Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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 P o/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

t 1/2 :

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

References

  1. Mileo AM, Miccadei S. Polyphenols as modulator of oxidative stress in cancer disease: new therapeutic strategies. Oxidative Med Cell Longev. 2016;2016:6475624.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  5. Jang M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218–20.

    Article  CAS  PubMed  Google Scholar 

  6. Kundu JK, Surh Y-J. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett. 2008;269(2):243–61.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Jones PA, Issa J-PJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–41.

    Article  CAS  PubMed  Google Scholar 

  10. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  11. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  12. Siemann DW, Horsman MR. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol Ther. 2015;153:107–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Chapter  Google Scholar 

  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.

    Chapter  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Chapter  Google Scholar 

  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.

    Chapter  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  32. Navarro G, Pan J, Torchilin VP. Micelle-like nanoparticles as carriers for DNA and siRNA. Mol Pharm. 2015;12(2):301–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mura S, Couvreur P. Nanotheranostics for personalized medicine. Adv Drug Deliv Rev. 2012;64(13):1394–416.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  45. Catalgol B, Batirel S, Taga Y, Ozer N. Resveratrol: French paradox revisited. Front Pharmacol. 2012;3:141.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  54. Robinson K, Mock C, Liang D. Pre-formulation studies of resveratrol. Drug Dev Ind Pharm. 2015;41(9):1464–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  56. Varoni EM, Lo Faro AF, Sharifi-Rad J, Iriti M. Anticancer molecular mechanisms of resveratrol. Front Nutr. 2016;3:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  65. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005;49(5):472–81.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  75. Zamora-Ros R. Resveratrol: marcador dietètic i biològic del consum de vi: Universitat de Barcelona. Departament de Nutrició i Bromatologia; 2008. Doctoral thesis.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  83. Wang P, Sang S. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors. 2018;44:16–25.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  86. Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  98. Das S, Das DK. Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets. 2007;6(3):168–73.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  114. Wijaya J, Fukuda Y, Schuetz JD. Obstacles to brain tumor therapy: key ABC transporters. Int J Mol Sci. 2017;18(12):2544.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  121. Feng Y, Zhou J, Jiang Y. Resveratrol in lung cancer—a systematic review. J BUON. 2016;21(4):950–3.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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.

Author information

Author notes

  1. Ana Cláudia Santos and Irina Pereira contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Ana Cláudia Santos, Irina Pereira, Mariana Magalhães, Miguel Pereira-Silva, Mariana Caldas, Laura Ferreira, Ana Figueiras, António J. Ribeiro & Francisco Veiga

  2. REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Ana Cláudia Santos, Irina Pereira, Mariana Magalhães, Ana Figueiras & Francisco Veiga

  3. i3S, Group Genetics of Cognitive Dysfunction, Institute for Molecular and Cell Biology, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal

    António J. Ribeiro

Authors
  1. Ana Cláudia Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariana Magalhães
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miguel Pereira-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariana Caldas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ana Figueiras
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. António J. Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francisco Veiga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Cláudia Santos.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santos, A.C., Pereira, I., Magalhães, M. et al. Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence. AAPS J 21, 57 (2019). https://doi.org/10.1208/s12248-019-0325-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-019-0325-y

KEY WORDS

Search

Navigation