Food-grade nanostructured delivery systems for oral administration of astaxanthin: Bioprocessing strategies and therapeutic applications

1. Baralic, I. et al. Effect of astaxanthin supplementation on salivary IgA, oxidative stress, and inflammation in young soccer players. Evid.-based Complement. Altern. Med. 2015, 783761 (2015).

   Google Scholar 

2. Hu, J., Nagarajan, D., Zhang, Q., Chang, J.-S. & Lee, D.-J. Heterotrophic cultivation of microalgae for pigment production: a review. Biotechnol. Adv. 36, 54–67 (2018).

   Google Scholar 

3. Chuyen, H. V., Roach, P. D., Golding, J. B., Parks, S. E. & Nguyen, M. H. Encapsulation of carotenoid-rich oil from Gac peel: optimisation of the encapsulating process using a spray drier and the storage stability of encapsulated powder. Powder Technol. 344, 373–379 (2019).

   Google Scholar 

4. Taksima, T., Limpawattana, M. & Klaypradit, W. Astaxanthin encapsulated in beads using ultrasonic atomizer and application in yogurt as evaluated by consumer sensory profile. LWT-Food Sci. Technol. 62, 431–437 (2015).

   Google Scholar 

5. Higuera-Ciapara, I., Felix-Valenzuela, L. & Goycoolea, F. Astaxanthin: a review of its chemistry and applications. Crit. Rev. Food Sci. Nutr. 46, 185–196 (2006).

   Google Scholar 

6. Tirado, D. F. et al. Astaxanthin encapsulation in ethyl cellulose carriers by continuous supercritical emulsions extraction: a study on particle size, encapsulation efficiency, release profile and antioxidant activity. J. Supercrit. Fluids 150, 128–136 (2019).

   Google Scholar 

7. Liu, G. et al. Enhancing the stability of astaxanthin by encapsulation in poly-(l-lactic acid) microspheres using a supercritical anti-solvent process. Particuology 44, 54–62 (2019).

   Google Scholar 

8. Qiang, M., Pang, X., Ma, D., Ma, C. & Liu, F. Effect of membrane surface modification using chitosan hydrochloride and lactoferrin on the properties of astaxanthin-loaded liposomes. Molecules 25, 610 (2020).

   Google Scholar 

9. Kulkarni, S. A. & Feng, S.-S. Effects of particle size and surface modification on cellular uptake and biodistribution of polymeric nanoparticles for drug delivery. Pharm. Res. 30, 2512–2522 (2013).

   Google Scholar 

10. Sangsuriyawong, A., Limpawattana, M., Siriwan, D. & Klaypradit, W. Properties and bioavailability assessment of shrimp astaxanthin loaded liposomes. Food Sci. Biotechnol. 28, 529–537 (2019).

    Google Scholar 

11. Rostamabadi, H., Falsafi, S. R. & Jafari, S. M. Nanoencapsulation of carotenoids within lipid-based nanocarriers. J. Control. Release 298, 38–67 (2019).

    Google Scholar 

12. Hu, Q., Hu, S., Fleming, E., Lee, J.-Y. & Luo, Y. Chitosan-caseinate-dextran ternary complex nanoparticles for potential oral delivery of astaxanthin with significantly improved bioactivity. Int. J. Biol. Macromol. 151, 747–756 (2020).

    Google Scholar 

13. Rabiee, N. et al. Multifunctional 3D hierarchical bioactive green carbon-based nanocomposites. ACS Sustain. Chem. Eng. 9, 8706–8720 (2021).

    Google Scholar 

14. Rabiee, N. et al. Diatoms with invaluable applications in nanotechnology, biotechnology, and biomedicine: recent advances. ACS Biomater. Sci. Eng. 7, 3053–3068 (2021).

    Google Scholar 

15. Rahimnejad, M. et al. Prevascularized micro-/nano-sized spheroid/bead aggregates for vascular tissue engineering. Nano-Micro Lett. 13, 182 (2021).

    Google Scholar 

16. Zare, H. et al. Carbon nanotubes: smart drug/gene delivery carriers. Int. J. Nanomed. 1681–1706 (2021). https://doi.org/10.2147/IJN.S299448. eCollection 2021.

17. Balietti, M. et al. The effect of astaxanthin on the aging rat brain: gender-related differences in modulating inflammation. J. Sci. Food Agric. 96, 615–618 (2016).

    Google Scholar 

18. Angell, A., de Nys, R., Mangott, A. & Vucko, M. J. The effects of concentration and supplementation time of natural and synthetic sources of astaxanthin on the colouration of the prawn Penaeus monodon. Algal Res. 35, 577–585 (2018).

    Google Scholar 

19. Jin, Y. et al. The alcohol dehydrogenase gene family in melon (Cucumis melo L.): bioinformatic analysis and expression patterns. Front. Plant Sci. 7, 670 (2016).

    Google Scholar 

20. Bjerkeng, B., Peisker, M., Von Schwartzenberg, K., Ytrestøyl, T. & Åsgård, T. Digestibility and muscle retention of astaxanthin in Atlantic salmon, Salmo salar, fed diets with the red yeast Phaffia rhodozyma in comparison with synthetic formulated astaxanthin. Aquaculture 269, 476–489 (2007).

    Google Scholar 

21. Ravishankar, G. A. & Rao A. R. Global Perspectives on Astaxanthin: from Industrial Production to Food, Health, and Pharmaceutical Applications (Academic Press, 2021).

22. Rodríguez-Sifuentes, L., Marszalek, J. E., Hernández-Carbajal, G. & Chuck-Hernández, C. Importance of downstream processing of natural astaxanthin for pharmaceutical application. Front. Chem. Eng. 2, 601483 (2021).

    Google Scholar 

23. Jafari, Z. et al. Nanotechnology-abetted astaxanthin formulations in multimodel therapeutic and biomedical applications. J. Med. Chem. 65, 2–36 (2021).

    Google Scholar 

24. Li, X. et al. Biotechnological production of astaxanthin from the microalga Haematococcus pluvialis. Biotechnol. Adv. 43, 107602 (2020).

    Google Scholar 

25. Zhao, L. et al. Isomerization of trans-astaxanthin induced by copper (II) ion in ethanol. J. Agric. Food Chem. 53, 9620–9623 (2005).

    Google Scholar 

26. Honda, M., Kageyama, H., Hibino, T., Sowa, T. & Kawashima, Y. Efficient and environmentally friendly method for carotenoid extraction from Paracoccus carotinifaciens utilizing naturally occurring Z-isomerization-accelerating catalysts. Process Biochem. 89, 146–154 (2020).

    Google Scholar 

27. Viazau, Y. V. et al. E/Z isomerization of astaxanthin and its monoesters in vitro under the exposure to light or heat and in overilluminated Haematococcus pluvialis cells. Bioresour. Bioprocess. 8, 55 (2021).

    Google Scholar 

28. Yang, C. et al. Bioaccessibility, cellular uptake, and transport of astaxanthin isomers and their antioxidative effects in human intestinal epithelial Caco-2 cells. J. Agric. Food Chem. 65, 10223–10232 (2017).

    Google Scholar 

29. Honda, M. et al. Improved carotenoid processing with sustainable solvents utilizing Z-isomerization-induced alteration in physicochemical properties: a review and future directions. Molecules 24, 2149 (2019).

    Google Scholar 

30. Yang, C. et al. Anti-inflammatory effects of different astaxanthin isomers and the roles of lipid transporters in the cellular transport of astaxanthin isomers in Caco-2 cell monolayers. J. Agric. Food Chem. 67, 6222–6231 (2019).

    Google Scholar 

31. Liu, X., Chen, X., Liu, H. & Cao, Y. Antioxidation and anti-aging activities of astaxanthin geometrical isomers and molecular mechanism involved in Caenorhabditis elegans. J. Funct. Foods 44, 127–136 (2018).

    Google Scholar 

32. Honda, M., Maeda, H., Fukaya, T. & Goto, M. Effects of Z-isomerization on the bioavailability and functionality of carotenoids: a review. Prog. Carotenoid Res. 139–159. https://doi.org/10.5772/intechopen.78309 (2018).

33. Liu, X. & Osawa, T. Cis astaxanthin and especially 9-cis astaxanthin exhibits a higher antioxidant activity in vitro compared to the all-trans isomer. Biochem. Biophys. Res. Commun. 357, 187–193 (2007).

    Google Scholar 

34. Yang, C. et al. Rapid and efficient conversion of all-E-astaxanthin to 9 Z-and 13 Z-isomers and assessment of their stability and antioxidant activities. J. Agric. Food Chem. 65, 818–826 (2017).

    Google Scholar 

35. Niu, T. et al. Astaxanthin induces the Nrf2/HO-1 antioxidant pathway in human umbilical vein endothelial cells by generating trace amounts of ROS. J. Agric. Food Chem. 66, 1551–1559 (2018).

    Google Scholar 

36. Young, I. & Woodside, J. Antioxidants in health and disease. J. Clin. Pathol. 54, 176–186 (2001).

    Google Scholar 

37. Halliwell, B. Biochemistry of oxidative stress. Biochem. Soc. Trans. 35, 1147–1150 (2007).

    Google Scholar 

38. Santos-Sánchez, N. F., Hern ndez-Carlos, B., Torres-Ariño, A. & Salas-Coronado, R. Astaxanthin and its formulations as potent oxidative stress inhibitors. Pharmacogn. Rev. 14, 8–15 (2020).

    Google Scholar 

39. Rao, A. R., Sarada, R., Shylaja, M. D. & Ravishankar, G. Evaluation of hepatoprotective and antioxidant activity of astaxanthin and astaxanthin esters from microalga—Haematococcus pluvialis. J. Food Sci. Technol. 52, 6703–6710 (2015).

    Google Scholar 

40. Wu, D., Xu, H., Chen, J. & Zhang, L. Effects of astaxanthin supplementation on oxidative stress. Int. J. Vitam. Nutr. Res. 90, 179–194 (2020).

    Google Scholar 

41. Nowak, M. et al. Concentration dependence of anti-and pro-oxidant activity of polyphenols as evaluated with a light-emitting Fe²⁺–Egta–H₂O₂ system. Molecules 27, 3453 (2022).

    Google Scholar 

42. Ranga, R., Sarada, A. R., Baskaran, V. & Ravishankar, G. A. Identification of carotenoids from green alga Haematococcus pluvialis by HPLC and LC–MS (APCI) and their antioxidant properties. J. Microbiol. Biotechnol. 19, 1333–1341 (2009).

    Google Scholar 

43. Ranga Rao, A., Raghunath Reddy, R., Baskaran, V., Sarada, R. & Ravishankar, G. Characterization of microalgal carotenoids by mass spectrometry and their bioavailability and antioxidant properties elucidated in rat model. J. Agric. Food Chem. 58, 8553–8559 (2010).

    Google Scholar 

44. Hix, L. M. et al. Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative. Carcinogenesis 26, 1634–1641 (2005).

    Google Scholar 

45. Parisi, V. et al. Group CS. Carotenoids and antioxidants in age-related maculopathy Italian study: multifocal electroretinogram modifications after 1 year. Ophthalmology 115, 324–33.e2 (2008).

    Google Scholar 

46. Jyonouchi, H., Zhang, L., Gross, M. & Tomita, Y. Immunomodulating actions of carotenoids: enhancement of in vivo and in vitro antibody production to T-dependent antigens. Nutr. Cancer 21, 47–58 (1994).

    Google Scholar 

47. Lin, K.-H. et al. Astaxanthin, a carotenoid, stimulates immune responses by enhancing IFN-γ and IL-2 secretion in primary cultured lymphocytes in vitro and ex vivo. Int. J. Mol. Sci. 17, 44 (2015).

    Google Scholar 

48. Shatoor, A. S. & Al Humayed, S. Astaxanthin ameliorates high-fat diet-induced cardiac damage and fibrosis by upregulating and activating SIRT1. Saudi J. Biol. Sci. 28, 7012–7021 (2021).

    Google Scholar 

49. Coombes, J. S., Sharman, J. E. & Fassett, R. G. Astaxanthin has no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients: a randomized controlled trial (the XANTHIN trial). Am. J. Clin. Nutr. 103, 283–289 (2016).

    Google Scholar 

50. Brown, D. R., Gough, L. A., Deb, S. K., Sparks, S. A. & McNaughton, L. R. Astaxanthin in exercise metabolism, performance and recovery: a review. Front. Nutr. 4, 76 (2018).

    Google Scholar 

51. Kato, T. et al. Effects of 3-month astaxanthin supplementation on cardiac function in heart failure patients with left ventricular systolic dysfunction—a pilot study. Nutrients 12, 1896 (2020).

    Google Scholar 

52. Speranza, L. et al. Astaxanthin treatment reduced oxidative induced pro-inflammatory cytokines secretion in U937: SHP-1 as a novel biological target. Mar. Drugs 10, 890–899 (2012).

    Google Scholar 

53. Song, X. -d et al. Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol. Pharm. Bull. 34, 839–844 (2011).

    Google Scholar 

54. Kim, K.-N., Heo, S.-J., Kang, S.-M., Ahn, G. & Jeon, Y.-J. Fucoxanthin induces apoptosis in human leukemia HL-60 cells through a ROS-mediated Bcl-xL pathway. Toxicol. Vitr. 24, 1648–1654 (2010).

    Google Scholar 

55. Peng, C.-H., Chang, C.-H., Peng, R. Y. & Chyau, C.-C. Improved membrane transport of astaxanthine by liposomal encapsulation. Eur. J. Pharm. Biopharm. 75, 154–161 (2010).

    Google Scholar 

56. Al-Amin, M. M. et al. The antioxidant effect of astaxanthin is higher in young mice than aged: a region specific study on brain. Metab. Brain Dis. 30, 1237–1246 (2015).

    Google Scholar 

57. Ying, C. -J et al. Anti-inflammatory effect of astaxanthin on the sickness behavior induced by diabetes mellitus. Cell. Mol. Neurobiol. 35, 1027–1037 (2015).

    Google Scholar 

58. Suganuma, K., Nakajima, H., Ohtsuki, M. & Imokawa, G. Astaxanthin attenuates the UVA-induced up-regulation of matrix-metalloproteinase-1 and skin fibroblast elastase in human dermal fibroblasts. J. Dermatol. Sci. 58, 136–142 (2010).

    Google Scholar 

59. Tominaga, K., Hongo, N., Karato, M. & Yamashita, E. Cosmetic benefits of astaxanthin on humans subjects. Acta Biochim. Pol. 59, 43–47 (2012).

    Google Scholar 

60. Fakhri, S., Yosifova Aneva, I., Farzaei, M. H. & Sobarzo-Sánchez, E. The neuroprotective effects of astaxanthin: therapeutic targets and clinical perspective. Molecules 24, 2640 (2019).

    Google Scholar 

61. Galasso, C. et al. On the neuroprotective role of astaxanthin: new perspectives?. Mar. Drugs 16, 247 (2018).

    Google Scholar 

62. Lobos, P. et al. Astaxanthin protects primary hippocampal neurons against noxious effects of Aβ-oligomers. Neural Plast. 2016, 3456783 (2016).

    Google Scholar 

63. Davinelli, S., Nielsen, M. E. & Scapagnini, G. Astaxanthin in skin health, repair, and disease: a comprehensive review. Nutrients 10, 522 (2018).

    Google Scholar 

64. Li, X., Huang, R. & Luo, H. Exploring the mechanism of astaxanthin against lipopolysaccharide-induced acute lung injury by network pharmacology and experimental validation. Preprint at https://doi.org/10.21203/rs.3.rs-334157/v1 (2021).

65. Guo, S. et al. Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4/MyD88/NF-κB axis and upregulating heme oxygenase-1. Sci. Rep. 11, 6679 (2021).

    Google Scholar 

66. Suzuki, Y. et al. Suppressive effects of astaxanthin against rat endotoxin-induced uveitis by inhibiting the NF-κB signaling pathway. Exp. Eye Res. 82, 275–281 (2006).

    Google Scholar 

67. Giannaccare, G. et al. Clinical applications of astaxanthin in the treatment of ocular diseases: emerging insights. Mar. drugs 18, 239 (2020).

    Google Scholar 

68. Zaafan, M. & Abdelhamid, A. The cardioprotective effect of astaxanthin against isoprenaline-induced myocardial injury in rats: involvement of TLR4/NF-κB signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 25, 4099–4105 (2021).

    Google Scholar 

69. Zarneshan, S. N., Fakhri, S., Farzaei, M. H., Khan, H. & Saso, L. Astaxanthin targets PI3K/Akt signaling pathway toward potential therapeutic applications. Food Chem. Toxicol. 145, 111714 (2020).

    Google Scholar 

70. Krzemińska, J., Wronka, M., Młynarska, E., Franczyk, B., & Rysz, J. Arterial hypertension-oxidative stress and inflammation. Antioxidants (Basel, Switzerland) 11, 172 (2022).

71. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010).

    Google Scholar 

72. Fu, J. et al. Astaxanthin alleviates spinal cord ischemia-reperfusion injury via activation of PI3K/Akt/GSK-3 β pathway in rats. J. Orthop. Surg. Res. 15, 1–11 (2020).

    Google Scholar 

73. Odeberg, J. M., Lignell, Å, Pettersson, A. & Höglund, P. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. Eur. J. Pharm. Sci. 19, 299–304 (2003).

    Google Scholar 

74. Choi, H. D., Kang, H. E., Yang, S. H., Lee, M. G. & Shin, W. G. Pharmacokinetics and first-pass metabolism of astaxanthin in rats. Br. J. Nutr. 105, 220–227 (2011).

    Google Scholar 

75. Okada, Y., Ishikura, M. & Maoka, T. Bioavailability of astaxanthin in Haematococcus algal extract: the effects of timing of diet and smoking habits. Biosci. Biotechnol. Biochem. 73, 1928–1932 (2009).

    Google Scholar 

76. Østerlie, M., Bjerkeng, B. & Liaaen-Jensen, S. Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin. J. Nutr. Biochem. 11, 482–490 (2000).

    Google Scholar 

77. Yang, Y., Kim, B. & Lee, J. Y. Astaxanthin structure, metabolism, and health benefits. J. Hum. Nutr. Food Sci. 1, 1–1003 (2013).

    Google Scholar 

78. Coral-Hinostroza, G. N., Ytrestøyl, T., Ruyter, B. & Bjerkeng, B. Plasma appearance of unesterified astaxanthin geometrical E/Z and optical R/S isomers in men given single doses of a mixture of optical 3 and 3′ R/S isomers of astaxanthin fatty acyl diesters. Comp. Biochem. Physiol. Part C: Toxicol. Pharmacol. 139, 99–110 (2004).

    Google Scholar 

79. Chauhan, I., Yasir, M., Verma, M. & Singh, A. P. Nanostructured lipid carriers: a groundbreaking approach for transdermal drug delivery. Adv. Pharm. Bull. 10, 150 (2020).

    Google Scholar 

80. Islan, G. A., Cacicedo, M. L., Bosio, V. E. & Castro, G. R. Advances in smart nanopreparations for oral drug delivery. In Smart Pharmaceutical Nanocarriers Ch. 14 (ed., Torchilin, V.) 479–521 (World Scientific-Imperial College Press, 2016).

81. Martínez-Álvarez, Ó, Calvo, M. M. & Gómez-Estaca, J. Recent advances in astaxanthin micro/nanoencapsulation to improve its stability and functionality as a food ingredient. Mar. Drugs 18, 406 (2020).

    Google Scholar 

82. Yeung, A. W. K. et al. Big impact of nanoparticles: analysis of the most cited nanopharmaceuticals and nanonutraceuticals research. Curr. Res. Biotechnol. 2, 53–63 (2020).

    Google Scholar 

83. Date, A. A., Hanes, J. & Ensign, L. M. Nanoparticles for oral delivery: design, evaluation and state-of-the-art. J. Control. Release 240, 504–526 (2016).

    Google Scholar 

84. Fernandez, P., André, V., Rieger, J. & Kühnle, A. Nano-emulsion formation by emulsion phase inversion. Colloids Surf. A: Physicochem. Eng. Asp. 251, 53–58 (2004).

    Google Scholar 

85. Jaiswal, M., Dudhe, R. & Sharma, P. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech 5, 123–127 (2015).

    Google Scholar 

86. Jeevanandam, J., San Chan, Y. & Danquah, M. K. Nano-formulations of drugs: recent developments, impact and challenges. Biochimie 128, 99–112 (2016).

    Google Scholar 

87. Kumar, M., Bishnoi, R. S., Shukla, A. K. & Jain, C. P. Techniques for formulation of nanoemulsion drug delivery system: a review. Prev. Nutr. Food Sci. 24, 225 (2019).

    Google Scholar 

88. Haung, H.-Y. et al. A novel oral astaxanthin nanoemulsion from Haematococcus pluvialis induces apoptosis in lung metastatic melanoma. Oxid. Med. Cell. Longev. 2020, 2647670 (2020).

    Google Scholar 

89. Shen, X., Fang, T., Zheng, J. & Guo, M. Physicochemical properties and cellular uptake of astaxanthin-loaded emulsions. Molecules 24, 727 (2019).

    Google Scholar 

90. Domínguez-Hernández, C., García-Alvarado, M., García-Galindo, H., Salgado-Cervantes, M. & Beristáin, C. Stability, antioxidant activity and bioavailability of nano-emulsified astaxanthin. Rev. Mex. Ing. Quím. 15, 457–468 (2016).

    Google Scholar 

91. Affandi, M. M. M., Julianto, T. & Majeed, A. Enhanced oral bioavailability of astaxanthin with droplet size reduction. Food Sci. Technol. Res. 18, 549–554 (2012).

    Google Scholar 

92. Boonlao, N., Ruktanonchai, U. R. & Anal, A. K. Enhancing bioaccessibility and bioavailability of carotenoids using emulsion-based delivery systems. Colloids Surf. B: Biointerfaces 209, 112211 (2022).

    Google Scholar 

93. Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol. Sci. 30, 592–599 (2009).

    Google Scholar 

94. Gregoriadis, G. & Florence, A. T. Liposomes in drug delivery: clinical, diagnostic and ophthalmic potential. Drugs 45, 15–28 (1993).

    Google Scholar 

95. Kazi, K. M. et al. Niosome: a future of targeted drug delivery systems. J. Adv. Pharm. Technol. Res. 1, 374–380 (2010).

    Google Scholar 

96. Santonocito, D. et al. Astaxanthin-loaded stealth lipid nanoparticles (AST-SSLN) as potential carriers for the treatment of alzheimer’s disease: formulation development and optimization. Nanomaterials 11, 391 (2021).

    Google Scholar 

97. Muchow, M., Maincent, P. & Müller, R. H. Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for oral drug delivery. Drug Dev. Ind. Pharm. 34, 1394–1405 (2008).

    Google Scholar 

98. Talegaonkar, S. & Bhattacharyya, A. Potential of lipid nanoparticles (SLNs and NLCs) in enhancing oral bioavailability of drugs with poor intestinal permeability. AAPS PharmSciTech 20, 121 (2019).

    Google Scholar 

99. Wang, T., Hu, Q., Lee, J.-Y. & Luo, Y. Solid lipid–polymer hybrid nanoparticles by in situ conjugation for oral delivery of astaxanthin. J. Agric. Food Chem. 66, 9473–9480 (2018).

    Google Scholar 

100. Li, M., Zahi, M. R., Yuan, Q., Tian, F. & Liang, H. Preparation and stability of astaxanthin solid lipid nanoparticles based on stearic acid. Eur. J. Lipid Sci. Technol. 118, 592–602 (2016).

     Google Scholar 

101. Jain, P., Rahi, P., Pandey, V., Asati, S. & Soni, V. Nanostructure lipid carriers: a modish contrivance to overcome the ultraviolet effects. Egypt. J. Basic Appl. Sci. 4, 89–100 (2017).

     Google Scholar 

102. López-García, R. & Ganem-Rondero, A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC): occlusive effect and penetration enhancement ability. J. Cosmet. Dermatol. Sci. Appl. 5, 62 (2015).

     Google Scholar 

103. Mao, X. et al. Stability study and in vitro evaluation of astaxanthin nanostructured lipid carriers in food industry. Integr. Ferroelectr. 200, 208–216 (2019).

     Google Scholar 

104. Kim, E. S., Baek, Y., Yoo, H.-J., Lee, J.-S. & Lee, H. G. Chitosan-tripolyphosphate nanoparticles prepared by ionic gelation improve the antioxidant activities of astaxanthin in the in vitro and in vivo model. Antioxidants 11, 479 (2022).

     Google Scholar 

105. Zhu, Y. et al. Improved intestinal absorption and oral bioavailability of astaxanthin using poly (ethylene glycol)-graft-chitosan nanoparticles: preparation, in vitro evaluation, and pharmacokinetics in rats. J. Sci. Food Agric. 102, 1002–1011 (2022).

     Google Scholar 

106. Ku Aizuddin, K., Nurlina, M., Khuriah, A., Foo, C. & Mohd Affandi, M. Development of astaxanthin-loaded biodegradable nanoparticles by nanoprecipitation method. Int. J. Pharm. Technol. 5, 5962–5972 (2013).

     Google Scholar 

107. Azman, K. A. K., Seong, F. C. & Singh, G. K. S. Affandi MMRMM. Physicochemical characterization of astaxanthin-loaded PLGA formulation via nanoprecipitation technique. J. Appl. Pharm. Sci. 11, 056–061 (2021).

     Google Scholar 

108. Hu, F., Liu, W., Yan, L., Kong, F. & Wei, K. Optimization and characterization of poly (lactic-co-glycolic acid) nanoparticles loaded with astaxanthin and evaluation of anti-photodamage effect in vitro. R. Soc. Open Sci. 6, 191184 (2019).

     Google Scholar 

109. Liu, C., Zhang, S., McClements, D. J., Wang, D. & Xu, Y. Design of astaxanthin-loaded core–shell nanoparticles consisting of chitosan oligosaccharides and poly (lactic-co-glycolic acid): enhancement of water solubility, stability, and bioavailability. J. Agric. Food Chem. 67, 5113–5121 (2019).

     Google Scholar 

110. Landon, R. et al. Impact of astaxanthin on diabetes pathogenesis and chronic complications. Mar. Drugs 18, 357 (2020).

     Google Scholar 

111. McNulty, H. P., Byun, J., Lockwood, S. F., Jacob, R. F. & Mason, R. P. Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis. Biochim. Biophys. Acta (BBA)-Biomembr. 1768, 167–174 (2007).

     Google Scholar 

112. Kim, S. H. & Kim, H. Inhibitory effect of astaxanthin on oxidative stress-induced mitochondrial dysfunction—a mini-review. Nutrients 10, 1137 (2018).

     Google Scholar 

113. Yang, G. et al. Effect of berberine on the renal tubular epithelial-to-mesenchymal transition by inhibition of the Notch/snail pathway in diabetic nephropathy model KKAy mice. Drug Design Dev. Ther. 1065–1079. https://doi.org/10.2147/DDDT.S124971 (2017).

114. Dehdashtian, E. et al. Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sci. 193, 20–33 (2018).

     Google Scholar 

115. Kowluru, R. A., Kowluru, A., Mishra, M. & Kumar, B. Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy. Prog. Retin. Eye Res. 48, 40–61 (2015).

     Google Scholar 

116. Roy, S., Kern, T. S., Song, B. & Stuebe, C. Mechanistic insights into pathological changes in the diabetic retina: implications for targeting diabetic retinopathy. Am. J. Pathol. 187, 9–19 (2017).

     Google Scholar 

117. Yeh, P.-T., Huang, H.-W., Yang, C.-M., Yang, W.-S. & Yang, C.-H. Astaxanthin inhibits expression of retinal oxidative stress and inflammatory mediators in streptozotocin-induced diabetic rats. PLoS ONE 11, e0146438 (2016).

     Google Scholar 

118. Das P. P., Prathapan R., Ng K. W. Advances in biomaterials based food packaging systems: current status and the way forward. Biomater. Adv. 213988. https://doi.org/10.1016/j.bioadv.2024.213988 (2024).

119. Sun, Z. et al. Protective actions of microalgae against endogenous and exogenous advanced glycation endproducts (AGEs) in human retinal pigment epithelial cells. Food Funct. 2, 251–258 (2011).

     Google Scholar 

120. Benlarbi-Ben Khedher, M. et al. Astaxanthin inhibits aldose reductase activity in Psammomys obesus, a model of type 2 diabetes and diabetic retinopathy. Food Sci. Nutr. 7, 3979–3985 (2019).

     Google Scholar 

121. Roohbakhsh, A., Karimi, G. & Iranshahi, M. Carotenoids in the treatment of diabetes mellitus and its complications: a mechanistic review. Biomed. Pharmacother. 91, 31–42 (2017).

     Google Scholar 

122. Xu, L., Zhu, J., Yin, W. & Ding, X. Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. Int. J. Clin. Exp. Pathol. 8, 6083 (2015).

     Google Scholar 

123. Feng, Y. et al. The protective effect of astaxanthin on cognitive function via inhibition of oxidative stress and inflammation in the brains of chronic T2DM rats. Front. Pharmacol. 9, 748 (2018).

     Google Scholar 

124. Stirban, A., Gawlowski, T. & Roden, M. Vascular effects of advanced glycation endproducts: clinical effects and molecular mechanisms. Mol. Metab. 3, 94–108 (2014).

     Google Scholar 

125. Strain, W. D. & Paldánius, P. Diabetes, cardiovascular disease and the microcirculation. Cardiovasc. Diabetol. 17, 1–10 (2018).

     Google Scholar 

126. Chan, K. C., Pen, P. J. & Yin, M. C. Anticoagulatory and antiinflammatory effects of astaxanthin in diabetic rats. J. Food Sci. 77, H76–H80 (2012).

     Google Scholar 

127. Hussein, G. et al. Antihypertensive potential and mechanism of action of astaxanthin: III. Antioxidant and histopathological effects in spontaneously hypertensive rats. Biol. Pharm. Bull. 29, 684–688 (2006).

     Google Scholar 

128. Iwamoto, T. et al. Inhibition of low-density lipoprotein oxidation by astaxanthin. J. Atheroscler. Thromb. 7, 216–222 (2000).

     Google Scholar 

129. Naito, Y. et al. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors 20, 49–59 (2004).

     Google Scholar 

130. Manabe, E. et al. Astaxanthin protects mesangial cells from hyperglycemia-induced oxidative signaling. J. Cell. Biochem. 103, 1925–1937 (2008).

     Google Scholar 

131. Sila, A. et al. Astaxanthin from shrimp by-products ameliorates nephropathy in diabetic rats. Eur. J. Nutr. 54, 301–307 (2015).

     Google Scholar 

132. Zhu, X., Chen, Y., Chen, Q., Yang, H. & Xie, X. Astaxanthin promotes Nrf2/ARE signaling to alleviate renal fibronectin and collagen IV accumulation in diabetic rats. J. Diabetes Res. 2018, 6730315 (2018).

     Google Scholar 

133. Zhang, H. et al. Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am. J. Physiol.-Ren. Physiol. 299, F91–F98 (2010).

     Google Scholar 

134. Chen, Z. et al. Kidney-targeted astaxanthin natural antioxidant nanosystem for diabetic nephropathy therapy. Eur. J. Pharm. Biopharm. 156, 143–154 (2020).

     Google Scholar 

135. Farjadian, F. et al. Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: set the bugs to work?. Biotechnol. Adv. 36, 968–985 (2018).

     Google Scholar 

136. Rabiee, N. et al. Polymeric nanoparticles for nasal drug delivery to the brain: relevance to Alzheimer’s disease. Adv. Ther. 4, 2000076 (2021).

     Google Scholar 

137. Rabiee, N., Bagherzadeh, M. & Rabiee, M. A perspective to the correlation between brain insulin resistance and Alzheimer: medicinal chemistry approach. Curr. Diabetes Rev. 15, 255–258 (2019).

     Google Scholar 

138. Sugandhi, V. V. et al. Intranasal delivery of rapamycin via brain-targeting polymeric micelles for Alzheimer’s disease treatment. Int. J. Pharm. 126011. https://doi.org/10.1016/j.ijpharm.2025.126011 (2025).

139. Slika, H. et al. 1335 intracranial nanogel pellets carrying temozolomide and paclitaxel for adjuvant glioblastoma therapy. Neurosurgery 71, 223 (2025).

     Google Scholar 

140. Slika, H. et al. Intracranial nanogel pellets carrying temozolomide and paclitaxel for adjuvant brain cancer therapy. Mol. Pharm. 22, 131–141 (2024).

     Google Scholar 

141. Stawicki, B., Schacher, T. & Cho, H. Nanogels as a versatile drug delivery system for brain cancer. Gels 7, 63 (2021).

     Google Scholar 

142. Siegal, T. et al. In vivo assessment of the window of barrier opening after osmotic blood—brain barrier disruption in humans. J. Neurosurg. 92, 599–605 (2000).

     Google Scholar 

143. Rabiee, N. et al. Carbosilane dendrimers: drug and gene delivery applications. J. Drug Deliv. Sci. Technol. 59, 101879 (2020).

     Google Scholar 

144. Rabiee, N. et al. Recent advances in porphyrin-based nanocomposites for effective targeted imaging and therapy. Biomaterials 232, 119707 (2020).

     Google Scholar 

145. Hynynen, K. et al. Focal disruption of the blood–brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J. Neurosurg. 105, 445–454 (2006).

     Google Scholar 

146. Maghsoudi S., et al. Burgeoning polymer nano blends for improved controlled drug release: a review. Int. J. Nanomed. 4363–4392. https://doi.org/10.2147/IJN.S252237 (2020).

147. Rabiee, N. et al. Nanotechnology-assisted microfluidic systems: from bench to bedside. Nanomedicine 16, 237–258 (2021).

     Google Scholar 

148. Fanaee-Danesh, E. et al. Astaxanthin exerts protective effects similar to bexarotene in Alzheimer’s disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 2224–2245 (2019).

     Google Scholar 

149. Bellavance, M.-A., Blanchette, M. & Fortin, D. Recent advances in blood–brain barrier disruption as a CNS delivery strategy. AAPS J. 10, 166–177 (2008).

     Google Scholar 

150. Dube, T., Chibh, S., Mishra, J. & Panda, J. J. Receptor targeted polymeric nanostructures capable of navigating across the blood–brain barrier for effective delivery of neural therapeutics. ACS Chem. Neurosci. 8, 2105–2117 (2017).

     Google Scholar 

151. Shabana, P., Bonthagarala, B., Harini, A. L. & Dasari, V. Nasal drug delivery: a potential route for brain targeting. Int. J. Adv. Sci. Res. 1, 65–70 (2015).

     Google Scholar 

152. Nasseri, B., Kocum, I. C., Seymen, C. M. & Rabiee, N. Penetration depth in nanoparticles incorporated radiofrequency hyperthermia into the tissue: comprehensive study with histology and pathology observations. IET Nanobiotechnol. 13, 634–639 (2019).

     Google Scholar 

153. Pardridge, W. M. Molecular Trojan horses for blood–brain barrier drug delivery. Curr. Opin. Pharmacol. 6, 494–500 (2006).

     Google Scholar 

154. Pardridge, W. M. Delivery of biologics across the blood–brain barrier with molecular Trojan horse technology. BioDrugs 31, 503–519 (2017).

     Google Scholar 

155. Thassu, D., Pathak, Y. & Deleers, M. Nanoparticulate drug-delivery systems: an overview. Nanopart. Drug Deliv. Syst. 1–31 (2007).

156. Rabiee, N. et al. Aptamer hybrid nanocomplexes as targeting components for antibiotic/gene delivery systems and diagnostics: a review. Int. J. Nanomed. 4237–4256. https://doi.org/10.2147/IJN.S248736 (2020).

157. Rabiee, N. et al. Turning toxic nanomaterials into a safe and bioactive nanocarrier for co-delivery of DOX/pCRISPR. ACS Appl. Bio Mater. 4, 5336–5351 (2021).

     Google Scholar 

158. Silva, G. A. Nanotechnology approaches to crossing the blood–brain barrier and drug delivery to the CNS. BMC Neurosci. 9, S4 (2008).

     Google Scholar 

159. Tang, W. et al. Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics. Chem. Soc. Rev. 48, 2967–3014 (2019).

     Google Scholar 

160. Tillotson, G. S. Trojan horse antibiotics—a novel way to circumvent Gram-negative bacterial resistance?. Infect. Dis.: Res. Treat. 9, IDRT. S31567 (2016).

     Google Scholar 

161. Fang, F. et al. Non-invasive approaches for drug delivery to the brain based on the receptor mediated transport. Mater. Sci. Eng.: C 76, 1316–1327 (2017).

     Google Scholar 

162. Jain, K. Nanobiotechnology-based drug delivery to the central nervous system. Neurodegener. Dis. 4, 287–291 (2007).

     Google Scholar 

163. Naqvi, S., Panghal, A. & Flora, S. Nanotechnology: a promising approach for delivery of neuroprotective drugs. Front. Neurosci. 14, 494 (2020).

     Google Scholar 

164. Masserini, M. Nanoparticles for brain drug delivery. Int. Sch. Res. Not. 2013, 238428 (2013).

     Google Scholar 

165. Pietroiusti, A., Campagnolo, L. & Fadeel, B. Interactions of engineered nanoparticles with organs protected by internal biological barriers. Small 9, 1557–1572 (2013).

     Google Scholar 

166. Fakhri, S., Abbaszadeh, F., Dargahi, L. & Jorjani, M. Astaxanthin: a mechanistic review on its biological activities and health benefits. Pharmacol. Res. 136, 1–20 (2018).

     Google Scholar 

167. Barros, M. P., Poppe, S. C. & Bondan, E. F. Neuroprotective properties of the marine carotenoid astaxanthin and omega-3 fatty acids, and perspectives for the natural combination of both in krill oil. Nutrients 6, 1293–1317 (2014).

     Google Scholar 

168. Graber, J. J. & Dhib-Jalbut, S. Protective autoimmunity in the nervous system. Pharmacol. Ther. 121, 147–159 (2009).

     Google Scholar 

169. Lin, T.-C. et al. Nanotechnology-based drug delivery treatments and specific targeting therapy for age-related macular degeneration. J. Chin. Med. Assoc. 78, 635–641 (2015).

     Google Scholar 

170. Shen, H. et al. Astaxanthin reduces ischemic brain injury in adult rats. FASEB J. 23, 1958 (2009).

     Google Scholar 

171. Pan, L., Zhou, Y., Li, X. -f, Wan, Q. -j & Yu, L. -h Preventive treatment of astaxanthin provides neuroprotection through suppression of reactive oxygen species and activation of antioxidant defense pathway after stroke in rats. Brain Res. Bull. 130, 211–220 (2017).

     Google Scholar 

172. Rahman, S. O. et al. Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Aβ peptides in animal model of Alzheimer’s disease. Biomed. Pharmacother. 110, 47–58 (2019).

     Google Scholar 

173. Che, H. et al. Effects of astaxanthin and docosahexaenoic-acid-acylated astaxanthin on Alzheimer’s disease in APP/PS1 double-transgenic mice. J. Agric. Food Chem. 66, 4948–4957 (2018).

     Google Scholar 

174. Gorska-Ciebiada, M., Saryusz-Wolska, M., Borkowska, A., Ciebiada, M. & Loba, J. Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. PloS ONE 10, e0120433 (2015).

     Google Scholar 

175. Modrego, P. J., Fayed, N. & Pina, M. A. Conversion from mild cognitive impairment to probable Alzheimer’s disease predicted by brain magnetic resonance spectroscopy. Am. J. Psychiatry 162, 667–675 (2005).

     Google Scholar 

176. Kessing, L. V. et al. Antidiabetes agents and incident depression: a nationwide population-based study. Diabetes Care 43, 3050–3060 (2020).

     Google Scholar 

177. Fonseka, T. M., McIntyre, R. S., Soczynska, J. K. & Kennedy, S. H. Novel investigational drugs targeting IL-6 signaling for the treatment of depression. Expert Opin. Investig. Drugs 24, 459–475 (2015).

     Google Scholar 

178. Mazza, M., Pomponi, M., Janiri, L., Bria, P. & Mazza, S. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 31, 12–26 (2007).

     Google Scholar 

179. Zhou, Y. et al. High-dose astaxanthin supplementation suppresses antioxidant enzyme activity during moderate-intensity swimming training in mice. Nutrients 11, 1244 (2019).

     Google Scholar 

180. Wibrand, K. et al. Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats. Lipids Health Dis. 12, 1–13 (2013).

     Google Scholar 

181. Ghasemi, N. The evaluation of astaxanthin effects on differentiation of human adipose derived stem cells into oligodendrocyte precursor cells. Avicenna J. Med. Biotechnol. 10, 69 (2018).

     Google Scholar 

182. Utikal, J. et al. Numerical abnormalities of the Cyclin D1 gene locus on chromosome 11q13 in non-melanoma skin cancer. Cancer Lett. 219, 197–204 (2005).

     Google Scholar 

183. Susin, S. A. et al. Two distinct pathways leading to nuclear apoptosis. J. Exp. Med. 192, 571–580 (2000).

     Google Scholar 

184. Thompson, C. B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995).

     Google Scholar 

185. Zhou, G. P. & Doctor, K. Subcellular location prediction of apoptosis proteins. Proteins: Struct. Funct. Bioinform. 50, 44–48 (2003).

     Google Scholar 

186. Fesik, S. W. & Shi, Y. Controlling the caspases. Science 294, 1477–1478 (2001).

     Google Scholar 

187. Murphy, K., Ranganathan, V., Farnsworth, M., Kavallaris, M. & Lock, R. B. Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells. Cell Death Differ. 7, 102–111 (2000).

     Google Scholar 

188. Tang, G., Yang, J., Minemoto, Y. & Lin, A. Blocking caspase-3-mediated proteolysis of IKKβ suppresses TNF-α-induced apoptosis. Mol. Cell 8, 1005–1016 (2001).

     Google Scholar 

189. Tang, X., Liu, B., Wang, X., Yu, Q. & Fang, R. Epidermal growth factor, through alleviating oxidative stress, protect IPEC-J2 cells from lipopolysaccharides-induced apoptosis. Int. J. Mol. Sci. 19, 848 (2018).

     Google Scholar 

190. Anderson, M. L. A preliminary investigation of the enzymatic inhibition of 5α-reductase and growth of prostatic carcinoma cell line LNCap-FGC by natural astaxanthin and saw palmetto lipid extract in vitro. J. Herb. Pharmacother. 5, 17–26 (2005).

     Google Scholar 

191. Chen, Y.-T. et al. Astaxanthin reduces MMP expressions, suppresses cancer cell migrations, and triggers apoptotic caspases of in vitro and in vivo models in melanoma. J. Funct. Foods 31, 20–31 (2017).

     Google Scholar 

192. Liao, K.-S. et al. Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells. Regul. Toxicol. Pharmacol. 81, 353–361 (2016).

     Google Scholar 

193. Nagaraj, S. et al. Antiproliferative potential of astaxanthin-rich alga Haematococcus pluvialis Flotow on human hepatic cancer (HepG2) cell line. Biomed. Prev. Nutr. 2, 149–153 (2012).

     Google Scholar 

194. Bharathiraja, S. et al. Astaxanthin conjugated polypyrrole nanoparticles as a multimodal agent for photo-based therapy and imaging. Int. J. Pharm. 517, 216–225 (2017).

     Google Scholar 

195. Wang, L. V. Multiscale photoacoustic microscopy and computed tomography. Nat. Photonics 3, 503–509 (2009).

     Google Scholar 

196. Cho, E. C., Glaus, C., Chen, J., Welch, M. J. & Xia, Y. Inorganic nanoparticle-based contrast agents for molecular imaging. Trends Mol. Med. 16, 561–573 (2010).

     Google Scholar 

197. Smith, A. M., Mancini, M. C. & Nie, S. Second window for in vivo imaging. Nat. Nanotechnol. 4, 710–711 (2009).

     Google Scholar 

198. Nguyen, V. P., Park, S., Oh, J. & Wook Kang, H. Biocompatible astaxanthin as novel contrast agent for biomedical imaging. J. Biophotonics 10, 1053–1061 (2017).

     Google Scholar 

199. Makvandi, P. et al. Stimuli-responsive transdermal microneedle patches. Mater. Today 47, 206–222 (2021).

     Google Scholar 

200. Bolzinger, M.-A., Briançon, S., Pelletier, J. & Chevalier, Y. Penetration of drugs through skin, a complex rate-controlling membrane. Curr. Opin. Colloid Interface Sci. 17, 156–165 (2012).

     Google Scholar 

201. Iqbal, B., Ali, J. & Baboota, S. Recent advances and development in epidermal and dermal drug deposition enhancement technology. Int. J. Dermatol. 57, 646–660 (2018).

     Google Scholar 

202. Chamundeeswari, M., Jeslin, J. & Verma, M. L. Nanocarriers for drug delivery applications. Environ. Chem. Lett. 17, 849–865 (2019).

     Google Scholar 

203. Dayan, N. Pathways for skin penetration. Cosmet. Toilet. 120, 67–76 (2005).

     Google Scholar 

204. Zhang, H., Zhai, Y., Yang, X. & Zhai, G. Breaking the skin barrier: achievements and future directions. Curr. Pharm. Des. 21, 2713–2724 (2015).

     Google Scholar 

205. Al Shaal, L., Shegokar, R. & Müller, R. H. Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. Int. J. Pharm. 420, 133–140 (2011).

     Google Scholar 

206. Batheja, P., Sheihet, L., Kohn, J., Singer, A. J. & Michniak-Kohn, B. Topical drug delivery by a polymeric nanosphere gel: formulation optimization and in vitro and in vivo skin distribution studies. J. Control. Release 149, 159–167 (2011).

     Google Scholar 

207. Prow, T. W. et al. Nanoparticles and microparticles for skin drug delivery. Adv. Drug Deliv. Rev. 63, 470–491 (2011).

     Google Scholar 

208. Ashtiani, H. A., Bishe, P., Lashgari, N.-A., Nilforoushzadeh, M. A. & Zare, S. Liposomes in cosmetics. J. Skin Stem Cell 3, e65815 (2016).

     Google Scholar 

209. Tabata, N., O’Goshi, K., Zhen, Y., Kligman, A. & Tagami, H. Biophysical assessment of persistent effects of moisturizers after their daily applications: evaluation of corneotherapy. Dermatology 200, 308–313 (2000).

     Google Scholar 

210. Makvandi, P. et al. Engineering microneedle patches for improved penetration: analysis, skin models and factors affecting needle insertion. Nano-Micro Lett. 13, 1–41 (2021).

     Google Scholar 

211. Bagheri, M., Validi, M., Gholipour, A., Makvandi, P. & Sharifi, E. Chitosan nanofiber biocomposites for potential wound healing applications: antioxidant activity with synergic antibacterial effect. Bioeng. Transl. Med. 7, e10254 (2022).

     Google Scholar 

212. Visioli, F. & Artaria, C. Astaxanthin in cardiovascular health and disease: mechanisms of action, therapeutic merits, and knowledge gaps. Food Funct. 8, 39–63 (2017).

     Google Scholar 

213. Svobodova, A., Walterova, D. & Vostalova, J. Ultraviolet light induced alteration to the skin. Biomed. Pap.-Palacky. Univ. Olomouc 150, 25 (2006).

     Google Scholar 

214. Rafi, M. M., Yadav, P. N. & Reyes, M. Lycopene inhibits LPS-induced proinflammatory mediator inducible nitric oxide synthase in mouse macrophage cells. J. Food Sci. 72, S069–S074 (2007).

     Google Scholar 

215. Chew, B. P. et al. Dietary astaxanthin enhances immune response in dogs. Vet. Immunol. Immunopathol. 140, 199–206 (2011).

     Google Scholar 

216. Santocono, M., Zurria, M., Berrettini, M., Fedeli, D. & Falcioni, G. Influence of astaxanthin, zeaxanthin and lutein on DNA damage and repair in UVA-irradiated cells. J. Photochem. Photobiol. B: Biol. 85, 205–215 (2006).

     Google Scholar 

217. Chalyk, N. E., Klochkov, V. A., Bandaletova, T. Y., Kyle, N. H. & Petyaev, I. M. Continuous astaxanthin intake reduces oxidative stress and reverses age-related morphological changes of residual skin surface components in middle-aged volunteers. Nutr. Res. 48, 40–48 (2017).

     Google Scholar 

218. Ito, N., Seki, S. & Ueda, F. The protective role of astaxanthin for UV-induced skin deterioration in healthy people—a randomized, double-blind, placebo-controlled trial. Nutrients 10, 817 (2018).

     Google Scholar 

219. McCall, B., McPartland, C. K., Moore, R., Frank-Kamenetskii, A. & Booth, B. W. Effects of astaxanthin on the proliferation and migration of breast cancer cells in vitro. Antioxidants 7, 135 (2018).

     Google Scholar 

220. Yamashita, E. The effects of a dietary supplement containing astaxanthin on skin condition. Food Style 10, 91–95 (2006).

     Google Scholar 

221. Singh, K. N., Patil, S. & Barkate, H. Protective effects of astaxanthin on skin: recent scientific evidence, possible mechanisms, and potential indications. J. Cosmet. Dermatol. 19, 22–27 (2020).

     Google Scholar 

222. Tavassolifar, M. J., Vodjgani, M., Salehi, Z. & Izad, M. The influence of reactive oxygen species in the immune system and pathogenesis of multiple sclerosis. Autoimmune Dis. 2020, 5793817 (2020).

     Google Scholar 

223. Bennedsen, M., Wang, X., Willén, R., Wadström, T. & Andersen, L. P. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol. Lett. 70, 185–189 (2000).

     Google Scholar 

224. Park, J. S., Chyun, J. H., Kim, Y. K., Line, L. L. & Chew, B. P. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutr. Metab. 7, 1–10 (2010).

     Google Scholar 

225. Veeruraj, A., Liu, L., Zheng, J., Wu, J. & Arumugam, M. Evaluation of astaxanthin incorporated collagen film developed from the outer skin waste of squid Doryteuthis singhalensis for wound healing and tissue regenerative applications. Mater. Sci. Eng.: C 95, 29–42 (2019).

     Google Scholar 

226. Lyons, N. M. & O’Brien, N. M. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. J. Dermatol. Sci. 30, 73–84 (2002).

     Google Scholar 

227. Poljšak, B., Dahmane, R. G. & Godić, A. Intrinsic skin aging: the role of oxidative stress. Acta Dermatovenerol. Alp. Pannonica Adriat. 21, 33–36 (2012).

     Google Scholar 

228. Kishimoto, Y. et al. Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. Eur. J. Nutr. 49, 119–126 (2010).

     Google Scholar 

229. Priyadarshini, L. & Aggarwal, A. Astaxanthin inhibits cytokines production and inflammatory gene expression by suppressing IκB kinase-dependent nuclear factor κB activation in pre and postpartum Murrah buffaloes during different seasons. Vet. World 11, 782 (2018).

     Google Scholar 

230. Yoshihisa, Y., Rehman, M. U. & Shimizu, T. Astaxanthin, a xanthophyll carotenoid, inhibits ultraviolet-induced apoptosis in keratinocytes. Exp. Dermatol. 23, 178–183 (2014).

     Google Scholar 

231. Kikuchi, K. et al. Cytoprotective effect of astaxanthin in a model of normal intraocular pressure glaucoma. J. Ophthalmol. 2020, 9539681 (2020).

     Google Scholar 

232. Otsuka, T. et al. Astaxanthin protects against retinal damage: evidence from in vivo and in vitro retinal ischemia and reperfusion models. Curr. Eye Res. 41, 1465–1472 (2016).

     Google Scholar 

233. Rivera, J. C. et al. Ischemic retinopathies: oxidative stress and inflammation. Oxid. Med. Cell. Longev. 2017, 3940241 (2017).

     Google Scholar 

234. Semeraro, F. et al. Diabetic retinopathy: vascular and inflammatory disease. J. Diabetes Res. 2015, 582060 (2015).

     Google Scholar 

235. Tha, K. K. et al. Changes in expressions of proinflammatory cytokines IL-1β, TNF-α and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res. 885, 25–31 (2000).

     Google Scholar 

236. Choi, S.-K., Park, Y.-S., Choi, D.-K. & Chang, H.-I. Effects of astaxanthin on the production of NO and the expression of COX-2 and iNOS in LPS-stimulated BV2 microglial cells. J. Microbiol. Biotechnol. 18, 1990–1996 (2008).

     Google Scholar 

237. Lennikov, A. et al. Amelioration of ultraviolet-induced photokeratitis in mice treated with astaxanthin eye drops. Mol. Vis. 18, 455–464 (2012).

     Google Scholar 

238. Yamagishi, R. & Aihara, M. Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis. Mol. Vis. 20, 1796–1805 (2014).

     Google Scholar 

239. Cort, A. et al. Suppressive effect of astaxanthin on retinal injury induced by elevated intraocular pressure. Regul. Toxicol. Pharmacol. 58, 121–130 (2010).

     Google Scholar 

240. Schwartz, S. D. et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385, 509–516 (2015).

     Google Scholar 

241. Nayak, K. & Misra, M. A review on recent drug delivery systems for posterior segment of eye. Biomed. Pharmacother. 107, 1564–1582 (2018).

     Google Scholar 

242. Jafari, Z. et al. Nanotechnology-abetted astaxanthin formulations in multimodel therapeutic and biomedical applications. J. Med. Chem. 65, 2–36 (2022).

     Google Scholar 

243. Agrahari, V. et al. A comprehensive insight on ocular pharmacokinetics. Drug Deliv. Transl. Res. 6, 735–754 (2016).

     Google Scholar 

244. Fakhri, S., Abbaszadeh, F., Dargahi, L. & Jorjani, M. Astaxanthin: a mechanistic review on its biological activities and health benefits. Pharm. Res. 136, 1–20 (2018).

     Google Scholar 

245. Fratter, A., Biagi, D. & Cicero, A. F. G. Sublingual delivery of astaxanthin through a novel ascorbyl palmitate-based nanoemulsion: preliminary data. Mar. Drugs 17, (2019).

246. Shimokawa, T. et al. Efficacy of high-affinity liposomal astaxanthin on up-regulation of age-related markers induced by oxidative stress in human corneal epithelial cells. J. Clin. Biochem. Nutr. 64, 27–35 (2019).

     Google Scholar 

247. Schopf, L. R. et al. Topical ocular drug delivery to the back of the eye by mucus-penetrating particles. Transl. Vis. Sci. Technol. 4, 11 (2015).

     Google Scholar 

248. Weng, Y. et al. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm. Sin. B 7, 281–291 (2017).

     Google Scholar 

249. Patel, A., Cholkar, K., Agrahari, V. & Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharmacol. 2, 47–64 (2013).

     Google Scholar 

250. Abdol Wahab, N. R., Meor Mohd Affandi, M. M. R., Fakurazi, S., Alias, E. & Hassan, H. Nanocarrier system: state-of-the-art in oral delivery of astaxanthin. Antioxidants (Basel) 11, (2022).

251. Gaspar, R. et al. Regulatory issues surrounding nanomedicines: setting the scene for the next generation of nanopharmaceuticals. Nanomedicine (London) 2, 143–147 (2007).

     Google Scholar 

252. Tan, B. L., Norhaizan, M. E., Liew, W. P. & Sulaiman Rahman, H. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front. Pharmacol. 9, 1162 (2018).

     Google Scholar 

253. Bjelakovic, G., Nikolova, D. & Gluud, C. Antioxidant supplements and mortality. Curr. Opin. Clin. Nutr. Metab. Care 17, 40–44 (2014).

     Google Scholar 

254. Ndhlala, A. R., Moyo, M. & Van Staden, J. Natural antioxidants: fascinating or mythical biomolecules?. Molecules 15, 6905–6930 (2010).

     Google Scholar 

255. Ganesan, P., Arulselvan, P. & Choi, D. K. Phytobioactive compound-based nanodelivery systems for the treatment of type 2 diabetes mellitus—current status. Int. J. Nanomed. 12, 1097–1111 (2017).

     Google Scholar 

256. Liu, R. H. Dietary bioactive compounds and their health implications. J. Food Sci. 78, A18–A25 (2013).

     Google Scholar 

257. Magne, T. M. et al. Graphene and its derivatives: understanding the main chemical and medicinal chemistry roles for biomedical applications. J. Nanostruct. Chem. 12, 693–727 (2022).

     Google Scholar 

Download references