Nanoemulsions and Solid Lipid Nanoparticles with Encapsulated Doxorubicin and Thymoquinone

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Nanoemulsions (NEs) and solid lipid nanoparticles (SLNs) are promising drug delivery systems. In this work, paraffin oil NEs and stearic acid SLNs stabilized with Tween 60 and Span 60 have been studied. NEs with an average droplet diameter of ~50 nm and suspensions of SLNs with an average size of ~30 nm are stable to aggregation for more than 90 days. The rates of penetration of lipid particles into cancer cells (C6 and MCF-7) depend on their sizes. After incubation for 1 h, lipid nanoparticles ~50 nm in size penetrate into cells, are distributed in their internal space, and concentrate in the nuclei. The cytotoxicity of doxorubicin- or thymoquinone-loaded NEs and SLNs against MCF-7 and HTC 116 cell lines is higher than the cytotoxicity of the individual substances. Wherein, unloaded NEs and SLNs show low cytotoxicity. The obtained results demonstrate that paraffin oil NEs and stearic acid SLNs are promising to be used as carriers of both lipophilic and amphiphilic drugs, including doxorubicin and thymoquinone. The accumulation of lipid nanoparticles with sizes smaller than 100 nm in cell nuclei is an advantage of such systems for the delivery of anticancer drugs, because this leads to DNA replication suppression followed by cell apoptosis.

About the authors

E. V. Mishchenko

Mendeleev University of Chemical Technology of Russia, 125047, Moscow, Russia

Email: mishchenkoek@list.ru
Россия, 125047, Москва, Миусская пл., д. 9

A. M. Gileva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

Email: m.yu.kor@gmail.com
Россия, 117997, Москва, ул. Миклухо-Маклая, д. 16/10

E. A. Markvicheva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

Email: m.yu.kor@gmail.com
Россия, 117997, Москва, ул. Миклухо-Маклая, д. 16/10

M. Yu. Koroleva

Mendeleev University of Chemical Technology of Russia, 125047, Moscow, Russia

Author for correspondence.
Email: m.yu.kor@gmail.com
Россия, 125047, Москва, Миусская пл., д. 9

References

  1. McClements D.J., Decker E.A., Weiss J. Emulsion-based delivery systems for lipophilic bioactive components // J. Food Sci. 2007. V. 72. № 8. P. 109–124. https://doi.org/10.1111/j.1750-3841.2007.00507.x
  2. Salah E., Abouelfetouh M.M., Pan Y., Chen D., Xie S. Solid lipid nanoparticles for enhanced oral absorption: A review // Colloids Surf. B. 2020. V. 196. 111305. https://doi.org/10.1016/j.colsurfb.2020.111305
  3. Koroleva M.Y., Yurtov E.V. Nanoemulsions: The properties, methods of preparation and promising applications // Russ. Chem. Rev. 2012. V. 81. № 1. P. 21–43. https://doi.org/10.1070/RC2012v081n01ABEH004219
  4. Koroleva M., Nagovitsina T., Yurtov E. Nanoemulsions stabilized by non-ionic surfactants: Stability and degradation mechanisms // PCCP. 2018. V. 20. P. 10369–10377. https://doi.org/10.1039/C7CP07626F
  5. Mirgorodskaya A.B., Koroleva M.Y., Kushnazarova R.A., Mishchenko E.V., Petrov K.A., Lenina O.A., Vyshtakalyuk A.B., Voloshina A.D., Zakharova L.Y. Microemulsions and nanoemulsions modified with cationic surfactants for improving the solubility and therapeutic efficacy of loaded drug indomethacin // Nanotechnology. 2022. V. 33. 155103. https://doi.org/10.1088/1361-6528/ac467d
  6. Koroleva M., Portnaya I., Mischenko E., Abutbul-Ionita I., Kolik-Shmuel L., Danino D. Solid lipid nanoparticles and nanoemulsions with solid shell: Physical and thermal stability // J. Colloid Interface Sci. 2022. V. 610. № 3. P. 61–69. https://doi.org/10.1016/j.jcis.2021.12.010
  7. Мищенко Е.В., Тимофеева Е.Е., Артамонов А.С., Портная И.Б., Королева М.Ю. Наноэмульсии и нанокапсулы с олеиновой кислотой // Коллоид. журн. 2022. Т. 81. № 1. С. 67–73. https://doi.org/10.31857/S0023291222010086
  8. Koroleva M.Yu., Tokarev A.M., Yurtov E.V. Simulations of emulsion stabilization by silica nanoparticles // Mendeleev Communications. 2017. V. 27. № 5. P. 518–520. https://doi.org/10.1016/j.mencom.2017.09.030
  9. O’Shaughnessy J.A. Pegylated liposomal doxorubicin in the treatment of breast cancer // Clin. Breast Cancer. 2003. V. 4. P. 318−328. https://doi.org/10.3816/cbc.2003.n.037
  10. Perez A.T., Domenech G.H., Frankel C., Vogel C.L. Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: the Cancer Research Network, Inc., experience // Cancer Invest. 2002. V. 20. P. 22–29. https://doi.org/10.1081/cnv-120014883
  11. Symon Z., Peyser A., Tzemach D., Lyass O., Sucher E., Shezen E., Gabizon A. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes // Cancer. 1999. V. 86. P. 72–78.
  12. Ballout F., Habli Z., Rahal O.N., Fatfat M., Gali-Muhtasib H. Thymoquinone-based nanotechnology for cancer therapy // Drug Discov. Today. 2018. V. 23. № 5. P. 1089–1098. https://doi.org/10.1016/j.drudis.2018.01.043
  13. Salem A.A., El Haty I.A., Abdou I.M., Mu Y. Interaction of human telomeric G-quadruplex DNA with thymoquinone: A possible mechanism for thymoquinone anticancer effect // Biochimica Biophysica Acta. 2015. V. 1850. № 2. P. 329–342. https://doi.org/10.1016/j.bbagen.2014.10.018
  14. Alaaeldin E., Mostafa M., Mansour H.F., Soliman G.M. Spanlastics as an efficient delivery system for the enhancement of thymoquinone anticancer efficacy: Fabrication and cytotoxic studies against breast cancer cell lines // J. Drug Delivery Sci. Technol. 2021. V. 65. 102725. https://doi.org/10.1016/j.jddst.2021.102725
  15. Afrose S.S., Junaid M., Akter Y., Tania M., Zheng M., Khan M. A. Targeting kinases with thymoquinone: a molecular approach to cancer therapeutics // Drug Discovery Today. 2020. V. 25. № 12. P. 2294–2306. https://doi.org/10.1016/j.drudis.2020.07.019
  16. Fatfat M., Fakhoury I., Habli Z., Mismar R., Gali-Muhtasib, H. Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms // Life Sci. 2019. V. 232. P. 116628. https://doi.org/10.1016/j.lfs.2019.116628
  17. Zheng G., Zheng M., Yang B., Fu H., Li Y. Improving breast cancer therapy using doxorubicin loaded solid lipid nanoparticles: Synthesis of a novel arginine-glycine-aspartic tripeptide conjugated, pH sensitive lipid and evaluation of the nanomedicine in vitro and in vivo // Biomed. Pharmacotherapy. 2019. V. 116. P. 109006. https://doi.org/10.1016/j.biopha.2019.109006
  18. Ying X.Y., Cui D., Yu L., Du Y.Z. Solid lipid nanoparticles modified with chitosan oligosaccharides for the controlled release of doxorubicin // Carbohydrate Polym. 2011. V. 84. P. 1357–1364. https://doi.org/10.1016/j.carbpol.2011.01.037
  19. Jain A., Kesharwani P., Garg N.K., Jain A., Jain S.A., Jain A.K., Jain A.K., Nirbhavane P., Ghanghoria R., Tyagi R.K., Katare O.P. Galactose engineered solid lipid nanoparticles for targeted delivery of doxorubicin // Colloids Surf. B. 2015. V. 134. P. 47–58. https://doi.org/10.1016/j.colsurfb.2015.06.027
  20. Subedi R.K., Kang K.W., Choi H.K. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin // Eur. J. Pharm. Sci. 2009. V. 37. № 3. P. 508–513. https://doi.org/10.1016/j.ejps.2009.04.008
  21. Oliveira M.S., Aryasomayajula B., Pattni B., Mussi S.V., Ferreira L.A.M., Torchilin V.P. Solid lipid nanoparticles co-loaded with doxorubicin and α-tocopherol succinate are effective against drug-resistant cancer cells in monolayer and 3-D spheroid cancer cell models // Int. J. Pharm. 2016. V. 512. № 1. P. 202–300. https://doi.org/10.1016/j.ijpharm.2016.08.049
  22. Battaglia L., Gallarate M., Peira E., Chirio D., Muntoni E., Biasibetti E., Capucchio M.T., Valazza A., Panciani P.P., Lanotte M., Schiffer D., Annovazzi L., Caldera V., Mellai M., Riganti C. Solid lipid nanoparticles for potential doxorubicin delivery in glioblastoma treatment: Preliminary in vitro studies // J. Pharm. Sci. 2014. V. 103. № 7. P. 2157–2165. https://doi.org/10.1002/jps.24002
  23. Kuo Y.C., Lee I.H. Delivery of doxorubicin to glioblastoma multiforme in vitro using solid lipid nanoparticles with surface aprotinin and melanotransferrin antibody for enhanced chemotherapy // J. Taiwan Institute Chem. Eng, 2016. V. 61. P. 32–45. https://doi.org/10.1016/j.jtice.2015.12.012
  24. Kuo Y.C., Liang C.T. Catanionic solid lipid nanoparticles carrying doxorubicin for inhibiting the growth of U87MG cells // Colloids Surf. B. V. 85. № 2. P. 131–137. https://doi.org/10.1016/j.colsurfb.2011.02.011
  25. Miglietta A., Cavalli R., Bocca C., Gabriel L., Gasco R.M. Cellular uptake and cytotoxicity of solid lipid nanospheres (SLN) incorporating doxorubicin or paclitaxel // Int. J. Pharm. 2000. V. 210. № 1–2. P. 61–67. https://doi.org/10.1016/s0378-5173(00)00562-7
  26. Ramachandran S., Thangarajan S. A novel therapeutic application of solid lipid nanoparticles encapsulated thymoquinone (TQ-SLNs) on 3-nitroproponic acid induced Huntington’s disease-like symptoms in wistar rats // Chem. Biol. Interact. 2016. V. 256. P. 25–36. https://doi.org/10.1016/j.cbi.2016.05.020
  27. Ali A., Ali S., Aqil M., Imam S.S., Ahad A., Qadir A. Thymoquinone loaded dermal lipid nano particles: Box Behnken design optimization to preclinical psoriasis assessment // J. Drug Delivery Sci. Technol. 2019. V. 52. P. 713–721. https://doi.org/10.1016/j.jddst.2019.05.041
  28. Alam M., Zameer S., Najmi A.K., Ahmad F.J., Imam S.S., Akhtar M. Thymoquinone loaded solid lipid nanoparticles demonstrated antidepressant-like activity in rats via indoleamine 2,3-dioxygenase pathway // Drug Research. 2020. V. 70. № 5. P. 1131–7793. https://doi.org/10.1055/a-1131-7793
  29. Qizilbash F.F., Ashhar M.U., Zafar A., Qamar Z., Annu A.J., Baboota S., Ghoneim M.M. Alshehri S., Ali A. Thymoquinone-enriched naringenin-loaded nanostructured lipid carrier for brain delivery via nasal route: In vitro prospect and in vivo therapeutic efficacy for the treatment of depression // Pharm. 2022. V. 14. № 3. P. 656. https://doi.org/10.3390/pharmaceutics14030656
  30. Radwan M.F., El-Moselhy M.A., Alarif W.M., Orif M., Alruwaili N.K., Alhakamy N.A. Optimization of thymoquinone-loaded self-nanoemulsion for management of indomethacin-induced ulcer // Dose-Response. 2021. V. 19. № 1. 15593258211013655. https://doi.org/10.1177/15593258211013655
  31. Desai J., Thakkar H. Enhanced oral bioavailability and brain uptake of Darunavir using lipid nanoemulsion formulation // Colloids Surf. B. 2018. V. 175. P. 143–149. https://doi.org/10.1016/j.colsurfb.2018.11.057
  32. Chawla J.S., Amiji M.M. Biodegradable poly(ε-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen // Int. J. Pharm. 2002. V. 249. № 1–2. P. 127–138. https://doi.org/10.1016/s0378-5173(02)00483-0
  33. Granja A., Nunes C., Sousa C.T., Reis S. Folate receptor-mediated delivery of mitoxantrone-loaded solid lipid nanoparticles to breast cancer cells // Biomed. Pharmacotherapy. 2022. V. 154. P. 113525. https://doi.org/10.1016/j.biopha.2022.113525
  34. Parvez S., Karole A., Mudavath S.L. Transport mechanism of hydroxy-propyl-beta-cyclodextrin modified solid lipid nanoparticles across human epithelial cells for the oral absorption of antileishmanial drugs // BBA. 2022. V. 1866. № 8. P. 130157. https://doi.org/10.1016/j.bbagen.2022.130157
  35. Vighi E., Montanari M., Ruozi B., Tosi G., Magli A., Leo E. Nuclear localization of cationic solid lipid nanoparticles containing Protamine as transfection promoter // Eur. J. Pharm. Biopharm. 2010. V. 76. № 3. P. 384–393. https://doi.org/10.1016/j.ejpb.2010.07.012
  36. Gao Y., Cheng X., Wang Z., Wang J., Gao T., Li P., Kong M., Chen X. Transdermal delivery of 10,11-methylenedioxycamptothecin by hyaluronic acid based nanoemulsion for inhibition of keloid fibroblast // Carbohydr. Polym. 2014. V. 112. P. 376–386. https://doi.org/10.1016/j.carbpol.2014.05.026
  37. Periasamy V.S., Athinarayanan J., Alshatwi, A.A. Anticancer activity of an ultrasonic nanoemulsion formulation of Nigella sativa L. essential oil on human breast cancer cells // Ultrason. Sonochem. 2016. V. 31. P. 449–455. https://doi.org/10.1016/j.ultsonch.2016.01.035
  38. Miyake M., Kakizawa Y., Tobori N., Kurioka M., Tabuchi N., Kon R., Shimokawa N., Tsujino, Y., Takagi M. Membrane permeation of giant unilamellar vesicles and corneal epithelial cells with lipophilic vitamin nanoemulsions // Colloids Surf. B. 2018. V. 169. P. 444–452. https://doi.org/10.1016/j.colsurfb.2018.05.052
  39. Rodrigues G.B., Brancini G.T.P., Pinto M.R., Primo F.L., Wainwright M., Tedesco A.C., Braga G.Ú.L. Photodynamic inactivation of Candida albicans and Candida tropicalis with aluminum phthalocyanine chloride nanoemulsion // Fungal Biology. 2020. V. 124. № 5. P. 297–303. https://doi.org/10.1016/j.funbio.2019.08.004
  40. Izquierdo P., Feng J., Esquena J., Tadros T.F., Dederen J.C., Garcia M.J., Azemar N., Solans C. The influence of surfactant mixing ratio on nano-emulsion formation by the pit method // J. Colloid Interface Sci. 2005. V. 285. № 1. P. 388–394. https://doi.org/10.1016/j.jcis.2004.10.047
  41. Joshi M.D., Muller R.H. Lipid nanoparticles for parenteral delivery of actives // Eur. J. Pharm. Biopharm. 2009. V. 71. № 2. P. 161–172. https://doi.org/10.1016/j.ejpb.2008.09.003
  42. Salmani J.M., Asghar S., Lv H., Zhou J. Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; Probing the effects of solvents, pH and light // Molecules. 2014. V. 19. № 5. P. 5925–5939. https://doi.org/10.3390/molecules19055925
  43. Motaghed M., Al-Hassan F.M., Hamid, S.S. Cellular responses with thymoquinone treatment in human breast cancer cell line MCF-7 // Pharmacognosy Res. 2012. V. 5. № 3. P. 200–206. https://doi.org/10.4103/0974-8490.112428
  44. Parisi C., Moret F., Fraix A., Menilli L., Failla M., Sodano F., Conte C., Quaglia F., Reddi E., Sortino S. Doxorubicin–NO releaser molecular hybrid activatable by green light to overcome resistance in breast cancer cells // ACS Omega. 2022. V. 7. № 9. P. 7452–7459. https://doi.org/10.1021/acsomega.1c03988
  45. Tian Y., Tam M.K., Hatton, T.A., Bromberg, L. Titration microcalorimetry study: Interaction of drug and ionic microgel system // Chemistry. 2004. P. 1–5. http://hdl.handle.net/1721.1/3953.
  46. Akter H., Rashid Md.M., Islam Md.S., Hossen Md.A., Rahman Md.A., Algheshairy R.M., Almujaydil M.S., Alharbi H.F., Alnajeebi A.M. Biometabolites of Tamarindus indica play a remarkable cardioprotective role as a functional food in doxorubicin-induced cardiotoxicity models // J. Func. Foods. 2022. V. 96. P. 105212. https://doi.org/10.1016/j.jff.2022.105212
  47. Hansch C., Leo A., Hoekman D. Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. Washington: American Chemical Society, 1995.

Supplementary files

Supplementary Files
Action
1. JATS XML
2.

Download (283KB)
3.

Download (702KB)
4.

Download (427KB)
5.

Download (349KB)


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies