogle Scholar
  77. 77.
    Boocock DJ, Patel KR, Faust GES, Normolle DP, Marczylo TH, Crowell JA, et al. Quantitation of trans-resveratrol and detection of its metabolites in human plasma and urine by high performance liquid chromatography. J Chromatogr B Anal Technol Biomed Life Sci. 2007;848(2):182–7.Google Scholar
  78. 78.
    Colom H, Alfaras I, Maijó M, Juan ME, Planas JM. Population pharmacokinetic modeling of trans-resveratrol and its glucuronide and sulfate conjugates after oral and intravenous administration in rats. Pharm Res. 2011;28(7):1606–21.PubMedGoogle Scholar
  79. 79.
    Vijayakumar MR, Kumari L, Patel KK, Vuddanda PR, Vajanthri KY, Mahto SK, et al. Intravenous administration of trans-resveratrol-loaded TPGS-coated solid lipid nanoparticles for prolonged systemic circulation, passive brain targeting and improved in vitro cytotoxicity against C6 glioma cell lines. RSC Adv. 2016;6(55):50336–48.Google Scholar
  80. 80.
    Das S, Lin H-S, Ho PC, Ng K-Y. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res. 2008;25(11):2593–600.PubMedGoogle Scholar
  81. 81.
    Juan MEL, Buenafuente J, Casals I, Planas JM. Plasmatic levels of trans-resveratrol in rats. Food Res Int. 2002;35(2–3):195–9.Google Scholar
  82. 82.
    Ishida T, Takeda T, Koga T, Yahata M, Ike A, Kuramoto C, et al. Attenuation of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin toxicity by resveratrol: a comparative study with different routes of administration. Biol Pharm Bull. 2009;32(5):876–81.PubMedGoogle Scholar
  83. 83.
    Wang P, Sang S. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors. 2018;44:16–25.PubMedGoogle Scholar
  84. 84.
    Zunino SJ, Storms DH, Newman JW, Pedersen TL, Keen CL, Ducore JM. Resveratrol given intraperitoneally does not inhibit the growth of high-risk t (4; 11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model. Int J Oncol. 2012;40(4):1277–84.PubMedGoogle Scholar
  85. 85.
    Canistro D, Bonamassa B, Pozzetti L, Sapone A, Abdel-Rahman SZ, Biagi GL, et al. Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice. Food Chem Toxicol. 2009;47(2):454–61.PubMedGoogle Scholar
  86. 86.
    Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Sengottuvelan M, Deeptha K, Nalini N. Influence of dietary resveratrol on early and late molecular markers of 1,2-dimethylhydrazine-induced colon carcinogenesis. Nutrition. 2009;25(11–12):1169–76.PubMedGoogle Scholar
  88. 88.
    Ferraz da Costa DC, Fialho E, Silva JL. Cancer chemoprevention by resveratrol: the p53 tumor suppressor protein as a promising molecular target. Molecules. 2017;22(6):1014.PubMedCentralGoogle Scholar
  89. 89.
    Zhang S, Cao HJ, Davis FB, Tang HY, Davis PJ, Lin HY. Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells. Br J Cancer. 2004;91(1):178–85.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Kai L, Samuel SK, Levenson AS. Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. Int J Cancer. 2010;126(7):1538–48.PubMedGoogle Scholar
  91. 91.
    Su JL, Yang CY, Zhao M, Kuo ML, Yen ML. Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. J Biol Chem. 2007;282(27):19385–98.PubMedGoogle Scholar
  92. 92.
    Hsieh TC, Burfeind P, Laud K, Backer JM, Traganos F, Darzynkiewicz Z, et al. Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials. Int J Oncol. 1999;15(2):245–52.PubMedGoogle Scholar
  93. 93.
    Yu XD, Yang JL, Zhang WL, Liu DX. Resveratrol inhibits oral squamous cell carcinoma through induction of apoptosis and G2/M phase cell cycle arrest. Tumour Biol. 2016;37(3):2871–7.PubMedGoogle Scholar
  94. 94.
    Polycarpou E, Meira LB, Carrington S, Tyrrell E, Modjtahedi H, Carew MA. Resveratrol 3-O-D-glucuronide and resveratrol 4'-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest. Mol Nutr Food Res. 2013;57(10):1708–17.PubMedGoogle Scholar
  95. 95.
    Wong JC, Fiscus RR. Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs. Anticancer Res. 2015;35(1):273–81.PubMedGoogle Scholar
  96. 96.
    Sun C, Hu Y, Liu X, Wu T, Wang Y, He W, et al. Resveratrol downregulates the constitutional activation of nuclear factor-kappa B in multiple myeloma cells, leading to suppression of proliferation and invasion, arrest of cell cycle, and induction of apoptosis. Cancer Genet Cytogenet. 2006;165(1):9–19.PubMedGoogle Scholar
  97. 97.
    Tang FY, Chiang EP, Sun YC. Resveratrol inhibits heregulin-beta1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells. J Nutr Biochem. 2008;19(5):287–94.PubMedGoogle Scholar
  98. 98.
    Das S, Das DK. Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets. 2007;6(3):168–73.PubMedGoogle Scholar
  99. 99.
    Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappa B, cyclooxygenase-2, and matrix metalloprotease-9. Cancer Res. 2002;62(17):4945–54.PubMedGoogle Scholar
  100. 100.
    Sexton E, Van Themsche C, LeBlanc K, Parent S, Lemoine P, Asselin E. Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer. 2006;5:45.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Golkar L, Ding XZ, Ujiki MB, Salabat MR, Kelly DL, Scholtens D, et al. Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007;138(2):163–9.PubMedGoogle Scholar
  102. 102.
    Jose S, Anju SS, Cinu TA, Aleykutty NA, Thomas S, Souto EB. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. Int J Pharm. 2014;474(1–2):6–13.PubMedGoogle Scholar
  103. 103.
    Guo L, Peng Y, Yao J, Sui L, Gu A, Wang J. Anticancer activity and molecular mechanism of resveratrol-bovine serum albumin nanoparticles on subcutaneously implanted human primary ovarian carcinoma cells in nude mice. Cancer Biother Radiopharm. 2010;25(4):471–7.PubMedGoogle Scholar
  104. 104.
    Geng T, Zhao X, Ma M, Zhu G, Yin L. Resveratrol-loaded albumin nanoparticles with prolonged blood circulation and improved biocompatibility for highly effective targeted pancreatic tumor therapy. Nanoscale Res Lett. 2017;12(1):437.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Dai L, Liu R, Hu L-Q, Zou Z-F, Si C-L. Lignin nanoparticle as a novel green carrier for the efficient delivery of resveratrol. ACS Sustain Chem Eng. 2017;5(9):8241–8249.Google Scholar
  106. 106.
    Jung KH, Lee JH, Park JW, Quach CH, Moon SH, Cho YS, et al. Resveratrol-loaded polymeric nanoparticles suppress glucose metabolism and tumor growth in vitro and in vivo. Int J Pharm. 2015;478(1):251–7.PubMedGoogle Scholar
  107. 107.
    Guo W, Li A, Jia Z, Yuan Y, Dai H, Li H. Transferrin modified PEG-PLA-resveratrol conjugates: in vitro and in vivo studies for glioma. Eur J Pharmacol. 2013;718(1–3):41–7.PubMedGoogle Scholar
  108. 108.
    Xu H, Jia F, Singh PK, Ruan S, Zhang H, Li X. Synergistic anti-glioma effect of a coloaded nano-drug delivery system. Int J Nanomedicine. 2017;12:29–40.PubMedGoogle Scholar
  109. 109.
    Figueiro F, Bernardi A, Frozza RL, Terroso T, Zanotto-Filho A, Jandrey EH, et al. Resveratrol-loaded lipid-core nanocapsules treatment reduces in vitro and in vivo glioma growth. J Biomed Nanotechnol. 2013;9(3):516–26.PubMedGoogle Scholar
  110. 110.
    Feng M, Zhong LX, Zhan ZY, Huang ZH, Xiong JP. Enhanced antitumor efficacy of resveratrol-loaded nanocapsules in colon cancer cells: physicochemical and biological characterization. Eur Rev Med Pharmacol Sci. 2017;21(2):375–82.PubMedGoogle Scholar
  111. 111.
    Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, et al. Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway. PLoS One. 2013;8(11):e78700.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Jung KH, Lee JH, Thien Quach CH, Paik JY, Oh H, Park JW, et al. Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1alpha activation. J Nucl Med. 2013;54(12):2161–7.PubMedGoogle Scholar
  113. 113.
    Gagliano N, Aldini G, Colombo G, Rossi R, Colombo R, Gioia M, et al. The potential of resveratrol against human gliomas. Anti-Cancer Drugs. 2010;21(2):140–50.PubMedGoogle Scholar
  114. 114.
    Wijaya J, Fukuda Y, Schuetz JD. Obstacles to brain tumor therapy: key ABC transporters. Int J Mol Sci. 2017;18(12):2544.PubMedCentralGoogle Scholar
  115. 115.
    Xiong W, Yin A, Mao X, Zhang W, Huang H, Zhang X. Resveratrol suppresses human glioblastoma cell migration and invasion via activation of RhoA/ROCK signaling pathway. Oncol Lett. 2016;11(1):484–90.PubMedGoogle Scholar
  116. 116.
    Pistollato F, Bremer-Hoffmann S, Basso G, Cano SS, Elio I, Vergara MM, et al. Targeting glioblastoma with the use of phytocompounds and nanoparticles. Target Oncol. 2016;11(1):1–16.PubMedGoogle Scholar
  117. 117.
    Calzolari A, Larocca LM, Deaglio S, Finisguerra V, Boe A, Raggi C, et al. Transferrin receptor 2 is frequently and highly expressed in glioblastomas. Transl Oncol. 2010;3(2):123–34.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Liu Y, Tong L, Luo Y, Li X, Chen G, Wang Y. Resveratrol inhibits the proliferation and induces the apoptosis in ovarian cancer cells via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway. J Cell Biochem. 2018;119:6162–6172.PubMedGoogle Scholar
  120. 120.
    Guo LY, Yao JP, Sui LH. Preparation and effects of resveratrol bovine serum albumin nanoparticles on proliferation of human ovarian carcinoma cell SKOV3. Chem J Chin Univ. 2009;30(3):474–7.Google Scholar
  121. 121.
    Feng Y, Zhou J, Jiang Y. Resveratrol in lung cancer—a systematic review. J BUON. 2016;21(4):950–3.PubMedGoogle Scholar
  122. 122.
    Kim S, Shi Y, Kim JY, Park K, Cheng J-X. Overcoming the barriers in micellar drug delivery: loading efficiency, in vivo stability, and micelle–cell interaction. Expert Opin Drug Deliv. 2010;7(1):49–62.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Ana Cláudia Santos
    • 1
    • 2
    Email author
  • Irina Pereira
    • 1
    • 2
  • Mariana Magalhães
    • 1
    • 2
  • Miguel Pereira-Silva
    • 1
  • Mariana Caldas
    • 1
  • Laura Ferreira
    • 1
  • Ana Figueiras
    • 1
    • 2
  • António J. Ribeiro
    • 1
    • 3
  • Francisco Veiga
    • 1
    • 2
  1. 1.Department of Pharmaceutical Technology, Faculty of PharmacyUniversity of CoimbraCoimbraPortugal
  2. 2.REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of PharmacyUniversity of CoimbraCoimbraPortugal
  3. 3.i3S, Group Genetics of Cognitive DysfunctionInstitute for Molecular and Cell BiologyPortoPortugal

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