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Effects of lipid nanoparticles on physicochemical properties, cellular uptake, and lymphatic uptake of 6-methoxflavone

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Abstract

Purpose

Recently, therapeutic effects of 6-methoxyflavone (6MF) have been reported. However, the use of 6MF is limited due to its poor water solubility. The low aqueous solubility of 6MF results in its low plasma level after oral administration, which limits its clinical application. Lymphatic uptake is a promising way to enhance oral bioavailability. Thus, the purpose of this study was to investigate the effect of solid lipid nanoparticles (SLN) and nanostructured lipid carrier (NLC) on the lymphatic uptake of 6MF.

Methods

6MF-loaded solid lipid nanoparticle (6MF-SLN) and 6MF-loaded nanostructured lipid carrier (6MF-NLC) were fabricated with a hot homogenization and sonication technique. These 6MF-SLN and 6MF-NLC were characterized for their particle sizes, zeta potentials, in vitro release, cytotoxicity, and cellular uptake. They were also subjected to in vivo lymphatic uptake studies.

Results

In this study, 6MF-SLNs and 6MF-NLC were fabricated to achieve improved oral bioavailability and sustained therapeutic effect of 6MF. The composition of lipid matrix affected physicochemical properties and release profiles of 6MF. Encapsulation of 6MF in lipid nanoparticles resulted in an enhanced cellular uptake in Caco-2 cells. In vivo lymphatic uptake study in rats revealed that SLN and NLC significantly improved lymphatic uptake of 6MF than the control without SLN or NLC (6MF alone).

Conclusion

SLN and NLC could be promising oral delivery platforms for 6MF.

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References

  • Awaad A, Nakamura M, Ishimura K (2012) Imaging of size-dependent uptake and identification of novel pathways in mouse peyer’s patches using fluorescent organosilica particles. Nanomedicine: NBM 8(5):627–236

    Article  CAS  Google Scholar 

  • Baek JS, Cho CW (2017a) Surface modification of solid lipid nanoparticles for oral delivery of curcumin: improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake. Eur J Pharm Biopharm 117:132–140

    Article  CAS  PubMed  Google Scholar 

  • Baek JS, Cho CW (2017b) A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells. Oncotarget 8(18):30369–30382

    Article  PubMed  PubMed Central  Google Scholar 

  • Baek JS, Hwang CJ, Jung HW, Park YK, Kim YH et al (2013) Comparative pharmacokinetics of a marker compound, baicalin in KOB extract after oral administration to normal and allergic-induced rats. Drug Deliv 21(6):453–458

    Article  Google Scholar 

  • Baek JS, Choo CC, Qian C, Tan NS, Shen Z et al (2016) Multi-drug-loaded microcapsules with controlled release for management of Parkinson’s disease. Small 12(27):3712–3722

    Article  CAS  PubMed  Google Scholar 

  • Baek JS, Yeo EW, Lee YH, Tan NS, Loo SCJ (2017) Controlled-release nanoencapsulating microcapsules to combat inflammatory diseases. Drug Des Dev Ther 11:1707–1717

    Article  CAS  Google Scholar 

  • Baek JS, Tan CH, Ng NKJ, Yeo YP, Rice SA et al (2018) A programmable lipid-polymer hybrid nanoparticle system for localized, sustained antibiotic delivery to Gram-positive and Gram-negative bacterial biofilms. Nanoscale Horiz 3(3):305–311

    Article  CAS  PubMed  Google Scholar 

  • Battaglia L, Ugazio E (2019) Lipid nano- and microparticles: an overview of patent-related research. J Nanomater 2019:1–22

    Article  Google Scholar 

  • Bhalekar MR, Upadhaya PG, Madgulkar AR, Kshirsagar SJ, Dube A et al (2015) In-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir. Drug Deliv 23(7):2581–2586

    Article  PubMed  Google Scholar 

  • Bhaskar K, Anbu J, Ravichandiran V, Venkateswarlu V, Rao YM (2009) Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation in vitro, ex vivo and in vivo studies. Lipids Health Dis 8(1):6–20

    Article  PubMed  PubMed Central  Google Scholar 

  • Caliph SM, Charman WN, Porter CJ (2000) Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci 89(8):1073–1084

    Article  CAS  PubMed  Google Scholar 

  • Daha A, Horrman A (2006) Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res 23(9):2165–2174

    Article  Google Scholar 

  • Doktorovova S, Souto EB, Silva AM (2014) Nanotoxicology applied to solid lipid nanoparticles and nanostructured lipid carriers—a systematic review of in vitro data. Eur J Pharm Biopharm 87(1):1–18

    Article  CAS  PubMed  Google Scholar 

  • Druker DJ (2020) Advances in oral peptide therapeutics. Nat Rev Drug Discov 19(4):277–289

    Article  Google Scholar 

  • Duan Y, Dhar A, Patel C, Khimani M, Neogi S et al (2020) A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv 10(45):26777–26791

    Article  CAS  Google Scholar 

  • Freitas C, Müller RH (1998) Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN™) dispersions. Int J Pharm 168(2):221–229

    Article  CAS  Google Scholar 

  • Gan L, Zhang C, Wu FJ, Li H, Zhang WP et al (2018) Microencapsulated nanostructured lipid carriers as delivery system for rutin. Mater Technol 32(2):357–363

    Article  Google Scholar 

  • Haider M, Abdin SM, Kamal L, Orive G (2020) Nanostructured lipid carriers for delivery of chemotherapeutics: a review. Pharmaceutics 12(3):288

    Article  CAS  PubMed Central  Google Scholar 

  • Hajialyani M, Tewari D, Sorbarzo-sanchez E, Nabavi SM, Farzaei MH et al (2018) Natural product-based nanomedicines for wound healing purpose: therapeutic targets and drug delivery systems. Int J Nanomed 13:5023–5043

    Article  CAS  Google Scholar 

  • Hall BJ, Karim N, Chebib M, Johnston GAR, Hanrahan JR (2014) Modulation of ionotropic GABA receptors by 6-methoxyflavanone and 6-methoxyflavone. Neurochem Res 39(6):1068–1078

    Article  CAS  PubMed  Google Scholar 

  • Huh HW, Na YG, Bang KH, Kim SJ, Kim M et al (2020) Extended intake of mulberry leaf extract delayed metformin elimination via inhibiting the organic cation transporter 2. Pharmaceutics 12(1):49

    Article  CAS  PubMed Central  Google Scholar 

  • Idrees H, Zaidi SZJ, Sabir A, Khan RU, Zhang X et al (2020) A review of biodegradable natural polymer-based nanoparticles for drug delivery applications. Nanomaterials 10(10):1970

    Article  CAS  PubMed Central  Google Scholar 

  • Jain P, Rahi P, Pandey V, Asati S, Soni V (2017) Nanostructure lipid carriers: a modish contrivance to overcome the ultraviolet effects. Egypt J Basic Appl Sci 4(2):89–100

    Google Scholar 

  • Jia L (2015) Nanoparticle formulation increases oral bioavailability of poorly soluble drugs: approaches experimental evidences and theory. Curr Nanosci 1(3):237–243

    Article  Google Scholar 

  • Khan S, Baboota S, Ali J, Khan S, Narang RS et al (2015) Nanostructured lipid carriers: an emerging platform for improving oral bioavailability of liphophilic drugs. Int J Pharm Investig 5(4):182–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khosa A, Reddi S, Saha RN (2018) Nanostructured lipid carriers for site-specific drug delivery. Biomed Pharmacother 103:598–613

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Baek JS, Park JK, Lee BJ, Kim MS et al (2017) Development of Houttuynia cordata extract-loaded solid lipid nanoparticles for oral delivery: high drug loading efficiency and controlled release. Molecules 22(12):2215

    Article  PubMed Central  Google Scholar 

  • Lakshmi P, Kumar GA (2010) Nanosuspension technology: a review. Int J Pharm Pharm Sci 2(4):35–40

    Google Scholar 

  • Makwana V, Jain R, Patel K, Nivsarkar M, Joshi A (2015) Solid lipid nanoparticles (SLN) of Efavirenz as lymph targeting drug delivery system: elucidation of mechanism of uptake using chylomicron flow blocking approach. Int J Pharm 495(1):439–446

    Article  CAS  PubMed  Google Scholar 

  • Markovic M, Ben-Shabat S, Keinan S, Aponick A, Zimmermann EM et al (2018) Lipidic prodrug approach for improved oral drug delivery and therapy. Med Res Rev 39(2):579–607

    Article  PubMed  Google Scholar 

  • Mishra V, Bansal KK, Verma A, Yadav N, Thakur S et al (2018) Solid lipid nanoparticles: emerging colloidal nano drug delivery systems. Pharmaceutics 10(4):191

    Article  CAS  PubMed Central  Google Scholar 

  • Montoto SS, Muraca G, Ruiz ME (2020) Solid lipid nanoparticles for drug delivery: pharmacological and biopharmaceutical aspects. Font Mol Biosci 7:587997

    Article  CAS  Google Scholar 

  • Müller RH, Mäder K, Gohla S (2000) Solid lipid nanoparticle (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm 50(1):161–177

    Article  PubMed  Google Scholar 

  • Müller RH, Jacobs C, Kayser O (2001) Nanosuspensions as particulate drug formulations in therapy Rationale for development and what we can expect for the future. Adv Drug Deliv Rev 47(1):3–19

    Article  PubMed  Google Scholar 

  • Mura P, Maestrelli F, D’Ambrosio M, Luceri C, Cirri M (2021) Evaluation and comparison of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as vectors to develop hydrochlorothiazide effective and safe pediatric oral liquid formulation. Pharmaceutics 13(4):437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murthy A, Ravi RR, Kathuria H, Malekar S (2020) Oral bioavailability enhancement of raloxifene with nanostructured lipid carriers. Nanomaterials 10(6):1085

    Article  CAS  PubMed Central  Google Scholar 

  • Ota M, Hashimoto Y, Sato M, Sato Y, Smith RL Jr, Inomata H (2016) Solubility of flavone, 6-methoxyflavone and anthracene in supercritical CO2 with/without a co-solvent of ethanol correlated by using a newly proposed entropy-based solubility parameter. Fluid Phase Equilib 425:65–71

    Article  CAS  Google Scholar 

  • Santos CMM, Silva AMS (2020) The antioxidant activity of prenylflavonoids. Molecules 25(3):696–728

    Article  CAS  PubMed Central  Google Scholar 

  • Shahid M, Subhan F, Ahmad N, Sewell RDE (2017) The flavonoid 6-methoxyflavone allays cisplatin-induced neuropathic allodynia and hypoalgesia. Biomed Pharmacother 95:1725–1733

    Article  CAS  PubMed  Google Scholar 

  • So JS, Kim GC, Song M, Lee CG, Park E et al (2014) 6-Methoxyflavon inhibits NFAT translocation into the nucleus and suppresses T cell activation. J Immunol Res 193(6):2772–2783

    CAS  Google Scholar 

  • Son GH, Na YG, Huh HW, Wang M, Kim MK et al (2019) Systemic design and evaluation of ticagrelor-loaded nanostructured lipid carriers for enhancing bioavailability and antiplatelet activity. Pharmaceutics 11(5):222

    Article  CAS  PubMed Central  Google Scholar 

  • Trevaskis NL, Kaminskas LM, Porter CJH (2015) From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov 14:781–803

    Article  CAS  PubMed  Google Scholar 

  • Tungmunnithum D, Thongboonyou A, Philboonn A, Yangsabai A (2018) Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: an overview. Medicines 5(3):93–108

    Article  CAS  PubMed Central  Google Scholar 

  • Vishwakarma N, Jain A, Sharma R, Mody N, Vyas S et al (2019) Lipid-based nanocarriers for lymphatic transportation. AAPS PharmSciTech 20(2):83

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Wang N, Zhang Y, Shen W, Gao X et al (2010) Solvent injection-lyophilization of tert-butyl alcohol/water cosolvent systems for the preparation of drug-loaded solid lipid nanoparticles. Colloids Surf B 79(1):254–261

    Article  CAS  Google Scholar 

  • Wang T, Li Q, Bi K (2018) Bioactive flavonoid in medicinal plants: structure, activity and biological fate. Asian J Pharm Sci 13(1):12–23

    Article  PubMed  Google Scholar 

  • Wright L, Barnes TJ, Prestidge CA (2020) Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vivo permeability prediction. Int J Pharm 585(2):119488

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Alfano J, Race D, Davé RN (2018) Zero-order release of poorly water-soluble drug from polymeric films made via aqueous slurry casting. Eur J Pharm Sci 117:245–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was funded by the Korean government (MSIT) (grant number 2020R1G1A101121112).

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Author notes

  1. Suji Ryu and Minki Jin have contributed equally to this work.

Authors and Affiliations

  1. Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Gangwon-do, 24341, South Korea

    Suji Ryu, Myeong-Hyeon Wang & Jong-Suep Baek

  2. College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon, 305-764, South Korea

    Minki Jin & Cheong-Weon Cho

  3. Animal Model Research Group, Jeonbuk Branch, Korea Institute of Toxicology (KIT), Jeongeup, Jeolla-buk-do, 53212, South Korea

    Hong-Ki Lee

  4. Department of Herbal Medicine Resource, Kangwon National University, Samcheok-si, Gangwon-do, 25949, South Korea

    Jong-Suep Baek

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  1. Suji Ryu
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Corresponding authors

Correspondence to Jong-Suep Baek or Cheong-Weon Cho.

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Conflict of interest

All authors (S. Ryu, M. Jin, H.‑K. Lee, M.‑H. Wang, J.‑S. Baek, and C.‑W. Cho) declare that they have no conflict of interest.

Ethical approval

All experiments were conducted according to the guidelines of the Animal Care Commission of Kangwon National University. This study was approved by Kangwon National University Institutional Animal Care Committee (Protocol no. KW-201117-5).

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Ryu, S., Jin, M., Lee, HK. et al. Effects of lipid nanoparticles on physicochemical properties, cellular uptake, and lymphatic uptake of 6-methoxflavone. J. Pharm. Investig. 52, 233–241 (2022). https://doi.org/10.1007/s40005-021-00557-5

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