The therapeutic application of flavonoids is limited by their low solubility, bioavailability, and metabolic stability. This study evaluates the peroxisome proliferator-activated receptor gamma (PPARγ) agonistic activity of two geranylated flavonoids from Paulownia tomentosa, mimulone and diplacone, and compares the efficacy of different nanoparticle delivery systems, including liposomes and cyclodextrins, in preserving their biological activity. Using the PPARγ CALUX reporter gene assay, it is shown that mimulone dissolved in DMSO and incubated with cell culture activates the PPARγ pathway, resulting in 2.97-fold and 3.9-fold increases in luciferase activity at concentrations of 5 and 2.5 μM, respectively. Diplacone, however, shows significant cytotoxicity, with an average cell viability of about 10% at 10 μM. Encapsulation in anionic, cationic, and neutral liposomes results in a significant reduction of biological activity of both flavonoids, with the best formulation (anionic liposomes) preserving only 54% of mimulone's activity. In contrast, hydroxypropyl-β-cyclodextrins (HP-β-CDs) retain up to 91.5% of mimulone's biological activity and significantly improve the viability profile of diplacone, maintaining cell viability at ≈100%. The performance of the HP-β-CDs can be attributed to their ability to form stable inclusion complexes with hydrophobic molecules. These results suggest that cyclodextrin-based delivery systems might effectively address solubility and stability challenges associated with flavonoid therapy.

Department of Molecular Pharmacy Faculty of Pharmacy Masaryk University Palackého tř 1946 1 612 00 Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy Masaryk University Palackého tř 1946 1 612 00 Brno Czech Republic

Department of Pharmacology and Toxicology Veterinary Research Institute Hudcova 296 70 621 00 Brno Czech Republic

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Ranjbar S., Emamjomeh A., Sharifi F., Zarepour A., Aghaabbasi K., Dehshahri A., Sepahvand A. M., Zarrabi A., Beyzaei H., Zahedi M. M., Mohammadinejad R., Pharmaceutics 2023, 15, 1944. PubMed PMC

Wang L., Waltenberger B., Pferschy‐Wenzig E.‐M., Blunder M., Liu X., Malainer C., Blazevic T., Schwaiger S., Rollinger J. M., Heiss E. H., Schuster D., Kopp B., Bauer R., Stuppner H., Dirsch V. M., Atanasov A. G., Biochem. Pharmacol. 2014, 92, 73. PubMed PMC

Song Y. H., Uddin Z., Jin Y. M., Li Z., Curtis‐Long M. J., Kim K. D., Cho J. K., Park K. H., J. Enzyme Inhib. Med. Chem. 2017, 32, 1195. PubMed PMC

Rigamonti E., Chinetti‐Gbaguidi G., Staels B., Arterioscler., Thromb., Vasc. Biol. 2008, 28, 1050. PubMed

Grygiel‐Gorniak B., Nutr. J. 2014, 13, 17. PubMed PMC

Xi Y., Zhang Y., Zhu S., Luo Y., Xu P., Huang Z., Cells 2020, 9, 352. PubMed PMC

de Almeida N. R., Conda‐Sheridan M., Med. Res. Rev. 2019, 39, 1372. PubMed PMC

Amber‐Vitos O., Chaturvedi N., Nachliel E., Gutman M., Tsfadia Y., Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2016, 1861, 1852. PubMed

Hamblin M., Chang L., Fan Y., Zhang J., Chen Y. E., Antioxid. Redox Signaling 2009, 11, 1415. PubMed PMC

Mirza A. Z., Althagafi I. I., Shamshad H., Eur. J. Med. Chem. 2019, 166, 502. PubMed

Huang M., Su E., Zheng F., Tan C., Food Funct. 2017, 8, 3198. PubMed

Mignet N., Seguin J., Romano M. R., Brullé L., Touil Y. S., Scherman D., Bessodes M., Chabot G. G., Int. J. Pharm. 2012, 423, 69. PubMed

Ang S.‐S., Thoo Y. Y., Siow L. F., Food Bioprocess Technol. 2024, 17, 424. PubMed PMC

Mignet N., Seguin J., Chabot G. G., Pharmaceutics 2013, 5, 457. PubMed PMC

Cesari A., Barretta G. U., Kirschner K. N., Pappalardo M., Basile L., Guccione S., Russotto C., Lauro M. R., Cavaliere F., Balzano F., New J. Chem. 2020, 44, 16431.

dos Santos Lima B., Shanmugam S., de Souza Siqueira Quintans J., Quintans‐Júnior L. J., de Souza Araújo A. A., Phytochem. Rev. 2019, 18, 1337.

Pittol V., Veras K. S., Doneda E., Silva A. D., Delagustin M. G., Koester L. S., Bassani V. L., Pharm. Dev. Technol. 2022, 27, 625. PubMed

Wdowiak K., Rosiak N., Tykarska E., Żarowski M., Płazińska A., Płaziński W., Cielecka‐Piontek J., Int. J. Mol. Sci. 2022, 23, 4000. PubMed PMC

Kim J.‐S., Prev. Nutr. Food Sci. 2020, 25, 449. PubMed PMC

Liang Y. C., Tsai S. H., Tsai D. C., Lin‐Shiau S. Y., Lin J. K., FEBS Lett. 2001, 496, 12. PubMed

Zoechling A., Liebner F., Jungbauer A., Food Funct. 2011, 2, 28. PubMed

Xu L.‐J., Yu M.‐H., Huang C.‐Y., Niu L.‐X., Wang Y.‐F., Wu C.‐Z., Yang P.‐M., Hu X., Fitoterapia 2018, 127, 109. PubMed

Ma S., Huang Y., Zhao Y., Du G., Feng L., Huang C., Li Y., Guo F., Phytochem. Lett. 2016, 16, 213.

Ballav S., Biswas B., Sahu V. K., Ranjan A., Basu S., Cells 2022, 11, 3215. PubMed PMC

Garg S., Khan S. I., Malhotra R. K., Sharma M. K., Kumar M., Kaur P., Nag T. C., RumaRay J. B., Arya D. S., Arch. Biochem. Biophys. 2020, 694, 108572. PubMed

Fang X.‐K., Gao J., Zhu D.‐N., Life Sci. 2008, 82, 615. PubMed

Weidner C., Wowro S. J., Freiwald A., Kodelja V., Abdel‐Aziz H., Kelber O., Sauer S., Mol. Nutr. Food Res. 2014, 58, 903. PubMed

Afzal S., Sattar M. A., Johns E. J., Eseyin O. A., Attiq A., PPAR Res. 2021, 2021, 6661181. PubMed PMC

Beekmann K., Rubió L., de Haan L. H. J., Actis‐Goretta L., van der Burg B., van Bladeren P. J., Rietjens I. M. C. M., Food Funct. 2015, 6, 1098. PubMed

Ghorbani A., Nazari M., Jeddi‐Tehrani M., Zand H., Eur. J. Nutr. 2012, 51, 39. PubMed

Yue M., Zeng N., Xia Y., Wei Z., Dai Y., Mol. Nutr. Food Res. 2018, 62, 1800202. PubMed

Barthel A., Krüger K.‐D., Roth R. A., Joost H.‐G., Naunyn‐Schmiedeberg's Arch. Pharmacol., 2002, 365, 290. PubMed

Liga S., Paul C., Péter F., Plants 2023, 12, 2732. PubMed PMC

Brezani V., Blondeau N., Kotouček J., Klásková E., Šmejkal K., Hošek J., Mašková E., Kulich P., Prachyawarakorn V., Heurteaux C., Mašek J., ACS Omega 2024, 9, 9027. PubMed PMC

Wesołowska O., Gąsiorowska J., Petrus J., Czarnik‐Matusewicz B., Michalak K., Biochim. Biophys. Acta, Biomembr. 2014, 1838, 173. PubMed

Johnston M. J. W., Semple S. C., Klimuk S. K., Ansell S., Maurer N., Cullis P. R., Biochim. Biophys. Acta 2007, 1768, 1121. PubMed

Kerdudo A., Dingas A., Fernandez X., Faure C., Food Chem. 2014, 159, 12. PubMed

Sadžak A., Brkljača Z., Eraković M., Kriechbaum M., Maltar‐Strmečki N., Přibyl J., Šegota S., J. Lipid Res. 2023, 64, 100430. PubMed PMC

Kang J. H., Jang W. Y., Ko Y. T., Pharm. Res. 2017, 34, 704. PubMed

Lu H., Zhang S., Wang J., Chen Q., Front. Nutr. 2021, 8, 10.3389/fnut.2021.783831. PubMed DOI PMC

Domínguez‐Villegas V., Clares‐Naveros B., García‐López M. L., Calpena‐Campmany A. C., Bustos‐Zagal P., Garduño‐Ramírez M. L., Colloids Surf., B 2014, 116, 183. PubMed

Meng X., Fryganas C., Fogliano V., Hoppenbrouwers T., Food Hydrocolloids 2024, 151, 109872.

Horablaga A., Şibu A., Megyesi C. I., Gligor D., Bujancă G. S., Velciov A. B., Morariu F. E., Hădărugă D. I., Mişcă C. D., Hădărugă N. G., Plants 2023, 12, 2352. PubMed PMC

Ghitman J., Voicu S. I., Carbohydr. Polym. Technol. Appl. 2023, 5, 100266.

Azzi J., Jraij A., Auezova L., Fourmentin S., Greige‐Gerges H., Food Hydrocolloids 2018, 81, 328.

Yao Q., Lin M.‐T., Lan Q.‐H., Huang Z.‐W., Zheng Y.‐W., Jiang X., Zhu Y.‐D., Kou L., Xu H.‐L., Zhao Y.‐Z., Drug Delivery 2020, 27, 54. PubMed PMC

Costescu C., Corpas L., Hădărugă N., Hădărugă D. I., Gârban Z., Stud. Univ. Babes‐Bolyai Chem. 2011, 56, 83.

Molčanová L., Kauerová T., Dall’Acqua S., Maršík P., Kollár P., Šmejkal K., Bioorg. Chem. 2021, 111, 104797. PubMed

Šmejkal K., Grycová L., Marek R., Lemière F., Jankovská D., Forejtníková H., Vančo J., Suchý V., J. Nat. Prod. 2007, 70, 1244. PubMed

Gijsbers L., van Eekelen H. D. L. M., de Haan L. H. J., Swier J. M., Heijink N. L., Kloet S. K., Man H.‐Y., Bovy A. G., Keijer J., Aarts J. M. M. J. G., van der Burg B., Rietjens I. M. C. M., J. Agric. Food Chem. 2013, 61, 3419. PubMed

Hanáková Z., Hošek J., Babula P., Dall’Acqua S., Václavík J., Šmejkal K., J. Nat. Prod. 2015, 78, 850. PubMed