GREEN SYNTHESIS OF SPIRULINA OIL-BASED NANOVESICLES AS A BIOENHANCER FOR THE INTRANASAL BRAIN TARGETING OF STATINS: CELL LINE STUDY ON HUMAN BRAIN CANCER CELL SNB-75 AND PHARMACOKINETICS ON RATS
DOI:
https://doi.org/10.22159/ijap.2025v17i5.54735Keywords:
Spirusomes, Atorvastatin calcium, Pharmacokinetics, Cytotoxicity, Glioma, Spirulina oilAbstract
Objective: This study presents a novel glioma treatment strategy using intranasally administered statin-loaded Spirusomes, integrating Spirulina oil as a bioenhancer to potentiate statins’ anticancer effects, optimize bioavailability, and minimize systemic exposure.
Methods: Eight atorvastatin-loaded Spirusome formulae were prepared and assessed concerning vesicle size, charge, entrapment efficiency, and in vitro release profile. F1, containing 10 mg of atorvastatin, 100 mg of lecithin, and 1 mg of Spirulina oil, achieved a desirability score of 0.859 based on Design Expert® analysis. Raman spectroscopy was used to test for any possible drug interactions. In vitro cytotoxicity studies on SNB-75 human brain cancer cells were carried out to evaluate the anticancer efficacy of the optimized Spirusomes. In vivo pharmacokinetic studies on albino rats were used to examine the drug’s pharmacokinetic profile in plasma and brain tissues after intranasal and oral administration.
Results: The optimized formula (F1) achieved nearly complete drug release within 24 h, with no drug interactions confirmed via Raman spectroscopy. In vitro cytotoxicity studies showed an IC50 of 39.48±2.01 µg/ml for atorvastatin-loaded Spirusomes, which was lower than that for plain atorvastatin. In vivo pharmacokinetics revealed a 7-fold increase in brain bioavailability (AUC0-24 = 4660.685±216.849 ng. h/gm), indicating enhanced selectivity following intranasal administration.
Conclusion: This investigation reveals that atorvastatin-loaded Spirusomes might serve as an effective and selective delivery system for brain cancer treatment. The optimized formula demonstrated excellent physicochemical properties, efficient drug release, potent anticancer activity, and promising pharmacokinetics, indicating substantial preclinical potential as a brain-targeted drug delivery system. However, further studies employing glioma-bearing animal models are necessary to evaluate therapeutic efficacy and validate these findings in a disease-relevant context.
References
1. Qiu Q, Ding X, Chen J, Chen S, Wang J. Nanobiotechnology based treatment strategies for malignant relapsed glioma. J Control Release. 2023 Jun;358:681-705. doi: 10.1016/j.jconrel.2023.05.016, PMID 37196900.
2. Alrosan AZ, Heilat GB, Al Subeh ZY, Alrosan K, Alrousan AF, Abu Safieh AK. The effects of statin therapy on brain tumors particularly glioma: a review. Anti Cancer Drugs. 2023;34(9):985-94. doi: 10.1097/CAD.0000000000001533, PMID 37466094.
3. Zhou X, Wu X, Wang R, Han L, Li H, Zhao W. Mechanisms of 3-hydroxyl 3-methylglutaryl CoA reductase in alzheimers disease. Int J Mol Sci. 2023;25(1):170. doi: 10.3390/ijms25010170, PMID 38203341.
4. Dong H, Li M, Yang C, Wei W, He X, Cheng G. Combination therapy with oncolytic viruses and immune checkpoint inhibitors in head and neck squamous cell carcinomas: an approach of complementary advantages. Cancer Cell Int. 2023;23(1):1. doi: 10.1186/s12935-022-02846-x, PMID 36604694.
5. Sarbassova G, Nurlan N, Raddam Al Shammari B, Francis N, Alshammari M, Aljofan M. Investigating potential anti-proliferative activity of different statins against five cancer cell lines. Saudi Pharm J. 2023;31(5):727-35. doi: 10.1016/j.jsps.2023.03.013, PMID 37181137.
6. Zarif Attalla K, Hassan DH, Teaima MH, Yousry C, El Nabarawi MA, Said MA. Enhanced intranasal delivery of atorvastatin via superparamagnetic iron-oxide loaded nanocarriers: cytotoxicity and inflammation evaluation and in vivo in silico and network pharmacology study for targeting glioblastoma management. Pharmaceuticals (Basel). 2025;18(3):421. doi: 10.3390/ph18030421, PMID 40143197.
7. Telange DR, Bhaktani NM, Hemke AT, Pethe AM, Agrawal SS, Rarokar NR. Development and characterization of pentaerythritol EudragitRS100 co-processed excipients as solid dispersion carriers for enhanced aqueous solubility in vitro dissolution and ex vivo permeation of atorvastatin. ACS Omega. 2023;8(28):25195-208. doi: 10.1021/acsomega.3c02280, PMID 37483203.
8. Ariaeinia M, Rahimpour E, Mirzaeei S, Fathi Azarbayjani A, Jouyban A. Thermodynamic analysis of atorvastatin calcium in solvent mixtures at several temperatures. Phys Chem Liq. 2023;61(4):275-84. doi: 10.1080/00319104.2023.2208255.
9. Singh S, Khurana K, Chauhan SB, Singh I. Emulsomes: new lipidic carriers for drug delivery with special mention to brain drug transport. Future J Pharm Sci. 2023;9(1):78. doi: 10.1186/s43094-023-00530-z.
10. Yadav AK, Jain K. Novel carrier systems for targeted and controlled drug delivery: springer; 2024 Dec 23.
11. Abdelbari MA, Elshafeey AH, Abdelbary AA, Mosallam S. Implementing nanovesicles for boosting the skin permeation of non-steroidal anti-inflammatory drugs. AAPS PharmSciTech. 2023;24(7):195. doi: 10.1208/s12249-023-02649-x, PMID 37770750.
12. Demirci Z, Islek Z, Siginc HI, Sahin F, Ucisik MH, Bolat ZB. Curcumin loaded emulsome nanoparticles induces apoptosis through p53 signaling pathway in pancreatic cancer cell line PANC-1. Toxicol In Vitro. 2025 Jan;102:105958. doi: 10.1016/j.tiv.2024.105958, PMID 39442639.
13. Elnady RE, Amin MM, Zakaria MY. A review on lipid based nanocarriers mimicking chylomicron and their potential in drug delivery and targeting infectious and cancerous diseases. AAPS Open. 2023;9(1):13. doi: 10.1186/s41120-023-00080-x.
14. El Zaafarany GM, Soliman ME, Mansour S, Awad GA. Identifying lipidic emulsomes for improved oxcarbazepine brain targeting: in vitro and rat in vivo studies. Int J Pharm. 2016;503(1-2):127-40. doi: 10.1016/j.ijpharm.2016.02.038, PMID 26924357.
15. Aldawsari HM, Ahmed OA, Alhakamy NA, Neamatallah T, Fahmy UA, Badr-Eldin SM. Lipidic nano sized emulsomes potentiates the cytotoxic and apoptotic effects of raloxifene hydrochloride in MCF-7 human breast cancer cells: factorial analysis and in vitro anti-tumor activity assessment. Pharmaceutics. 2021;13(6):783. doi: 10.3390/pharmaceutics13060783, PMID 34073780.
16. Alhakamy NA, Badr Eldin SM, Ahmed OA, Asfour HZ, Aldawsari HM, Algandaby MM. Piceatannol loaded emulsomes exhibit enhanced cytostatic and apoptotic activities in colon cancer cells. Antioxidants (Basel). 2020;9(5):419. doi: 10.3390/antiox9050419, PMID 32414040.
17. Bigagli E, D Ambrosio M, Cinci L, Pieraccini G, Romoli R, Biondi N. A comparative study of metabolites profiles anti-inflammatory and antioxidant activity of methanolic extracts from three arthrospira strains in RAW 264.7 macrophages. Algal Res. 2023;73(11):103171. doi: 10.1016/j.algal.2023.103171.
18. Gomez PI, Mayorga J, Flaig D, Castro Varela P, Jaupi A, Ulloa PA. Looking beyond Arthrospira: comparison of antioxidant and anti-inflammatory properties of ten cyanobacteria strains. Algal Res. 2023 Jul;74:103182. doi: 10.1016/j.algal.2023.103182.
19. Czerwonka A, Kalawaj K, Slawinska Brych A, Lemieszek MK, Bartnik M, Wojtanowski KK. Anticancer effect of the water extract of a commercial Spirulina (Arthrospira platensis) product on the human lung cancer A549 cell line. Biomed Pharmacother. 2018 Oct;106:292-302. doi: 10.1016/j.biopha.2018.06.116, PMID 29966973.
20. El Menshawe SF, Shalaby K, Elkomy MH, Aboud HM, Ahmed YM, Abdelmeged AA. Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: pronounced efficacy through up-regulation of Wnt/β-catenin pathway in DMH-induced tumorigenesis. Int J Pharm X. 2024 Jun;7:100225. doi: 10.1016/j.ijpx.2023.100225, PMID 38230407.
21. Al Jayoush AR, Hassan HA, Asiri H, Jafar M, Saeed R, Harati R. Niosomes for nose to brain delivery: a non-invasive versatile carrier system for drug delivery in neurodegenerative diseases. J Drug Deliv Sci Technol. 2023 Nov;89:105007. doi: 10.1016/j.jddst.2023.105007.
22. Centis V, Vermette P. Physico-chemical properties and cytotoxicity assessment of PEG-modified liposomes containing human hemoglobin. Colloids Surf B Biointerfaces. 2008;65(2):239-46. doi: 10.1016/j.colsurfb.2008.04.009, PMID 18538549.
23. Liu S, Abu Hajar HA, Riefler G, Stuart BJ. Lipid extraction from Spirulina sp. and Schizochytrium sp. using supercritical CO2 with methanol. BioMed Res Int. 2018;2018(1):2720763. doi: 10.1155/2018/2720763, PMID 30627545.
24. Neag E, Stupar Z, Varaticeanu C, Senila M, Roman C. Optimization of lipid extraction from Spirulina spp. by ultrasound application and mechanical stirring using the Taguchi method of experimental design. Molecules. 2022;27(20):6794. doi: 10.3390/molecules27206794, PMID 36296385.
25. Abo El Enin HA, Mostafa RE, Ahmed MF, Naguib IA, A Abdelgawad M, Ghoneim MM. Assessment of nasal brain targeting efficiency of new developed mucoadhesive emulsomes encapsulating an anti-migraine drug for effective treatment of one of the major psychiatric disorders symptoms. Pharmaceutics. 2022;14(2):410. doi: 10.3390/pharmaceutics14020410, PMID 35214142.
26. Kamel R, AbouSamra MM, Afifi SM, Galal AF. Phyto-emulsomes as a novel nano-carrier for morine hydrate to combat leukemia: in vitro and pharmacokinetic study. J Drug Deliv Sci Technol. 2022 Sep;75:103700. doi: 10.1016/j.jddst.2022.103700.
27. Karroum R, Ucısık MH. Efficacy and safety of sulforaphane loaded emulsomes as tested on MCF7 and MCF10A cells. Turk J Biochem. 2024;49(5):629-36. doi: 10.1515/tjb-2023-0210.
28. Yassein AS, Elamary RB, Alwaleed EA. Biogenesis characterization and applications of Spirulina selenium nanoparticles. Microb Cell Factories. 2025;24(1):39. doi: 10.1186/s12934-025-02656-6, PMID 39915798.
29. Baiomy AM, Younis MK, Kharshoum RM, Alsalhi A, Zaki RM, Afzal O. Optimized delivery of enalapril maleate via polymeric Invasomal in situ gel for glaucoma treatment: in vitro, in vivo, and histological studies. J Drug Deliv Sci Technol. 2025 Apr;106:106685. doi: 10.1016/j.jddst.2025.106685.
30. Shulyak N, Liushuk K, Semeniuk O, Yarema N, Uglyar T, Popovych D. Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro. Pharmacia. 2022;69(1):61-7. doi: 10.3897/pharmacia.69.e77319.
31. Patil PS, Dhawale SC. Development of ritonavir loaded nanoparticles: in vitro and in vivo characterization. Asian J Pharm Clin Res. 2018;11(3)284-8. doi: 10.22159/ajpcr.2018.v11i3.23145.
32. Ramesh D, Bakkannavar SM, Bhat VR, Pai KS, Sharan K. Comparative study on drug encapsulation and release kinetics in extracellular vesicles loaded with snake venom L-amino acid oxidase. BMC Pharmacol Toxicol. 2025;26(1):98. doi: 10.1186/s40360-025-00938-8, PMID 40340782.
33. Wu KW, Sweeney C, Dudhipala N, Lakhani P, Chaurasiya ND, Tekwani BL. Primaquine loaded solid lipid nanoparticles (SLN) nanostructured lipid carriers (NLC) and nanoemulsion (NE): effect of lipid matrix and surfactant on drug entrapment in vitro release and ex vivo hemolysis. AAPS PharmSciTech. 2021;22(7):240. doi: 10.1208/s12249-021-02108-5, PMID 34590195.
34. Alhakamy NA, Badr Eldin SM, Aldawsari HM, Alfarsi A, Neamatallah T, Okbazghi SZ. Fluvastatin loaded emulsomes exhibit improved cytotoxic and apoptosis in prostate cancer cells. AAPS PharmSciTech. 2021;22(5):177. doi: 10.1208/s12249-021-02021-x, PMID 34128106.
35. Elgendy HA, Makky AM, Elakkad YE, Awad HH, Hassab MA, Younes NF. Atorvastatin loaded lecithin coated zein nanoparticles based thermogel for the intra-articular management of osteoarthritis: in silico, in vitro, and in vivo studies. J Pharm Investig. 2024;54(4):497-518. doi: 10.1007/s40005-024-00666-x.
36. Chopra A, Singh S, Kanoungo A, Singh G, Gupta NK, Sharma S. Multi-objective optimization of nitrile rubber and thermosets modified bituminous mix using desirability approach. PLOS One. 2023;18(2):e0281418. doi: 10.1371/journal.pone.0281418, PMID 36809361.
37. Asfour MH, Salama AA. Coating with tripolyphosphate crosslinked chitosan as a novel approach for enhanced stability of emulsomes following oral administration: Rutin as a model drug with improved anti-hyperlipidemic effect in rats. Int J Pharm. 2023 Sep 25;644:123314. doi: 10.1016/j.ijpharm.2023.123314, PMID 37579826.
38. Mahajan A, Kaur S, Kaur S. Design formulation and characterization of stearic acid-based solid lipid nanoparticles of candesartan cilexetil to augment its oral bioavailability. Asian J Pharm Clin Res. 2018;11(4):344-50. doi: 10.22159/ajpcr.2018.v11i4.23849.
39. Sun Z, Lin B, Yang X, Zhao B, Zhang H, Dong Q. Review of the application of Raman spectroscopy in qualitative and quantitative analysis of drug polymorphism. Curr Top Med Chem. 2023;23(14):1340-51. doi: 10.2174/1568026623666221223113342, PMID 36567287.
40. Lim YI, Han J, Woo YA, Kim J, Kang MJ. Rapid quantitation of atorvastatin in process pharmaceutical powder sample using Raman spectroscopy and evaluation of parameters related to accuracy of analysis. Spectrochim Acta A Mol Biomol Spectrosc. 2018 Jul 5;200:26-32. doi: 10.1016/j.saa.2018.04.017, PMID 29660679.
41. El Menshawi BS, Fayad W, Mahmoud K, El Hallouty SM, El Manawaty M, Olofsson MH. Screening of natural products for therapeutic activity against solid tumors. Indian J Exp Biol. 2010;48(3):258-64. PMID 21046978.
42. Ahmadi Y, Fard JK, Ghafoor D, Eid AH, Sahebkar A. Paradoxical effects of statins on endothelial and cancer cells: the impact of concentrations. Cancer Cell Int. 2023;23(1):43. doi: 10.1186/s12935-023-02890-1, PMID 36899388.
43. Abou Baker DH, Abbas HS. Antimicrobial activity of biosynthesized Cuo/Se nanocomposite against Helicobacter pylori. Arab J Chem. 2023;16(9):105095. doi: 10.1016/j.arabjc.2023.105095.
44. Moriasi G, Ngugi M, Mwitari P, Omwenga G. Cytotoxicity antiprostate cancer effects and phytochemical composition of the dichloromethane stem bark extract of Acacia gerrardii (Benth.). Next Res. 2025;2(1):100167. doi: 10.1016/j.nexres.2025.100167.
45. Wlodkowic D, Skommer J, Darzynkiewicz Z. Flow cytometry based apoptosis detection. Apoptosis: methods and protocols. 2nd ed; 2009. p. 19-32.
46. Sil S, Roy UK, Biswas S, Mandal P, Pal K. A study to compare hypolipidemic effects of Allium sativum (Garlic) alone and in combination with atorvastatin or ezetimibe in experimental model. Serbian Journal of Experimental and Clinical Research. 2021;22(1):11-9. doi: 10.2478/sjecr-2020-0058.
47. Gadhave D, Tupe S, Tagalpallewar A, Gorain B, Choudhury H, Kokare C. Nose to brain delivery of amisulpride loaded lipid based poloxamer gellan gum nanoemulgel: in vitro and in vivo pharmacological studies. Int J Pharm. 2021 Sep 25;607:121050. doi: 10.1016/j.ijpharm.2021.121050, PMID 34454028.
48. Stanisz B, Kania L. Validation of HPLC method for determination of atorvastatin in tablets and for monitoring stability in solid phase. Acta Pol Pharm. 2006;63(6):471-6. PMID 17438862.
49. Kumar T, Panigrahi B, Nariya M, Thakar A. Pharmacokinetic analysis of Tulasi Swarasadi Taila administered through Nasya (therapeutic nasal administration) and oral route in albino rats. AYU (An Int Q J Res Ayurveda). 2023;44(3):107-13. doi: 10.4103/ayu.ayu_366_21.
50. Seo YB, Kim JH, Song JH, Jung W, Nam KY, Kim N. Safety and pharmacokinetic comparison between fenofibric acid 135 mg capsule and 110 mg enteric coated tablet in healthy volunteers. Transl Clin Pharmacol. 2023;31(2):95-104. doi: 10.12793/tcp.2023.31.e7, PMID 37440778.
51. Omar SH, Osman R, Mamdouh W, Abdel Bar HM, Awad GA. Bioinspired lipid-polysaccharide modified hybrid nanoparticles as a brain-targeted highly loaded carrier for a hydrophilic drug. Int J Biol Macromol. 2020;165(A):483-94. doi: 10.1016/j.ijbiomac.2020.09.170, PMID 32987085.
52. Sahil S, Bodh S, Verma P. Spirulina platensis: a comprehensive review of its nutritional value antioxidant activity and functional food potential. J Cell Biotechnol. 2024;10(2):159-72. doi: 10.3233/JCB-240151.
53. Nikolova K, Gentscheva G, Gyurova D, Pavlova V, Dincheva I, Velikova M. Metabolomic profile of Arthrospira platensis from a Bulgarian bioreactor a potential opportunity for inclusion in dietary supplements. Life (Basel). 2024;14(2):174. doi: 10.3390/life14020174, PMID 38398682.
54. Begum N, Qi F, Yang F, Khan QU, Faizan FQ, Fu Q. Nutritional composition and functional properties of a platensis derived peptides: a green and sustainable protein rich supplement. Processes. 2024;12(11):2608. doi: 10.3390/pr12112608.
55. Cai Z, Lei X, Lin Z, Zhao J, Wu F, Yang Z. Preparation and evaluation of sustained release solid dispersions co-loading gastrodin with borneol as an oral brain targeting enhancer. Acta Pharm Sin B. 2014;4(1):86-93. doi: 10.1016/j.apsb.2013.12.012, PMID 26579369.
56. Banks WA, Sharma P, Bullock KM, Hansen KM, Ludwig N, Whiteside TL. Transport of extracellular vesicles across the blood brain barrier: brain pharmacokinetics and effects of inflammation. Int J Mol Sci. 2020;21(12):4407. doi: 10.3390/ijms21124407, PMID 32575812.
57. Xia HM, Su LN, Guo JW, Liu GM, Pang ZQ, Jiang XG. Determination of vinpocetine and its primary metabolite apovincaminic acid in rat plasma by liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(22):1959-66. doi: 10.1016/j.jchromb.2010.05.029, PMID 20561830.
58. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. doi: 10.3390/pharmaceutics10020057, PMID 29783687.
59. Malviya V. Preparation and evaluation of emulsomes as a drug delivery system for bifonazole. Indian J Pharm Educ Res. 2021;55(1):86-94. doi: 10.5530/ijper.55.1.12.
60. Vyas SP, Subhedar R, Jain S. Development and characterization of emulsomes for sustained and targeted delivery of an antiviral agent to liver. J Pharm Pharmacol. 2006;58(3):321-6. doi: 10.1211/jpp.58.3.0005, PMID 16536898.
61. Ucisik MH, Sleytr UB, Schuster B. Emulsomes meet S-layer proteins: an emerging targeted drug delivery system. Curr Pharm Biotechnol. 2015;16(4):392-405. doi: 10.2174/138920101604150218112656, PMID 25697368.
62. Clementino AR, Pellegrini G, Banella S, Colombo G, Cantu L, Sonvico F. Structure and fate of nanoparticles designed for the nasal delivery of poorly soluble drugs. Mol Pharm. 2021;18(8):3132-46. doi: 10.1021/acs.molpharmaceut.1c00366, PMID 34259534.
63. Tang Q. Structure and rheological properties of airway mucus and counterion condensation around charged nanoparticles. University of North Carolina at Chapel Hill; 2021. doi: 10.17615/jf89-br13.
64. Knudsen KB, Northeved H, Ek PK, Permin A, Andresen TL, Larsen S. Differential toxicological response to positively and negatively charged nanoparticles in the rat brain. Nanotoxicology. 2014;8(7):764-74. doi: 10.3109/17435390.2013.829589, PMID 23889261.
65. Dunnhaupt S, Kammona O, Waldner C, Kiparissides C, Bernkop Schnurch A. Nano-carrier systems: strategies to overcome the mucus gel barrier. Eur J Pharm Biopharm. 2015 Oct;96:447-53. doi: 10.1016/j.ejpb.2015.01.022, PMID 25712487.
66. Dante S, Petrelli A, Petrini EM, Marotta R, Maccione A, Alabastri A. Selective targeting of neurons with inorganic nanoparticles: revealing the crucial role of nanoparticle surface charge. ACS Nano. 2017;11(7):6630-40. doi: 10.1021/acsnano.7b00397, PMID 28595006.
67. Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization pharmacokinetic and pharmacodynamic evaluation. Drug Deliv. 2016;23(2):395-404. doi: 10.3109/10717544.2014.914986, PMID 24865287.
68. Xu Q, Nakajima M, Liu Z, Shii T. Soybean based surfactants and their applications. In: Ng TB, editor. Soybean applications and technology. InTech; 2011. p. 341-64. doi: 10.5772/15261.
69. Aldawsari HM, Ahmed OA, Alhakamy NA, Neamatallah T, Fahmy UA, Badr Eldin SM. Lipidic nano-sized emulsomes potentiates the cytotoxic and apoptotic effects of raloxifene hydrochloride in MCF-7 human breast cancer cells: factorial analysis and in vitro anti-tumor activity assessment. Pharmaceutics. 2021;13(6):783. doi: 10.3390/pharmaceutics13060783, PMID 34073780.
70. Sultana S, Alzahrani N, Alzahrani R, Alshamrani W, Aloufi W, Ali A. Stability issues and approaches to stabilised nanoparticles based drug delivery system. J Drug Target. 2020;28(5):468-86. doi: 10.1080/1061186X.2020.1722137, PMID 31984810.
71. Helmy HS, El Sahar AE, Sayed RH, Shamma RN, Salama AH, Elbaz EM. Therapeutic effects of lornoxicam loaded nanomicellar formula in experimental models of rheumatoid arthritis. Int J Nanomedicine. 2017;12:7015-23. doi: 10.2147/IJN.S147738, PMID 29026298.
72. Salama AH, Abdelkhalek AA, Elkasabgy NA. Etoricoxib loaded bio-adhesive hybridized polylactic acid based nanoparticles as an intra-articular injection for the treatment of osteoarthritis. Int J Pharm. 2020 Mar 30;578:119081. doi: 10.1016/j.ijpharm.2020.119081, PMID 32006623.
73. Stetefeld J, McKenna SA, Patel TR. Dynamic light scattering: a practical guide and applications in biomedical sciences. Biophys Rev. 2016;8(4):409-27. doi: 10.1007/s12551-016-0218-6, PMID 28510011.
74. Eita AS, Makky AM, Anter A, Khalil IA. Atorvastatin loaded emulsomes foam as a topical antifungal formulation. Int J Pharm X. 2022 Nov 21;4:100140. doi: 10.1016/j.ijpx.2022.100140, PMID 36465276.
75. Mehanna MM, Mneimneh AT. Formulation and applications of lipid based nanovehicles: spotlight on self-emulsifying systems. Adv Pharm Bull. 2021;11(1):56-67. doi: 10.34172/apb.2021.006, PMID 33747852.
76. Shinde NG, Aloorkar NH, Kulkarni AS. Recent advances in vesicular drug delivery system. Res J Pharm Dosage Forms Technol. 2014;6(2):110-20.
77. Pilch E, Musial W. Liposomes with an ethanol fraction as an application for drug delivery. Int J Mol Sci. 2018;19(12):3806. doi: 10.3390/ijms19123806, PMID 30501085.
78. Maeki M, Kimura N, Okada Y, Shimizu K, Shibata K, Miyazaki Y. Understanding the effects of ethanol on the liposome bilayer structure using microfluidic based time resolved small angle X-ray scattering and molecular dynamics simulations. Nanoscale Adv. 2024;6(8):2166-76. doi: 10.1039/d3na01073b, PMID 38633055.
79. Taiti C, Di Vito M, Di Mercurio M, Costantini L, Merendino N, Sanguinetti M. Detection of secondary metabolites proximate composition and bioactivity of organic dried Spirulina (Arthrospira platensis). Appl Sci. 2024;14(1):67. doi: 10.3390/app14010067.
80. Efendy Goon D, Sheikh Abdul Kadir SH, Latip NA, Rahim SA, Mazlan M. Palm oil in lipid based formulations and drug delivery systems. Biomolecules. 2019 Feb 13;9(2):64. doi: 10.3390/biom9020064.
81. El Hosary R, Teaima MH, El Nabarawi M, Yousry Y, Eltahan M, Bakr A. Topical delivery of extracted curcumin as curcumin loaded spanlastics anti-aging gel: optimization using experimental design and ex-vivo evaluation. Saudi Pharm J. 2024;32(1):101912. doi: 10.1016/j.jsps.2023.101912, PMID 38178851.
82. Takahashi HK, Nishibori M. The antitumour activities of statins. Curr Oncol. 2007;14(6):246. doi: 10.3747/co.2007.159, PMID 18080017.
83. Bolat ZB, Islek Z, Demir BN, Yilmaz EN, Sahin F, Ucisik MH. Curcumin and piperine loaded emulsomes as combinational treatment approach enhance the anticancer activity of curcumin on HCT116 colorectal cancer model. Front Bioeng Biotechnol. 2020 Feb;8:50. doi: 10.3389/fbioe.2020.00050, PMID 32117930.
84. Subramaiam H, Chu WL, Radhakrishnan AK, Chakravarthi S, Selvaduray KR, Kok YY. Evaluating anticancer and immunomodulatory effects of spirulina (Arthrospira) platensis and gamma tocotrienol supplementation in a syngeneic mouse model of breast cancer. Nutrients. 2021;13(7):2320. doi: 10.3390/nu13072320, PMID 34371830.
85. Das UN. Molecular mechanism of anti-cancer action of PUFAs with particular reference to GLA in glioma. In: Molecular biochemical aspects of cancer. New York: Springer US; 2020. p. 181-206. doi: 10.1007/978-1-0716-0741-1_5.
86. Dima C, Assadpour E, Dima S, Jafari SM. Nutraceutical nanodelivery; an insight into the bioaccessibility/bioavailability of different bioactive compounds loaded within nanocarriers. Crit Rev Food Sci Nutr. 2021;61(18):3031-65. doi: 10.1080/10408398.2020.1792409, PMID 32691612.
87. Hassanin SO, Hegab AM, Mekky RH, Said MA, Khalil MG, Hamza AA. Combining in vitro, in vivo, and network pharmacology assays to identify targets and molecular mechanisms of spirulina derived biomolecules against breast cancer. Mar Drugs. 2024;22(7):328. doi: 10.3390/md22070328, PMID 39057437.
88. Alarfi H, Youssef LA, Salamoon M. A prospective randomized placebo-controlled study of a combination of simvastatin and chemotherapy in metastatic breast cancer. J Oncol. 2020 Aug 10;2020:4174395. doi: 10.1155/2020/4174395, PMID 32849871.
89. Barua S, Mitragotri S. Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects. Nano Today. 2014;9(2):223-43. doi: 10.1016/j.nantod.2014.04.008, PMID 25132862.
90. Vanbilloen WJ, Rechberger JS, Anderson JB, Nonnenbroich LF, Zhang L, Daniels DJ. Nanoparticle strategies to improve the delivery of anticancer drugs across the blood–brain barrier to treat brain tumors. Pharmaceutics. 2023;15(7):1804. doi: 10.3390/pharmaceutics15071804, PMID 37513992.
91. Jeong SH, Jang JH, Lee YB. Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors. J Pharm Investig. 2023;53(1):119-52. doi: 10.1007/s40005-022-00589-5, PMID 35910081.
92. Gama F, Meirinho S, Pires PC, Tinoco J, Martins Gaspar MC, Baltazar G. Simvastatin is delivered to the brain by high strength intranasal cationic SMEDDS and nanoemulsions. Drug Deliv Transl Res. 2025;15(8):2749-64. doi: 10.1007/s13346-024-01769-6, PMID 39747745.
93. Yadav KS, Nijhawan HP, Nirale P, Singhal D, Soni G. Efficient nose to brain delivery of chitosan coated resveratrol nanoemulsion in rats: formulation optimized using D-optimal mixture design. J Dispers Sci Technol. 2025:1-15. doi: 10.1080/01932691.2025.2483899.
94. Bava B, Sharma K, Yadav V. Intranasal drug delivery system: a review. Res J Sci Technol. 2024;16(1):51-8. doi: 10.52711/2349-2988.2024.00009.
95. Agnihotri TG, Dahifale A, Gomte SS, Rout B, Peddinti V, Jain A. Nanosystems at nexus: navigating nose to brain delivery for glioblastoma treatment. Mol Pharm. 2025;22(2):599-619. doi: 10.1021/acs.molpharmaceut.4c00703, PMID 39746097.
96. Bonferoni MC, Rossi S, Sandri G, Ferrari F, Gavini E, Rassu G. Nanoemulsions for nose to brain drug delivery. Pharmaceutics. 2019;11(2):84. doi: 10.3390/pharmaceutics11020084, PMID 30781585.
97. Baghel P, Roy A, Verma S, Satapathy T, Bahadur S. Amelioration of lipophilic compounds in regards to bioavailability as self-emulsifying drug delivery system (SEDDS). Future J Pharm Sci. 2020;6:1-11.
98. Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141-60. doi: 10.2165/00003088-200342130-00005, PMID 14531725.
99. Elsharkawy M F, M Amin M, A Shamsel-Din H, Ibrahim W, Ibrahim AB, Sayed S. Self-assembling lecithin-based mixed polymeric micelles for nose to brain delivery of clozapine: in vivo assessment of drug efficacy via radiobiological evaluation. International Journal of Nanomedicine. 2023:1577-95.
100. Lin H, Xie L, Lv L, Chen J, Feng F, Liu W. Intranasally administered thermosensitive gel for brain-targeted delivery of rhynchophylline to treat Parkinson’s disease. Colloids Surf B Biointerfaces. 2023;222:113065. doi: 10.1016/j.colsurfb.2022.113065, PMID 36473372.
Published
How to Cite
Issue
Section
Copyright (c) 2025 Mahmoud Eltahan, Doha H. Abou Baker, Heba S Abbas, Rehab Abdelmonem , Mohamed El-Nabarawi, Alshaimaa Attia
This work is licensed under a Creative Commons Attribution 4.0 International License.
