Curcumin has been used as an edible health-promoting substance for thousands of years as part of traditional medicinal practices in Asia.

More recently, modern  scientific  methods  have demonstrated that curcumin exhibits a broad spectrum of biological activities  that may be beneficial to human health, including antioxidant, antimicrobial, anti-inflammatory, and antitumor activities.

Even so, there are a number of challenges that have  to be addressed when formulating curcumin-based functional foods or therapeutics,  including its low water solubility, chemical stability, and bioavailability.

In this article, we highlighted some of the methods that can be used to overcome these problems, including antioxidant, encapsulation, and  storage  strategies.  In  particular, we focused on  the  utilization of colloidal delivery systems, such  as micelles, liposomes, microemulsions, emulsions, solid lipid nanoparticles, biopolymer particles, and  nature-derived colloidal particles.

Each of these delivery systems has its own  advantages and  disadvantages for specific applications and  it is important to select the most appropriate formulation. For instance, there are differences in the appearances, textures, mouthfeels,  flavors,  shelf-lives, and environmental histories  of different curcumin-fortified functional food products (such as soft drinks, milky drinks, sauces, dressings, and bakery  goods),  which require different kinds of encapsulation technologies.

In the future, it will be important to compare  different formulations in terms of their cost, ease of manufacture, robustness,  pharmacokinetics, bioavailability, bioactivity, sustainability, and  environmental impact. The  most  suitable formulation for a specific application can then be selected.

Funding:  This  material was partly  based upon work  supported  by the National Institute of Food and Agriculture, USDA, Massachusetts Agricultural Experiment Station (Project Number 831) and USDA, AFRI Grants (2016-08782).

Acknowledgments: This  material  was partly based upon  work  supported by the National Institute  of Food and

Agriculture, USDA, Massachusetts Agricultural Experiment Station (Project Number 831). 

Conflicts of Interest: The authors  declare no conflict  of interest.

Abbreviations

C4-2B                        C4-2 Bone metastatic

1. coli Escherichia coli
2. faecalis Enterococcus faecalis

HCT 116                  Human Colorectal Carcinoma cell lines

IL                            Interleukin

LNCaP                 Lymph Node  Carcinoma of the Prostate

NFkB                     Nuclear Factor Kappa B

1. P. aeruginosa Pseudomonas aeruginosa Rko                            Rectal carcinoma cell line autrus                  Staphylococcus aureus

TNF-a                    Tumor Necrosis Factor Alpha

References

1. Sharma, R.; Gescher, A.;  Steward, W.  Curcumin:  The  story  so far.   Eur.   J. Cancer 2005, 41, 1955–1968. [CrossRef] [PubMed]
3. Shahidi, F.; Naczk, M. Phenolics in Food and Nutraceuticals; CRC Press:  Boca Raton, FL, USA, 2003.
5. Heger, M.; van Golen, R.F.;  Broekgaarden, M.; Michel, M.C.  The molecular basis for the pharmacokinetics and  pharmacodynamics of curcumin and  its metabolites in relation to cancer.   Pharmacol.  Rev. 2014, 66, 222–307. [CrossRef] [PubMed]

4. Priyadarsini, K.I. The  chemistry of curcumin:  From extraction to therapeutic agent.   Molecules 2014, 19, 20091–20112. [CrossRef] [PubMed]

5. Jurenka, J.S. Anti-inflammatory properties of curcumin, a major constituent  of curcuma longa:  A review of preclinical and clinical research.  Altern. Med. Rev. 2009, 14, 141–153. [PubMed]

6. Menon,  V.P.; Sudheer, A.R. Antioxidant and  anti-inflammatory properties of curcumin. In The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease; Springer: New York, NY, USA, 2007; pp. 105–125.

7. Ak,  T.; Gülçin, I˙. Antioxidant and radical  scavenging properties  of curcumin. Chem. Biol. Interact. 2008, 174, 27–37. [CrossRef] [PubMed]

8. Zorofchian Moghadamtousi, S.;  Abdul Kadir, H.;  Hassandarvish, P.;  Tajik, H.;  Abubakar, S.;  Zandi, K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed Res. Int. 2014, 2014, 1–12. [CrossRef] [PubMed]

9. Martins, C.; Da  Silva, D.;  Neres, A.;  Magalhaes, T.; Watanabe, G.; Modolo, L.;  Sabino, A.;  De Fátima, A.; De Resende,  M. Curcumin as a promising antifungal of clinical interest.  J. Antimicrob. Chemother. 2008, 63, 337–339. [CrossRef]

10. Bar-Sela, G.; Epelbaum, R.; Schaffer, M. Curcumin as an anti-cancer  agent: Review of the gap between basic and clinical applications. Curr. Med. Chem. 2010, 17, 190–197. [CrossRef]
12. Naksuriya, O.; Okonogi, S.; Schiffelers, R.M.;  Hennink, W.E.  Curcumin nanoformulations: A review of pharmaceutical properties and preclinical studies  and clinical data related to cancer treatment.  Biomaterials 2014, 35, 3365–3383. [CrossRef]

12. Anand, P.; Kunnumakkara, A.B.; Newman, R.A.;  Aggarwal, B.B. Bioavailability of curcumin: Problems  and promises. Mol. Pharm. 2007, 4, 807–818. [CrossRef]
14. Tønnesen, H.H.; Másson, M.;  Loftsson, T. Studies of curcumin and  curcuminoids. Xxvii.  Cyclodextrin complexation: Solubility, chemical and photochemical stability. Int. J. Pharm. 2002, 244, 127–135.
16. Kharat, M.; Du, Z.;  Zhang, G.; McClements, D.J.  Physical and  chemical stability of curcumin in aqueous solutions and emulsions: Impact  of ph, temperature, and molecular environment. J. Agric. Food Chem. 2017, 65, 1525–1532. [CrossRef]

15. McClements, D.J.; Decker, E.A.; Park, Y.;  Weiss,  J. Structural design principles for delivery of bioactive components in nutraceuticals and functional foods.  Crit. Rev. Food Sci. Nutr.  2009, 49, 577–606. CrossRef]
17. Garti, N. Delivery and Controlled Release of Bioactives in Foods and Nutraceuticals; Elsevier:   Amsterdam, The Netherlands, 2008.
19. Zhang, Z.; Zhang, R.; Decker, E.A.; McClements, D.J. Development of food-grade filled hydrogels for oral delivery of lipophilic active ingredients: Ph-triggered release. Food Hydrocoll. 2015, 44, 345–352. [CrossRef]
21. McClements, D.; Decker,  E.; Weiss, J. Emulsion-based delivery systems  for lipophilic bioactive  components.Food Sci. 2007, 72, R109–R124. [CrossRef] [PubMed]
23. Lee, W.-H.; Loo, C.-Y.; Bebawy,  M.; Luk, F.; Mason, R.S.; Rohanizadeh, R. Curcumin and its derivatives: Their application in neuropharmacology and  neuroscience in the 21st century. Curr.  Neuropharmacol.  2013, 11, 338–378. [CrossRef] [PubMed]

20. Bhatia, N.K.; Kishor, S.;  Katyal, N.;   Gogoi, P.;  Narang, P.;  Deep,  S.  Effect of  ph  and  temperature on conformational equilibria and aggregation behaviour of curcumin in aqueous binary mixtures of ethanol. RSC Adv. 2016, 6, 103275–103288. [CrossRef]
22. Manolova, Y.; Deneva, V.; Antonov, L.; Drakalska, E.; Momekova, D.; Lambov, N. The effect of the water on the curcumin tautomerism: A quantitative approach. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2014, 132, 815–820. [CrossRef] [PubMed]

22. Murugan, P.; Pari, L. Influence of tetrahydrocurcumin on hepatic and renal functional markers and protein levels  in experimental type 2 diabetic  rats. Basic Clin. Pharmacol. Toxicol. 2007, 101, 241–245. [CrossRef]
24. Willcox, J.K.;  Ash, S.L.;  Catignani, G.L. Antioxidants and  prevention of chronic disease.   Crit.  Rev. Food Sci. Nutr.  2004, 44, 275–295. [CrossRef] [PubMed]

24. Barclay, L.R.C.; Vinqvist, M.R.; Mukai, K.; Goto, H.; Hashimoto, Y.; Tokunaga, A.; Uno, H. On the antioxidant mechanism of curcumin: Classical methods are needed to determine antioxidant mechanism and activity. Org. Lett. 2000, 2, 2841–2843. [CrossRef] [PubMed]
26. Jayaprakasha, G.; Rao,  L.J.;  Sakariah, K. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chem. 2006, 98, 720–724. [CrossRef]
28. Goel, A.; Kunnumakkara, A.B.; Aggarwal, B.B. Curcumin as “curecumin”: From kitchen to clinic. Biochem. Pharmacol. 2008, 75, 787–809. [CrossRef] [PubMed]

27. Arun, N.; Nalini, N. Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. Plant Foods Hum. Nutr.  2002, 57, 41–52. [CrossRef] [PubMed]  

28. Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with  active rheumatoid arthritis. Phytother. Res. 2012, 26, 1719–1725. [CrossRef]
30. Anna, K.T.;  Suhana, M.;  Das,  S.;  Faizah, O.;  Hamzaini, A.  Anti-inflammatory effect of curcuma longa (turmeric) on collagen-induced arthritis: An  anatomico-radiological study.  Clin. Ter. 2011, 162, 201–207.

30. Yang, Q.Q.; Farha, A.K.; Kim, G.; Gul, K.;  Gan,  R.Y.; Corke, H.  Antimicrobial and anticancer applications and related mechanisms of curcumin-mediated photodynamic treatments. Trends Food Sci. Technol. 2020, 97, 341–354. [CrossRef]

31. Gupta, S.C.; Sung, B.; Kim, J.H.;  Prasad, S.; Li, S.Y.;  Aggarwal, B.B. Multitargeting by turmeric, the golden spice:  From  kitchen  to clinic.  Mol. Nutr.  Food Res. 2013, 57, 1510–1528. [CrossRef]
33. Vaughn, A.R.; Haas,  K.N.; Burney,  W.; Andersen, E.; Clark, A.K.; Crawford, R.; Sivamani, R.K. Potential role of curcumin against biofilm-producing organisms on the skin:  A review.  Phytother. Res. 2017, 31, 1807–1816. [CrossRef]
35. Tyagi, P.; Singh, M.;  Kumari, H.;  Kumari, A.;  Mukhopadhyay, K. Bactericidal activity of curcumin i is associated  with  damaging of bacterial  membrane.  PLoS ONE 2015, 10, e0121313. [CrossRef]
37. Tomeh, M.A.; Hadianamrei, R.; Zhao,  X. A review  of curcumin and its derivatives as anticancer agents. Int. J. Mol. Sci. 2019, 20, 1033. [CrossRef] [PubMed]

35. Arbiser, J.L.;  Klauber, N.;  Rohan, R.;  van  Leeuwen, R.;  Huang, M.-T.;  Fisher, C.;  Flynn, E.;  Byers, H.R. Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med. 1998, 4, 376–383. [CrossRef] [PubMed]

36. Teiten, M.-H.; Gaascht, F.; Eifes, S.; Dicato, M.; Diederich, M. Chemopreventive potential of curcumin in prostate cancer.  Genes Nutr.  2010, 5, 61. [CrossRef] [PubMed]
38. Dorai, T.; Dutcher, J.P.; Dempster, D.W.;  Wiernik, P.H.  Therapeutic potential of  curcumin in  prostate cancer—IV: Interference with the osteomimetic  properties  of hormone refractory  c4-2b prostate cancer cells. Prostate 2004, 60, 1–17. [CrossRef]
40. Liu, Q.; Loo, W.T.;  Sze, S.; Tong, Y. Curcumin inhibits cell proliferation of mda-mb-231 and  bt-483 breast cancer cells mediated by down-regulation of nfκb, cyclind and mmp-1  transcription. Phytomedicine 2009, 16, 916–922. [CrossRef]

39. Mudduluru, G.; George-William, J.N.; Muppala, S.; Asangani, I.A.; Kumarswamy, R.; Nelson, L.D.;  Allgayer, H. Curcumin regulates  mir-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci. Rep. 2011, 31, 185–197. [CrossRef]

40. Kunnumakkara, A.B.; Bordoloi, D.; Harsha, C.; Banik, K.; Gupta, S.C.;  Aggarwal, B.B. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin. Sci. 2017, 131, 1781–1799. [CrossRef]
42. Zhou, H.Y.; Beevers,  C.S.;  Huang, S.L. The  targets  of curcumin.  Curr.   Drug  Targets 2011, 12, 332–347. [CrossRef]
44. Cheng, A.-L.; Hsu, C.-H.; Lin, J.-K.;  Hsu, M.-M.;   Ho,  Y.-F.; Shen,  T.-S.; Ko,  J.-Y.;   Lin, J.-T.;  Lin, B.-R.; Ming-Shiang, W. Phase i clinical trial of curcumin, a chemopreventive agent, in patients  with  high-risk or pre-malignant lesions.  Anticancer Res. 2001, 21, 2895–2900.
46. Lao, C.D.; Ruffin, M.T.;  Normolle, D.;  Heath, D.D.; Murray, S.I.;  Bailey, J.M.;  Boggs, M.E.;  Crowell,  J.; Rock, C.L.; Brenner,  D.E. Dose escalation of a curcuminoid formulation. BMC Complementary Altern. Med. 2006, 6, 10. [CrossRef]

44. Rodriguez, J.C.; Santibanez, D.;  Narayanan, S.; Dave, A.  Ginger and  curcumin in cancer  prevention and health promotion. Bot. Med. Clin. Pract. 2008, 321.
46. Authority, E.F.S.  Refined exposure assessment for curcumin (e 100). EFSA J. 2014, 12, 3876. [CrossRef]
48. Hewlings, S.; Kalman, D. Curcumin: A review of its’ effects on human health. Foods 2017, 6, 92. [CrossRef] [PubMed]
50. DiSilvestro, R.A.; Joseph, E.;  Zhao, S.; Bomser, J. Diverse effects of a low  dose  supplement of lipidated curcumin in healthy  middle aged people.  Nutr.  J. 2012, 11, 79. [CrossRef] [PubMed]
52. Cianfruglia, L.; Minnelli, C.;  Laudadio, E.; Scire,  A.;  Armeni, T. Side  effects of curcumin: Epigenetic and antiproliferative implications for normal  dermal  fibroblast  and breast cancer cells.  Antioxidants 2019, 8, 382. [CrossRef] [PubMed]
54. Araiza-Calahorra, A.; Akhtar, M.; Sarkar, A. Recent advances in emulsion-based delivery approaches for curcumin: From  encapsulation to bioaccessibility. Trends Food Sci. Technol. 2018, 71, 155–169. [CrossRef]
55. Grynkiewicz, G.; S´lifirski, P. Curcumin and curcuminoids in quest for medicinal status.  Acta Biochim. Pol. 2012, 59, 201–212. [CrossRef]  

51. Bernabé-Pineda, M.; Ram´lrez-Silva, M.a.T.;  Romero-Romo, M.; González-Vergara, E.; Rojas-Hernández, A. Determination of acidity constants of curcumin in  aqueous solution and  apparent rate constant  of its decomposition. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2004, 60, 1091–1097. [CrossRef]

52. Schneider, C.; Gordon, O.N.; Edwards, R.L.; Luis, P.B.  Degradation of curcumin:  From mechanism to biological implications. J. Agric. Food Chem. 2015, 63, 7606–7614. [CrossRef]
53. Wang, Y.-J.; Pan, M.-H.; Cheng, A.-L.; Lin, L.-I.; Ho,  Y.-S.; Hsieh, C.-Y.; Lin, J.-K.  Stability of curcumin in buffer solutions  and characterization of its degradation products.  J. Pharm. Biomed. Anal. 1997, 15, 1867–1876. [CrossRef]
54. Zheng, B.; Peng, S.; Zhang, X.; McClements, D.J. Impact of delivery system type on curcumin bioaccessibility: Comparison of curcumin-loaded nanoemulsions with commercial curcumin supplements. J. Agric. Food Chem. 2018, 66, 10816–10826. [CrossRef]

55. Nelson, K.M.;  Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli,  G.F.; Walters, M.A.  The essential medicinal chemistry of curcumin: Miniperspective. J. Med. Chem. 2017, 60, 1620–1637. [CrossRef] [PubMed]
56. Priyadarsini, K.I. Photophysics, photochemistry and photobiology of curcumin:  Studies from  organic solutions,  bio-mimetics and living cells. J. Photochem. Photobiol. C Photochem. Rev. 2009, 10, 81–95. [CrossRef]
57. Wright, L.; Frye, J.B.; Gorti,  B.; Timmermann, B.N.;  Funk, J.L. Bioactivity of turmeric-derived curcuminoids and related metabolites in breast cancer.  Curr. Pharm. Des. 2013, 19, 6218–6225. [CrossRef] [PubMed]
58. Ogiwara, T.; Satoh, K.; Kadoma, Y.; Murakami, Y.; Unten, S.; Atsumi, T.; Sakagami, H.; Fujisawa, S. Radical scavenging activity and cytotoxicity of ferulic acid.  Anticancer Res. 2002, 22, 2711–2717. [PubMed]
59. Tai, A.; Sawano, T.; Yazama, F.;  Ito, H.  Evaluation of antioxidant activity of vanillin by  using multiple antioxidant assays.  Biochim. Biophys. Acta 2011, 1810, 170–177. [CrossRef]
60. Gordon, O.N.; Schneider, C.  Vanillin and  ferulic acid:  Not  the major  degradation products of curcumin. Trends Mol. Med. 2012, 18, 361–363. [CrossRef]

61. Gordon, O.N.; Luis, P.B.; Sintim, H.O.;  Schneider, C. Unraveling curcumin degradation autoxidation proceeds through spiroepoxide and vinylether intermediates en route to the main  bicyclopentadione. J. Biol. Chem. 2015, 290, 4817–4828. [CrossRef]

62. Griesser, M.; Pistis, V.; Suzuki, T.; Tejera, N.; Pratt, D.A.; Schneider, C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin. J. Biol. Chem. 2011, 286, 1114–1124. [CrossRef]
64. Sanidad, K.Z.; Zhu, J.; Wang, W.; Du, Z.; Zhang, G. Effects of stable degradation products of curcumin on cancer cell proliferation and inflammation. J. Agric. Food Chem. 2016, 64, 9189–9195. [CrossRef]
66. McClements, D.J.; Li, F.;  Xiao, H.  The  nutraceutical bioavailability  classification scheme:   Classifying nutraceuticals according to factors limiting their oral bioavailability. Annu.  Rev. Food Sci. Technol. 2015, 6, 299–327. [CrossRef] [PubMed]

65. Ravindranath, V.; Chandrasekhara, N.  Absorption and tissue  distribution of curcumin in rats.  Toxicology 1980, 16, 259–265. [CrossRef]

66. Sanidad, K.Z.; Sukamtoh, E.; Xiao, H.; McClements, D.J.; Zhang, G.D. Curcumin: Recent advances in the development of strategies to improve oral bioavailability. Annu.  Rev. Food Sci. Technol. 2019, 10, 597–617.[CrossRef]
68. Jain, G.; Patil, U.K. Strategies for enhancement  of bioavailability of medicinal agents with  natural  products. Int. J. Pharm. Sci. Res. 2015, 6, 5315–5324.

68. Mollazadeh, S.; Sahebkar, A.; Hadizadeh, F.; Behravan,  J.; Arabzadeh, S. Structural and functional aspects of p-glycoprotein and its inhibitors. Life Sci. 2018, 214, 118–123. [CrossRef] [PubMed]
70. Zhou, S.F.; Lim, L.Y.; Chowbay, B. Herbal modulation of p-glycoprotein. Drug Metab. Rev. 2004, 36, 57–104. [CrossRef]
72. Singh, D.V.;  Godbole, M.M.; Misra, K. A plausible explanation for enhanced bioavailability of p-gp substrates in presence of piperine:  Simulation for next generation of p-gp  inhibitors. J. Mol. Modeling 2013, 19, 227–238. [CrossRef]
74. Prasad, S.; Tyagi, A.K.; Aggarwal, B.B. Recent developments in delivery, bioavailability, absorption and metabolism  of curcumin: The golden pigment from golden spice. Cancer Res. Treat. 2014, 46, 2–18. [CrossRef]
76. Ireson, C.R.; Jones, D.J.; Orr, S.; Coughtrie, M.W.; Boocock,  D.J.; Williams, M.L.;  Farmer,  P.B.; Steward, W.P.; Gescher, A.J.  Metabolism of  the cancer  chemopreventive agent  curcumin in  human and  rat  intestine. Cancer Epidemiol. Prev. Biomark. 2002, 11, 105–111.  

73. Ireson, C.;  Orr,  S.; Jones, D.J.;  Verschoyle, R.;  Lim, C.-K.; Luo, J.-L.;  Howells, L.;  Plummer, S.; Jukes,  R.; Williams, M.  Characterization of  metabolites of  the  chemopreventive agent  curcumin in  human and rat hepatocytes and  in  the rat in vivo, and  evaluation of their  ability to inhibit phorbol ester-induced prostaglandin e2 production. Cancer Res. 2001, 61, 1058–1064.
75. Asai, A.; Miyazawa, T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma.  Life Sci. 2000, 67, 2785–2793. [CrossRef]
77. Sharma, R.A.; Euden,  S.A.; Platton, S.L.; Cooke,  D.N.;  Shafayat, A.; Hewitt,  H.R.;  Marczylo, T.H.;  Morgan,  B.; Hemingway, D.; Plummer, S.M. Phase i clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin. Cancer Res. 2004, 10, 6847–6854. [CrossRef] [PubMed]
79. Dubey, S.K.; Sharma, A.K.; Narain, U.; Misra, K.; Pati, U. Design, synthesis and characterization of some bioactive conjugates of curcumin with  glycine, glutamic acid,  valine and  demethylenated piperic acid and  study of their antimicrobial and  antiproliferative properties. Eur.  J. Med. Chem. 2008, 43, 1837–1846. [CrossRef] [PubMed]
81. Huang, Y.; Cao, S.; Zhang, Q.; Zhang, H.; Fan, Y.; Qiu,  F.; Kang, N. Biological and pharmacological effects of hexahydrocurcumin, a metabolite  of curcumin.  Arch.  Biochem. Biophys. 2018, 646, 31–37.  [CrossRef] [PubMed]
83. Srimuangwong, K.; Tocharus, C.; Chintana, P.Y.; Suksamrarn, A.; Tocharus, J. Hexahydrocurcumin enhances inhibitory effect of 5-fluorouracil on ht-29 human colon cancer cells.  World J. Gastroenterol. 2012, 18, 2383. [CrossRef]
85. Chen, C.-Y.; Yang, W.-L.; Kuo, S.-Y.  Cytotoxic activity and cell cycle analysis of hexahydrocurcumin on sw 480 human colorectal cancer cells.  Nat. Prod. Commun. 2011, 6, 1671–1672. [CrossRef]

80. Zhang, Z.; Luo, D.; Xie, J.; Lin, G.; Zhou, J.; Liu, W.; Li, H.; Yi, T.; Su, Z.; Chen,  J. Octahydrocurcumin, a final hydrogenated metabolite of curcumin, possesses superior anti-tumor activity through induction of cellular apoptosis. Food Funct. 2018, 9, 2005–2014. [CrossRef]
82. Luo,  D.-D.; Chen,  J.-F.; Liu, J.-J.; Xie, J.-H.; Zhang, Z.-B.;  Gu, J.-Y.; Zhuo, J.-Y.; Huang, S.; Su, Z.-R.; Sun, Z.-H. Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against  acetaminophen-induced liver  injury: Role of cyp2e1 and keap1-nrf2  pathway. Food Chem. Toxicol. 2019, 123, 349–362. [CrossRef]

82. Shoji,  M.; Nakagawa, K.;  Watanabe, A.;  Tsuduki, T.; Yamada, T.; Kuwahara, S.; Kimura, F.; Miyazawa, T. Comparison of the effects of curcumin and curcumin glucuronide in human hepatocellular carcinoma  hepg2 cells.  Food Chem. 2014, 151, 126–132. [CrossRef]

83. Shen, L.;  Liu, C.-C.; An, C.-Y.; Ji, H.-F. How does curcumin work with  poor  bioavailability? Clues from experimental and theoretical studies.  Sci. Rep. 2016, 6, 20872. [CrossRef]
85. Perkins, S.; Verschoyle, R.D.; Hill, K.; Parveen, I.; Threadgill, M.D.; Sharma, R.A.; Williams, M.L.; Steward, W.P.; Gescher, A.J. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model  of familial adenomatous polyposis. Cancer Epidemiol. Prev. Biomark. 2002, 11, 535–540.
87. Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine  & curcumin following oral intake in rats. Indian J. Med. Res. 2010, 131, 682–691. [PubMed]
89. Ravindranath, V.; Chandrasekhara, N. Metabolism of curcumn-studies with [3 h] curcumin. Toxicology 1981, 22, 337–344. [CrossRef]

87. Pan, M.-H.; Huang, T.-M.; Lin, J.-K.  Biotransformation of curcumin through reduction and glucuronidation in mice.  Drug Metab. Dispos. 1999, 27, 486–494. [PubMed]
89. Kakran, M.; Sahoo, N.G.; Tan, I.-L.; Li, L. Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods. J. Nanoparticle Res. 2012, 14, 757. [CrossRef]
91. Yadav, D.;  Kumar, N.  Nanonization of  curcumin by  antisolvent precipitation:  Process   development, characterization, freeze drying and stability performance. Int. J. Pharm. 2014, 477, 564–577. [CrossRef]
93. Patel, A.; Hu, Y.; Tiwari, J.K.; Velikov, K.P.  Synthesis  and characterisation  of zein-curcumin colloidal particles. Soft Mater 2010, 6, 6192–6199. [CrossRef]

91. Khan, F.I.; Ghoshal, A.K. Removal of volatile  organic  compounds from polluted air.  J. Loss Prev. Process Ind. 2000, 13, 527–545. [CrossRef]

92. Mozafari, M.R. Liposomes: An  overview of manufacturing techniques.  Cell. Mol. Biol. Lett. 2005, 10, 711.
94. Lesoin, L.; Crampon, C.; Boutin,  O.; Badens, E. Preparation of liposomes using the supercritical anti-solvent (sas) process and comparison with  a conventional method.  J. Supercrit. Fluids 2011, 57, 162–174. [CrossRef] 

115. Ginty, P.J.; Whitaker, M.J.; Shakesheff, K.M.; Howdle,  S.M. Drug delivery goes supercritical. Mater.  Today 2005, 8, 42–48. [CrossRef]
117. Peng, S.; Li, Z.;  Zou, L.;  Liu, W.; Liu, C.;  McClements, D.J.  Enhancement of curcumin bioavailability by encapsulation in sophorolipid-coated nanoparticles:  An  in vitro  and in vivo study.  J. Agric. Food Chem. 2018, 66, 1488–1497. [CrossRef]
119. Cheng, C.; Peng,  S.; Li, Z.;  Zou, L.;  Liu, W.;  Liu, C.  Improved bioavailability of curcumin in liposomes prepared using a ph-driven, organic solvent-free, easily scalable  process.  RSC Adv. 2017, 7, 25978–25986. [CrossRef]
121. Pan, K.;  Luo, Y.;  Gan,  Y.;  Baek,  S.J.;  Zhong, Q.  Ph-driven encapsulation of curcumin in  self-assembled casein nanoparticles for enhanced dispersibility and bioactivity. Soft Matter 2014, 10, 6820–6830. [CrossRef] [PubMed]
123. Zhou, M.; Wang, T.; Hu, Q.; Luo, Y. Low density lipoprotein/pectin complex nanogels as potential oral delivery vehicles for curcumin. Food Hydrocoll. 2016, 57, 20–29. [CrossRef]
125. Zheng, B.; Zhang, X.; Peng, S.; McClements, D.J. Impact of delivery system format on curcumin bioaccessibility: Nanocrystals, nanoemulsion droplets, and natural oil bodies. Food Funct.  2019, 10, 4339–4349. [CrossRef] [PubMed]
127. Cabrera-Trujillo, M.A.; Sotelo-Díaz, L.I.; Quintanilla-Carvajal, M.X. Effect of amplitude and  pulse  in low frequency ultrasound on oil/water emulsions. DYNA 2016, 83, 63–68. [CrossRef]
129. Kim, H.N.; Suslick, K.S. The effects of ultrasound on crystals: Sonocrystallization and sonofragmentation. Crystals 2018, 8, 280. [CrossRef]
131. Zou, L.; Zheng, B.; Zhang, R.; Zhang, Z.;  Liu, W.; Liu, C.;  Xiao, H.;  McClements, D.J.  Food  matrix effects on nutraceutical bioavailability:  Impact of protein on curcumin bioaccessibility and  transformation in nanoemulsion delivery systems  and excipient nanoemulsions. Food Biophys. 2016, 11, 142–153. [CrossRef]
133. Zou, L.; Zheng, B.; Zhang, R.; Zhang, Z.; Liu, W.; Liu, C.; Zhang, G.; Xiao, H.; McClements, D.J. Influence of lipid phase  composition of excipient emulsions on curcumin solubility, stability, and  bioaccessibility. Food Biophys. 2016, 11, 213–225. [CrossRef]
135. Zhu, J.L.; Sanidad, K.Z.; Sukamtoh, E.; Zhang, G.D. Potential roles of chemical  degradation in the biological activities of curcumin. Food Funct. 2017, 8, 907–914. [CrossRef] [PubMed]
137. Kharat, M.; Skrzynski, M.; Decker, E.A.; McClements, D.J. Enhancement of chemical stability of curcumin- enriched oil-in-water emulsions: Impact of antioxidant type and concentration.  Food Chem. 2020, 320, 126653. [CrossRef] [PubMed]
139. Zou, L.Q.; Zheng, B.J.; Zhang, R.J.; Zhang, Z.P.; Liu, W.; Liu, C.M.; Xiao,  H.; McClements, D.J. Food-grade nanoparticles for encapsulation, protection and delivery of curcumin: Comparison of lipid, protein, and phospholipid  nanoparticles under simulated gastrointestinal conditions.  RSC Adv.  2016, 6, 3126–3136. [CrossRef]
141. Dai, L.;  Zhou, H.L.; Wei,  Y.;  Gao,  Y.X.; McClements, D.J.  Curcumin encapsulation in  zein-rhamnolipid composite  nanoparticles using a ph-driven method.  Food Hydrocoll. 2019, 93, 342–350. [CrossRef]
143. Yallapu, M.M.; Jaggi, M.; Chauhan, S.C.  Curcumin nanoformulations: A future  nanomedicine for cancer. Drug Discov. Today. 2012, 17, 71–80. [CrossRef]
145. del Castillo, M.L.R.; Lopez-Tobar, E.; Sanchez-Cortes, S.; Flores, G.; Blanch, G.P.  Stabilization of curcumin against photodegradation by encapsulation in gamma-cyclodextrin: A study  based on chromatographic and spectroscopic (raman  and uv-visible) data. Vib. Spectrosc. 2015, 81, 106–111. [CrossRef]
147. Price, L.C.; Buescher, R.W. Decomposition of turmeric curcuminoids as affected by light, solvent and oxygen. Food Biochem. 1996, 20, 125–133. [CrossRef]
149. Higaki, K.; Yata, T.; Sone, M.; Ogawara, K.; Kimura, T. Estimation of absorption enhancement by medium-chain fatty acids in rat large intestine.  Res. Commun. Mol. Pathol. Pharmacol. 2001, 109, 231–240.
151. Aungst, B.J. Intestinal permeation enhancers. J. Pharm. Sci. 2000, 89, 429–442. [CrossRef]
153. Patra, A.K.; Amasheh, S.; Aschenbach, J.R. Modulation of gastrointestinal barrier and  nutrient transport function  in farm animals by natural  plant bioactive compounds—A  comprehensive review. Crit. Rev. Food Sci. Nutr.  2019, 59, 3237–3266. [CrossRef]
155. McClements, D.J. Nanoparticle- and Microparticle-Based Delivery Systems: Encapsulation, Protection and Release of Active Components; CRC Press:  Boca Raton, FL, USA, 2014. 
156.  
157. McClements, D.J. Enhancing nutraceutical bioavailability through food matrix design.  Curr. Opin. Food Sci. 2015, 4, 1–6. [CrossRef]

116. Dordevic, V.; Balanc, B.; Belscak-Cvitanovic, A.; Levic, S.; Trifkovic, K.; Kalusevic, A.; Kostic, I.; Komes, D.; Bugarski, B.; Nedovic, V. Trends in encapsulation technologies for delivery of food bioactive compounds. Food Eng. Rev. 2015, 7, 452–490. [CrossRef]
118. Wang, Z.L. Bioavailability of organic compounds solubilized in nonionic  surfactant micelles.  Appl. Microbiol. Biotechnol. 2011, 89, 523–534. [CrossRef] [PubMed]

118. Kimpel, F.; Schmitt, J.J. Review:  Milk proteins as nanocarrier systems for  hydrophobic  nutraceuticals. Food Sci. 2015, 80, R2361–R2366. [CrossRef]
120. Livney, Y.D. Milk proteins as vehicles for bioactives.  Curr.   Opin.   Colloid Interface Sci.  2010, 15, 73–83. [CrossRef]
122. Richtering, W. Rheology and shear induced structures in surfactant solutions.  Curr. Opin. Colloid Interface Sci. 2001, 6, 446–450. [CrossRef]

121. Torchilin, V.P. Micellar nanocarriers: Pharmaceutical perspectives. Pharm. Res. 2007, 24, 1–16. [CrossRef]
123. Wang, X.Y.; Gao, Y. Effects of length  and  unsaturation of the alkyl chain  on the hydrophobic binding of curcumin with  tween micelles.  Food Chem. 2018, 246, 242–248. [CrossRef]
125. Pan, K.; Zhong, Q.; Baek, S.J. Enhanced dispersibility and bioactivity of curcumin by encapsulation in casein nanocapsules. J. Agric. Food Chem. 2013, 61, 6036–6043. [CrossRef]
127. Schiborr, C.; Kocher,  A.; Behnam, D.; Jandasek, J.; Toelstede, S.; Frank,  J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol. Nutr.  Food Res. 2014, 58, 516–527. [CrossRef]
129. Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S.W.;  Zarghami, N.;  Hanifehpour, Y.; Samiei, M.; Kouhi, M.; Nejati-Koshki, K. Liposome: Classification, preparation, and applications. Nanoscale Res. Lett. 2013, 8, 102. [CrossRef] [PubMed]

126. Chen, X.; Zou, L.-Q.; Niu, J.; Liu, W.; Peng,  S.-F.;  Liu, C.-M. The  stability, sustained release  and  cellular antioxidant activity of curcumin nanoliposomes. Molecules 2015, 20, 14293–14311. [CrossRef] [PubMed]
128. Jin, H.-H.; Lu, Q.; Jiang, J.-G. Curcumin liposomes  prepared  with milk  fat globule  membrane phospholipids and soybean lecithin.  J. Dairy Sci. 2016, 99, 1780–1790. [CrossRef] [PubMed]
130. Takahashi, M.; Uechi, S.;  Takara, K.;  Asikin, Y.;  Wada, K. Evaluation of an  oral  carrier  system  in  rats: Bioavailability and antioxidant properties of liposome-encapsulated curcumin. J. Agric. Food Chem. 2009, 57, 9141–9146. [CrossRef] [PubMed]

129. Li, C.; Zhang, Y.; Su, T.; Feng, L.; Long, Y.; Chen,  Z. Silica-coated flexible  liposomes  as a nanohybrid delivery system for enhanced  oral bioavailability of curcumin. Int. J. Nanomed. 2012, 7, 5995. [CrossRef] [PubMed]
131. Bergonzi, M.; Hamdouch, R.; Mazzacuva, F.; Isacchi, B.; Bilia,  A. Optimization, characterization and in vitro evaluation of curcumin microemulsions. LWT Food Sci. Technol. 2014, 59, 148–155. [CrossRef]
133. Setthacheewakul, S.; Mahattanadul, S.;  Phadoongsombut, N.;  Pichayakorn, W.;  Wiwattanapatapee, R. Development  and   evaluation  of  self-microemulsifying liquid  and   pellet   formulations  of  curcumin, and absorption studies  in rats. Eur. J. Pharm. Biopharm. 2010, 76, 475–485. [CrossRef] [PubMed]

132. Hu, L.; Jia, Y.;  Niu, F.;  Jia, Z.;  Yang, X.;  Jiao,  K. Preparation and  enhancement of oral  bioavailability  of curcumin using microemulsions vehicle.  J. Agric. Food Chem. 2012, 60, 7137–7141. [CrossRef] [PubMed]
134. McClements, D.J. Food Emulsions: Principles, Practices, and Techniques; CRC Press: Boca Raton, FL,  USA, 2015.
136. McClements, D.J. Nanoemulsions  versus  microemulsions:   Terminology,  differences, and  similarities. Soft Matter 2012, 8, 1719–1729. [CrossRef]

135. Zheng, B.; Lin, H.; Zhang, X.; McClements, D.J. Fabrication of curcumin-loaded dairy  milks using  the ph-shift method:  Formation, stability, and bioaccessibility. J. Agric. Food Chem. 2019, 67, 12245–12254. [CrossRef] [PubMed]
137. Ma, P.;  Zeng, Q.;  Tai, K.;  He,  X.;  Yao, Y.;  Hong, X.;  Yuan, F.  Preparation of curcumin-loaded emulsion using high pressure homogenization: Impact of oil phase and concentration on physicochemical stability. LWT 2017, 84, 34–46. [CrossRef]
139. Zou, L.; Zheng, B.; Liu, W.; Liu, C.; Xiao, H.; McClements, D.J. Enhancing nutraceutical bioavailability using excipient  emulsions: Influence  of lipid droplet size on solubility and bioaccessibility of powdered curcumin. J. Funct. Foods 2015, 15, 72–83. [CrossRef]  

138. Onodera, T.; Kuriyama, I.; Andoh, T.; Ichikawa, H.; Sakamoto, Y.; Lee-Hiraiwa, E.; Mizushina, Y. Influence of particle size on the in vitro  and in vivo anti-inflammatory and anti-allergic activities of a curcumin lipid nanoemulsion. Int. J. Mol. Med. 2015, 35, 1720–1728. [CrossRef] [PubMed]
140. Mishra, V.; Bansal, K.K.; Verma, A.;  Yadav, N.;  Thakur, S.;  Sudhakar, K.;  Rosenholm, J.M.  Solid lipid nanoparticles: Emerging colloidal nano  drug delivery systems. Pharmaceutics 2018, 10, 191.  [CrossRef] [PubMed]
142. Müller, R.H.;  Radtke,  M.; Wissing, S.A.  Solid  lipid nanoparticles (sln) and nanostructured lipid carriers  (nlc) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev. 2002, 54, S131–S155. [CrossRef]

141. Helgason, T.; Salminen, H.; Kristbergsson, K.; McClements, D.J.; Weiss, J. Formation of transparent solid lipid nanoparticles by microfluidization: Influence of lipid physical state on appearance. J. Colloid Interface Sci. 2015, 448, 114–122. [CrossRef]

142. Xue, J.; Wang, T.; Hu, Q.; Zhou, M.; Luo, Y. Insight into natural biopolymer-emulsified solid lipid nanoparticles for encapsulation of curcumin: Effect of loading methods. Food Hydrocoll. 2018, 79, 110–116. [CrossRef]
144. Kakkar, V.; Singh, S.; Singla, D.; Kaur, I.P. Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol. Nutr. Food Res. 2011, 55, 495–503. [CrossRef]
146. Sadegh Malvajerd, S.; Azadi, A.; Izadi, Z.; Kurd, M.; Dara, T.; Dibaei,  M.; Sharif  Zadeh, M.; Akbari Javar, H.; Hamidi, M. Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: Preparation, optimization,  and  pharmacokinetic evaluation.   ACS Chem.   Neurosci.   2018, 10, 728–739. [CrossRef]
148. Gota, V.S.; Maru,  G.B.;  Soni,  T.G.; Gandhi, T.R.; Kochar, N.;  Agarwal, M.G.  Safety  and  pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients  and  healthy volunteers. J. Agric. Food Chem. 2010, 58, 2095–2099. [CrossRef]
150. McClements, D.J. Recent progress in hydrogel delivery systems for improving nutraceutical bioavailability. Food Hydrocoll. 2017, 68, 238–245. [CrossRef]

147. Zheng, B.; Zhang, Z.; Chen, F.; Luo, X.; McClements, D.J. Impact of delivery system type on curcumin stability: Comparison of curcumin degradation in aqueous solutions, emulsions, and hydrogel beads. Food Hydrocoll. 2017, 71, 187–197. [CrossRef]

148. Mohammadian, M.; Salami, M.; Momen, S.; Alavi, F.; Emam-Djomeh, Z. Fabrication of curcumin-loaded whey protein microgels: Structural properties,  antioxidant activity, and in vitro  release behavior.  LWT 2019, 103, 94–100. [CrossRef]

149. Zhang, Z.; Zhang, R.; Zou, L.; Chen, L.; Ahmed, Y.; Al Bishri, W.; Balamash, K.; McClements, D.J. Encapsulation of curcumin in polysaccharide-based hydrogel beads: Impact of bead type on lipid digestion and curcumin bioaccessibility. Food Hydrocoll. 2016, 58, 160–170. [CrossRef]
151. Esmaili, M.; Ghaffari, S.M.; Moosavi-Movahedi, Z.;  Atri, M.S.;  Sharifizadeh, A.;  Farhadi, M.; Yousefi, R.; Chobert, J.-M.;  Haertlé, T.; Moosavi-Movahedi, A.A. Beta casein-micelle as a nano  vehicle for solubility enhancement of curcumin; food industry application. LWT Food Sci. Technol. 2011, 44, 2166–2172. [CrossRef]
153. Purpura, M.; Lowery, R.P.; Wilson, J.M.; Mannan, H.;  Münch, G.; Razmovski-Naumovski, V. Analysis of different innovative formulations of curcumin for improved relative  oral bioavailability in human subjects. Eur. J. Nutr.  2018, 57, 929–938. [CrossRef] [PubMed]
155. Zheng, B.; Zhang, X.; Lin, H.; McClements, D.J. Loading natural emulsions with  nutraceuticals using the ph-driven method:  Formation & stability of curcumin-loaded soybean oils  bodies.   Food Funct.  2019, 10, 5473–5484.