Abstract
Silibinin is considered as a functionalized flavonoid and natural substitute for synthetic anticancer drugs like doxorubicin, paclitaxel, etc. However, the principle reasons for restraining the bioavailability of silibinin are low aqueous solubility, less penetration into the epithelial cells of the intestine and rapid systemic elimination. This present work focused on the development of inclusion complexes of silibinin with hydroxypropyl-β-cyclodextrin and further incorporated into hybrid liposomes to improve solubility, bioavailability and stability as well as to explore the anticancer activity of silibinin. Hybrid liposomes were prepared by thin lipid film hydration method. Molecular docking studies projected for the formation of complex with physicochemical structural changes which were confirmed by ATR-FTIR, DSC, XRD, 1H NMR and SEM studies. The particle size distribution of hybrid liposomal formulations was obtained in the range of 200–500 nm with zeta potential more than – 30 mV. The release of silibinin from hybrid liposomes was maximum (75.40% ± 0.73) with better solubility (73.95 mg/mL) and relative bioavailability (4.52). This drug delivery system exhibited higher cytotoxicity against kidney cancer cell line (A-498) through endocytic internalization into the cells and good pharmacokinetic properties as compared with silibinin. In near future, hybrid liposomes can be a promising carrier for increasing the solubility, bioavailability and stability of silibinin.
Graphic abstract
Similar content being viewed by others
References
Aadinath W, Bhushani A, Anandharamakrishnan C (2016) Synergistic radical scavenging potency of curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes. Mater Sci Eng C 64:293–302. https://doi.org/10.1016/j.msec.2016.03.095
Al-Burtomani SKS, Suliman FEO (2017) Inclusion complexes of norepinephrine with β-cyclodextrin, 18-crown-6 and cucurbit[7]uril: experimental and molecular dynamics study. RSC Adv 7:9888–9901. https://doi.org/10.1039/c6ra28638k
Aloisio C, Antimisiaris SG, Longhi MR (2017) Liposomes containing cyclodextrins or meglumine to solubilize and improve the bioavailability of poorly soluble drugs. J Mol Liq 229:106–113. https://doi.org/10.1016/j.molliq.2016.12.035
Azzi J, Jraij A, Auezova L et al (2018) Novel findings for quercetin encapsulation and preservation with cyclodextrins, liposomes, and drug-in-cyclodextrin-in-liposomes. Food Hydrocoll 81:328–340. https://doi.org/10.1016/j.foodhyd.2018.03.006
Baldim I, Oliveira AM, Souto EB, Oliveira WP (2022) Cyclodextrins-in-liposomes: a promising delivery system for lippia sidoides and syzygium aromaticum essential oils. Life 12:1–12. https://doi.org/10.3390/life12010095
Bijak M (2017) Silybin, a major bioactive component of milk thistle (Silybum Marianum L. Gaernt.)—chemistry, bioavailability, and metabolism. Molecules 22:1–11. https://doi.org/10.3390/molecules22111942
Castillo Cruz B, Flores Colón M, Rabelo Fernandez RJ et al (2022) A fresh look at the potential of cyclodextrins for improving the delivery of siRNA encapsulated in liposome nanocarriers. ACS Omega 7:3731–3737. https://doi.org/10.1021/acsomega.1c06436
Do Thi T, Nauwelaerts K, Froeyen M et al (2010) Comparison of the complexation between methylprednisolone and different cyclodextrins in solution by1H-NMR and molecular modeling studies. J Pharm Sci 99:3863–3873. https://doi.org/10.1002/jps.22227
Entezari M, Atabi F (2017) Preparation and characterization of Myristoylated chitosan Nanogel as carrier of Silibinin for breast cancer therapy. Galen Med J 6:136–144. https://doi.org/10.31661/gmj.v6i2.822
Fallah M, Davoodvandi A, Nikmanzar S et al (2021) Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer. Biomed Pharmacother 142:112024. https://doi.org/10.1016/j.biopha.2021.112024
Feldman NB, Gromovykh TI, Sedyakina NE et al (2018) Cytotoxic and antitumor activity of Liposomal Silibinin. Bionanoscience 8:971–976. https://doi.org/10.1007/s12668-018-0556-x
Fernández-Romero AM, Maestrelli F, Mura PA et al (2018) Novel findings about double-loaded curcumin-in-HPβcyclodextrin-in liposomes: effects on the lipid bilayer and drug release. Pharmaceutics 10:256. https://doi.org/10.3390/pharmaceutics10040256
Hammoud Z, Gharib R, Fourmentin S et al (2020) Drug-in-hydroxypropyl-β-cyclodextrin-in-lipoid S100/cholesterol liposomes: Effect of the characteristics of essential oil components on their encapsulation and release. Int J Pharm 579:119151. https://doi.org/10.1016/j.ijpharm.2020.119151
Jahanafrooz Z, Motamed N, Rinner B, Mokhtarzadeh A (2018) Silibinin to improve cancer therapeutic, as an apoptotic inducer, autophagy modulator, cell cycle inhibitor, and microRNAs regulator. Life Sci 213:236–247. https://doi.org/10.1016/j.lfs.2018.10.009
Karn PR, Cho W, Park HJ et al (2013) Characterization and stability studies of a novel liposomal cyclosporin a prepared using the supercritical fluid method: comparison with the modified conventional Bangham method. Int J Nanomed 8:365–377. https://doi.org/10.2147/IJN.S39025
Kellici TF, Ntountaniotis D, Leonis G et al (2015) Investigation of the Interactions of Silibinin with 2-Hydroxypropyl-β-cyclodextrin through biophysical techniques and computational methods. Mol Pharm 12:954–965. https://doi.org/10.1021/mp5008053
Liu J, Boonkaew B, Arora J et al (2015) Comparison of sorafenib-loaded poly (Lactic/Glycolic) acid and dppc liposome nanoparticles in the in vitro treatment of renal cell carcinoma. J Pharm Sci 104:1187–1196. https://doi.org/10.1002/jps.24318
Ma Z, Liu W, Zeng J et al (2015) Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in renal cell carcinoma. Oncol Rep 34:2461–2468. https://doi.org/10.3892/or.2015.4224
Molavi O, Narimani F, Asiaee F et al (2017) Silibinin sensitizes chemo-resistant breast cancer cells to chemotherapy. Pharm Biol 55:729–739. https://doi.org/10.1080/13880209.2016.1270972
Mura P (2020) Advantages of the combined use of cyclodextrins and nanocarriers in drug delivery: a review. Int J Pharm 579:119181. https://doi.org/10.1016/j.ijpharm.2020.119181
Ochi MM, Amoabediny G, Rezayat SM et al (2010) In Vitro Co-delivery evaluation of novel pegylated nano-liposomal herbal drugs of silibinin and glycyrrhizic acid (nano-phytosome) to hepatocellular carcinoma cells. Cell J 18:135–48
Pal A, Roy S, Kumar A et al (2020) Physicochemical characterization, molecular docking, and in vitro dissolution of glimepiride-captisol inclusion complexes. ACS Omega 5:19968–19977. https://doi.org/10.1021/acsomega.0c01228
Patel S, Waghela B, Shah K et al (2018) Silibinin, a natural blend in polytherapy formulation for targeting Cd44v6 expressing colon cancer stem cells. Sci Rep 8:1–13. https://doi.org/10.1038/s41598-018-35069-0
Qiu C, Gao LN, Yan K et al (2016) A promising antitumor activity of evodiamine incorporated in hydroxypropyl-β-cyclodextrin: Pro-apoptotic activity in human hepatoma HepG2 cells. Chem Cent J 10:1–11. https://doi.org/10.1186/s13065-016-0191-y
Sahibzada MUK, Sadiq A, Zahoor M et al (2020) Enhancement of bioavailability and hepatoprotection by silibinin through conversion to nanoparticles prepared by liquid antisolvent method. Arab J Chem 13:3682–3689. https://doi.org/10.1016/j.arabjc.2020.01.002
Shaji J, Iyer S (2012) Double-loaded liposomes encapsulating Quercetin and Quercetin beta-cyclodextrin complexes: Preparation, characterization and evaluation. Asian J Pharm 6:218–226. https://doi.org/10.4103/0973-8398.104840
Shende PK, Trotta F, Gaud RS et al (2012) Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges. J Incl Phenom Macrocycl Chem 74:447–454. https://doi.org/10.1007/s10847-012-0140-x
Sornsuvit C, Hongwiset D, Yotsawimonwat S et al (2018) The Bioavailability and pharmacokinetics of Silymarin SMEDDS formulation study in healthy Thai volunteers. Evidence-Based Complement Altern Med 2018:1507834. https://doi.org/10.1155/2018/1507834
Speciale A, Muscarà C, Molonia MS et al (2021) Silibinin as potential tool against SARS-Cov-2: In silico spike receptor-binding domain and main protease molecular docking analysis, and in vitro endothelial protective effects. Phyther Res 35:4616–4625. https://doi.org/10.1002/ptr.7107
Surai PF (2015) Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants (Basel, Switzerland) 4:204–247. https://doi.org/10.3390/antiox4010204
Suvarna V, Singh V, Sharma D, Murahari M (2021) Experimental and computational insight of the supramolecular complexes of Irbesartan with β-cyclodextrin based nanosponges. J Drug Deliv Sci Technol 63:102494. https://doi.org/10.1016/j.jddst.2021.102494
Takke A, Shende P (2019) Nanotherapeutic silibinin: an insight of phytomedicine in healthcare reformation. Nanomed Nanotechnol Biol Med 21: 102494.
Takke A, Shende P (2021) Magnetic-core-based silibinin nanopolymeric carriers for the treatment of renal cell cancer. Life Sci. https://doi.org/10.1016/j.lfs.2021.119377
Takke A, Shende P (2019b) Non-invasive biodiversified sensors: a modernized screening technology for cancer. Curr Pharm Des 25:4108–4120. https://doi.org/10.2174/1381612825666191022162232
Takke A, Shende P (2019) Nanotherapeutic silibinin: An insight of phytomedicine in healthcare reformation. Nanomed Nanotechnol Biol Med 21: 102057.
Tambe A, Pandita N, Kharkar P, Sahu N (2018) Encapsulation of boswellic acid with β- and hydroxypropyl-β-cyclodextrin: Synthesis, characterization, in vitro drug release and molecular modelling studies. J Mol Struct 1154:504–510. https://doi.org/10.1016/j.molstruc.2017.10.061
Tyagi AK, Agarwal C, Chan DCF, Agarwal R (2004) Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep 11:493–499. https://doi.org/10.3892/or.11.2.493
Vafaei SY, Dinarvand R, Esmaeili M et al (2014) Controlled-release drug delivery system based on fluocinolone acetonide – cyclodextrin inclusion complex incorporated in multivesicular liposomes. Pharm Develop Technol 7450:1–7. https://doi.org/10.3109/10837450.2014.920358
Yakavets I, Lassalle HP, Scheglmann D et al (2018) Temoporfin-in-cyclodextrin-in-liposome—a new approach for anticancer drug delivery: the optimization of composition. Nanomaterials 8:1–15. https://doi.org/10.3390/nano8100847
Yazdi Rouholamini SE, Moghassemi S, Maharat Z et al (2018) Effect of silibinin-loaded nano-niosomal coated with trimethyl chitosan on miRNAs expression in 2D and 3D models of T47D breast cancer cell line. Artif Cells, Nanomed, Biotechnol 46:524–535. https://doi.org/10.1080/21691401.2017.1326928
Zappacosta R, Cornelio B, Pilato S et al (2019) Effect of the incorporation of functionalized cyclodextrins in the liposomal bilayer. Molecules 24:1387. https://doi.org/10.3390/molecules24071387
Funding
Not applicable.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no potential conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Takke, A., Shende, P. Potential of cyclodextrin in hybrid liposomes for improving the solubility, bioavailability and stability of silibinin. Chem. Pap. 76, 6579–6589 (2022). https://doi.org/10.1007/s11696-022-02345-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-022-02345-3