Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Pharmaceutical Analysis
  4. Volume 20, Issue 7
  5. Article
Volume 20, Issue 7
  • ISSN: 1573-4129
  • E-ISSN: 1875-676X

Abstract

Background

This study investigates the application of polyamidoamine (PAMAM) dendrimers as an innovative drug delivery approach for enhancing the pharmacokinetic profile of ursolic acid (UA), a pentacyclic triterpenoid with multifaceted therapeutic properties. UA, sourced from plants like and , has been extensively studied for its pharmacological characteristics, including anti-inflammatory, antioxidant, and anti-diabetic properties, as recognized in Traditional Chinese Medicine (TCM). The clinical utility of UA is hampered by low bioavailability, which is attributed to its hydrophobic nature. To address this limitation, we explore the use of PAMAM dendrimers, known for their drug delivery potential.

Methods

The UA-PAMAM G0 dendrimers were synthesized with varying molar ratios. Characterization included size analysis, PDI, and zeta potential determination. FTIR confirmed the chemical structure. Male SD rats were acclimatized and administered UA control suspension and UA-G0 dendrimer complex orally. Blood samples were collected for pharmacokinetic analysis. The study obtained IAEC approval.

Results

The UA-PAMAM G0 dendrimer complexes exhibited varying sizes based on molar ratios, with the 2:1 ratio showing significantly smaller dimensions. FTIR confirmed successful conjugation. In the pharmacokinetic study, the UA-G0 dendrimer complex demonstrated higher plasma concentrations than UA alone, as indicated by increased Cmax and AUC values. The results suggest enhanced oral delivery and bioavailability of UA in the dendrimer complex.

Conclusion

This study demonstrated the successful synthesis of UA-PAMAM G0 dendrimer complexes with size variations based on molar ratios. The pharmacokinetic analysis revealed improved plasma concentrations and bioavailability of UA in the dendrimer complex compared to UA alone. These findings highlight the potential of PAMAM dendrimers for enhancing the oral delivery of hydrophobic compounds like UA, bridging the gap between traditional herbal medicine and modern drug delivery strategies. Further research can explore the broader applications of such dendrimer complexes in drug delivery systems.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cpa/10.2174/0115734129300077240813063934
2024-08-28
2025-01-22

  • From This Site

    /content/journals/cpa/10.2174/0115734129300077240813063934
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. FymatA.L. On dementia and other cognitive disorders.Clin Res Neuro20192114
     [Google Scholar]
  2. Global status report on the public health response to dementia.2021Available from: https://www.who.int/publications/i/item/9789240033245
  3. HuangL.Y. HuH.Y. WangZ.T. Association of occupational factors and dementia or cognitive impairment: A systematic review and meta-analysis.J. Alzheimers Dis.202078121722710.3233/JAD‑200605 32986670
     [Google Scholar]
  4. GhanemA. BerryD.S. BurkesA. Prevalence of and annual conversion rates to mild cognitive impairment and dementia: Prospective, longitudinal study of an essential tremor cohort.Ann. Neurol.20249561193120410.1002/ana.26927 38654628
     [Google Scholar]
  5. HaghayeghS. GaoC. SuggE. Association of rest-activity rhythm and risk of developing dementia or mild cognitive impairment in the middle-aged and older population: prospective cohort study.JMIR Public Health Surveill.202410e5521110.2196/55211 38713911
     [Google Scholar]
  6. HajjarI. SchumpertJ. HirthV. WielandD. EleazerG.P. The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment.J. Gerontol. A Biol. Sci. Med. Sci.2002577M414M41810.1093/gerona/57.7.M414 12084801
     [Google Scholar]
  7. SohnM. CheX. ParkH.J. Effects of future subjective expectations on cognitive decline and dementia among middle-aged and older adults.Behav. Sci. (Basel)202414542110.3390/bs14050421 38785912
     [Google Scholar]
  8. PrinceM. WimoA. GuerchetM. AliG.C. WuY.T. PrinaM. World alzheimer report 2015. The global impact of dementia: An analysis of prevalence, incidence, cost and trends.2015Available from: https://www.alzint.org/u/WorldAlzheimerReport2015.pdf
    [Google Scholar]
  9. PerluigiM. Di DomenicoF. ButterfieldD.A. Oxidative damage in neurodegeneration: Roles in the pathogenesis and progression of Alzheimer disease.Physiol. Rev.2024104110319710.1152/physrev.00030.2022 37843394
     [Google Scholar]
  10. BrumW.S. DochertyK.F. AshtonN.J. Effect of neprilysin inhibition on alzheimer disease plasma biomarkers: A secondary analysis of a randomized clinical trial.JAMA Neurol.202381219720010.1001/jamaneurol.2023.4719 38109077
     [Google Scholar]
  11. RissmanR.A. LangfordO. RamanR. Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease.Alzheimers Dement.20242021214122410.1002/alz.13542 37932961
     [Google Scholar]
  12. ZhengL. RubinskiA. DeneckeJ. Combined connectomics, MAPT gene expression, and amyloid deposition to explain regional tau deposition in alzheimer disease.Ann. Neurol.202495227428710.1002/ana.26818 37837382
     [Google Scholar]
  13. AdesuyanM. JaniY.H. AlsugeirD. Phosphodiesterase Type 5 inhibitors in men with erectile dysfunction and the risk of alzheimer disease.Neurology20241024e20913110.1212/WNL.0000000000209131 38324745
     [Google Scholar]
  14. BasuB. DuttaA. AshD. PrajapatiB. GaralaK. Dendrimers: A lipid-based drug delivery system. In: Lipid-Based Drug Delivery Systems.202429938510.1201/9781003459811‑9
     [Google Scholar]
  15. DutheyB. Background paper 6.11 alzheimer disease and other dementias.2013Available from: https://www.medbox.org/document/background-paper-611-alzheimer-disease-and-other-dementias
    [Google Scholar]
  16. NarayananL. MurrayA.D. What can imaging tell us about cognitive impairment and dementia?World J. Radiol.20168324025410.4329/wjr.v8.i3.240 27029053
     [Google Scholar]
  17. SinghA. AnsariV.A. MahmoodT. Receptor for advanced glycation end products: Dementia and cognitive impairment.Drug Res. (Stuttg.)202373524725010.1055/a‑2015‑8041 36889338
     [Google Scholar]
  18. SinghA. AnsariV.A. MahmoodT. AhsanF. WasimR. Dendrimers: A neuroprotective lead in alzheimer disease: A review on its synthetic approach and applications.Drug Res. (Stuttg.)202272841742310.1055/a‑1886‑3208 35931069
     [Google Scholar]
  19. SinghA. AnsariV.A. MahmoodT. AhsanF. WasimR. Neurodegeneration: Microglia: Nf-kappab signaling pathways.Drug Res. (Stuttg.)202272949649910.1055/a‑1915‑4861 36055286
     [Google Scholar]
  20. MaheshwariS. SinghA. AnsariV.A. Navigating the dementia landscape: Biomarkers and emerging therapies.Ageing Res. Rev.20249410219310.1016/j.arr.2024.102193 38215913
     [Google Scholar]
  21. NeopaneD. AnsariV.A. SinghA. Ferulic Acid: Signaling pathways in aging.Drug Res. (Stuttg.)202373631832410.1055/a‑2061‑7129 37220790
     [Google Scholar]
  22. SinghA. AnsariV.A. AnsariT.M. Consequence of dementia and cognitive impairment by primary nucleation pathway.Horm. Metab. Res.202355530431410.1055/a‑2052‑8462 37130536
     [Google Scholar]
  23. SinghA AnsariV A MahmoodT Emerging nanotechnology for the treatment of alzheimer's disease. CNS Neurol Disord Drug Targets202423668769610.2174/1871527322666230501232815
     [Google Scholar]
  24. SinghA. AnsariV.A. MahmoodT. Targeting abnormal tau phosphorylation for alzheimer’s therapeutics.Horm. Metab. Res.202456748248810.1055/a‑2238‑1384 38350636
     [Google Scholar]
  25. SamadA. AlamM. SaxenaK. Dendrimers: A class of polymers in the nanotechnology for the delivery of active pharmaceuticals.Curr. Pharm. Des.200915252958296910.2174/138161209789058200 19754372
     [Google Scholar]
  26. ModiC. PrajapatiB.G. SinghS. SinghA. MaheshwariS. Dendrimers in the management of Alzheimer’s disease.Alzheimer's Disease and Advanced Drug Delivery Strategies.Academic Press202423525110.1016/B978‑0‑443‑13205‑6.00028‑5
     [Google Scholar]
  27. Pérez-CarriónM.D. PosadasI. Dendrimers in neurodegenerative diseases.Processes (Basel)202311231910.3390/pr11020319
     [Google Scholar]
  28. MignaniS. BryszewskaM. ZablockaM. Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches.Prog. Polym. Sci.201764235110.1016/j.progpolymsci.2016.09.006
     [Google Scholar]
  29. MoorthyH. GovindarajuT. Dendrimer architectonics to treat cancer and neurodegenerative diseases with implications in theranostics and personalized medicine.ACS Appl. Bio Mater.2021421115113910.1021/acsabm.0c01319 35014470
     [Google Scholar]
  30. MaitiP.K. ÇaǧınT. WangG. GoddardW.A. Structure of PAMAM Dendrimers: Generations 1 through 11.Macromolecules200437166236625410.1021/ma035629b
     [Google Scholar]
  31. BoasU. ChristensenJ.B. HeegaardP.M.H. Dendrimers: Design, synthesis and chemical properties.J. Mater. Chem.200616383785379810.1039/b611813p
     [Google Scholar]
  32. NajafiF. Salami-KalajahiM. Roghani-MamaqaniH. A review on synthesis and applications of dendrimers.J. Indian Chem. Soc.2021183503517
     [Google Scholar]
  33. LyuZ. DingL. HuangA.Y.T. KaoC.L. PengL. Poly(amidoamine) dendrimers: Covalent and supramolecular synthesis.Mater. Today Chem.201913344810.1016/j.mtchem.2019.04.004
     [Google Scholar]
  34. IrfanM. SaeedA. AkramS. YameenS. Dendrimers chemistry and applications: A short review.Front Chem Sci202011294010.52700/fcs.v1i1.6
     [Google Scholar]
  35. FickerM. PaolucciV. ChristensenJ.B. Improved large-scale synthesis and characterization of small and medium generation PAMAM dendrimers.Can. J. Chem.201795995496410.1139/cjc‑2017‑0108
     [Google Scholar]
  36. KharwadeR. MoreS. WarokarA. AgrawalP. MahajanN. Starburst pamam dendrimers: Synthetic approaches, surface modifications, and biomedical applications.Arab. J. Chem.20201376009603910.1016/j.arabjc.2020.05.002
     [Google Scholar]
  37. Kanani-JaziM.H. AkbariS. StawskiD. Surface engineering of halloysite with PAMAM dendrimer via divergent and convergent synthetic routes: Quantitative and qualitative analysis.J. Mol. Liq.202440012445610.1016/j.molliq.2024.124456
     [Google Scholar]
  38. GraysonS.M. FréchetJ.M.J. Convergent dendrons and dendrimers: From synthesis to applications.Chem. Rev.2001101123819386810.1021/cr990116h 11740922
     [Google Scholar]
  39. PatleR.Y. MeshramJ.S. The advanced synthetic modifications and applications of multifunctional PAMAM dendritic composites.React. Chem. Eng.20217194010.1039/D1RE00074H
     [Google Scholar]
  40. DwivediD.K. SinghA.K. Dendrimers: A novel carrier system for drug delivery.J. Drug Deliv. Ther.2014451610.22270/jddt.v4i5.968
     [Google Scholar]
  41. SantosS.D. XavierM. LeiteD.M. PAMAM dendrimers: Blood-brain barrier transport and neuronal uptake after focal brain ischemia.J. Control. Release2018291657910.1016/j.jconrel.2018.10.006 30308255
     [Google Scholar]
  42. GothwalA. KumarH. NakhateK.T. Lactoferrin coupled lower generation PAMAM dendrimers for brain targeted delivery of memantine in aluminum-chloride-induced Alzheimer’s disease in mice.Bioconjug. Chem.201930102573258310.1021/acs.bioconjchem.9b00505 31553175
     [Google Scholar]
  43. MirzaF.J. AmberS. Sumera, Hassan D, Ahmed T, Zahid S. Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aβ1-42-induced mouse model of Alzheimer’s disease.Phytomedicine20218315349010.1016/j.phymed.2021.153490 33601255
     [Google Scholar]
  44. Ramos-HrybA.B. PaziniF.L. KasterM.P. RodriguesA.L.S. Therapeutic potential of ursolic acid to manage neurodegenerative and psychiatric diseases.CNS Drugs201731121029104110.1007/s40263‑017‑0474‑4 29098660
     [Google Scholar]
  45. ChenH. Ursolic acid inhibited proliferation and invasion of mda-mb-231 human breast cancer cells via regulating cellular signal transduction pathways.Cornell University2017
     [Google Scholar]
  46. RaiS.N. ZahraW. BirlaH. SinghS.S. SinghS.P. Therapeutic benefits of Ursolic acid in parkinson’s, alzheimer’s and psychiatric diseases.J. Biol. Eng. Res. Rev.2017421317
     [Google Scholar]
  47. NguyenH.T. LeX.T. Van NguyenT. Ursolic acid and its isomer oleanolic acid are responsible for the anti-dementia effects of Ocimum sanctum in olfactory bulbectomized mice.J. Nat. Med.202276362163310.1007/s11418‑022‑01609‑2 35218459
     [Google Scholar]
  48. LiuK. HuangY. WanP. Ursolic acid protects neurons in temporal lobe epilepsy and cognitive impairment by repressing inflammation and oxidation.Front. Pharmacol.20221387789810.3389/fphar.2022.877898 35677445
     [Google Scholar]
  49. XianchuL. KangL. HuanP. MingL. Ursolic acid mitigates cognitive dysfunction through amelioration of oxidative stress, inflammation and apoptosis in diabetic rats.Trop. J. Pharm. Res.202220480380710.4314/tjpr.v20i4.21
     [Google Scholar]
  50. HabtemariamS. Antioxidant and anti-inflammatory mechanisms of neuroprotection by ursolic acid: Addressing brain injury, cerebral ischemia, cognition deficit, anxiety, and depression.Oxid. Med. Cell. Longev.2019201911810.1155/2019/8512048 31223427
     [Google Scholar]
  51. SinghA. UjjwalR.R. NaqviS. Formulation development of tocopherol polyethylene glycol nanoengineered polyamidoamine dendrimer for neuroprotection and treatment of Alzheimer disease.J. Drug Target.202230777779110.1080/1061186X.2022.2063297 35382657
     [Google Scholar]
  52. VidalF. VásquezP. DíazC. NovaD. AldereteJ. GuzmánL. Mechanism of PAMAM dendrimers internalization in hippocampal neurons.Mol. Pharm.201613103395340310.1021/acs.molpharmaceut.6b00381 27556289
     [Google Scholar]
  53. KimI.D. LimC.M. KimJ.B. Neuroprotection by biodegradable PAMAM ester (e-PAM-R)-mediated HMGB1 siRNA delivery in primary cortical cultures and in the postischemic brain.J. Control. Release2010142342243010.1016/j.jconrel.2009.11.011 19944723
     [Google Scholar]
  54. ZhangF. Trent MagruderJ. LinY.A. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.J. Control. Release201724917318210.1016/j.jconrel.2017.01.032 28137632
     [Google Scholar]
  55. LiH. ZhaS. LiH. LiuH. WongK.L. AllA.H. Polymeric dendrimers as nanocarrier vectors for neurotheranostics.Small20221845220362910.1002/smll.202203629 36084240
     [Google Scholar]
  56. MilowskaK. SzwedA. ZablockaM. In vitro PAMAM, phosphorus and viologen-phosphorus dendrimers prevent rotenone-induced cell damage.Int. J. Pharm.20144741-2424910.1016/j.ijpharm.2014.08.010 25108046
     [Google Scholar]
  57. ZhangF. ZhangZ. AltJ. Dendrimer-enabled targeted delivery attenuates glutamate excitotoxicity and improves motor function in a rabbit model of cerebral palsy.J. Control. Release2023358274210.1016/j.jconrel.2023.04.017 37054778
     [Google Scholar]
  58. Arbez-GindreC. SteeleB.R. Micha-ScrettasM. Dendrimers in alzheimer’s disease: Recent approaches in multi-targeting strategies.Pharmaceutics202315389810.3390/pharmaceutics15030898 36986759
     [Google Scholar]
  59. KimH.T. YooM. YangE.J. SongK.S. ParkE.J. NaD.H. The importance of pH for the formation of stable and active quercetin–polyamidoamine dendrimer complex.Bull. Korean Chem. Soc.202344436336910.1002/bkcs.12669
     [Google Scholar]
  60. MouryaA. AkhtarA. AhujaS. SahS.P. KumarA. Synergistic action of ursolic acid and metformin in experimental model of insulin resistance and related behavioral alterations.Eur. J. Pharmacol.2018835314010.1016/j.ejphar.2018.07.056 30075220
     [Google Scholar]
  61. AlizadeS. FaramarziM. BanitalebiE. SaghaeiE. Effect of resistance and endurance training with ursolic acid on oxidative stress and cognitive impairment in hippocampal tissue in HFD/STZ-induced aged diabetic rats.Iran. J. Basic Med. Sci.2023261214491459 37970434
     [Google Scholar]
  62. ChauhanP S YadavD ArukhaA P Dietary nutrients and prevention of alzheimer's disease.CNS Neurol Disord Drug Targets202221321722710.2174/1871527320666210405141123
     [Google Scholar]
  63. AssiA.A. AbdelnabiS. AttaaiA. Abd-ellatiefR.B. Effect of ivabradine on cognitive functions of rats with scopolamine-induced dementia.Sci. Rep.20221211697010.1038/s41598‑022‑20963‑5 36216854
     [Google Scholar]
  64. ReidS.N.S. RyuJ. KimY. JeonB.H. GABA-enriched fermented Laminaria japonica improves cognitive impairment and neuroplasticity in scopolamine- and ethanol-induced dementia model mice.Nutr. Res. Pract.201812319920710.4162/nrp.2018.12.3.199 29854325
     [Google Scholar]
  65. ChenB.H. AhnJ.H. ParkJ.H. Effects of scopolamine and melatonin cotreatment on cognition, neuronal damage, and neurogenesis in the mouse dentate gyrus.Neurochem. Res.201843360060810.1007/s11064‑017‑2455‑x 29260493
     [Google Scholar]
  66. Wong-GuerraM. Jiménez-MartinJ. Pardo-AndreuG.L. Mitochondrial involvement in memory impairment induced by scopolamine in rats.Neurol. Res.201739764965910.1080/01616412.2017.1312775 28398193
     [Google Scholar]
  67. ZhouM. XueY. SunS. Effects of different fatty acids composition of phosphatidylcholine on brain function of dementia mice induced by scopolamine.Lipids Health Dis.201615113510.1186/s12944‑016‑0305‑5 27558491
     [Google Scholar]
  68. BoiangiuR.S. BrinzaI. HancianuM. Cognitive facilitation and antioxidant effects of an essential oil mix on scopolamine-induced amnesia in rats: Molecular modeling of in vitro and in vivo approaches.Molecules2020257151910.3390/molecules25071519 32230815
     [Google Scholar]
  69. HongS.M. SoeK.H. LeeT.H. KimI.S. LeeY.M. LimB.O. Cognitive improving effects by highbush blueberry (Vaccinium crymbosum L.) vinegar on scopolamine-induced amnesia mice model.J. Agric. Food Chem.20186619910710.1021/acs.jafc.7b03965 29260547
     [Google Scholar]
  70. SamirS.M. HassanH.M. ElmowafyR. Neuroprotective effect of ranolazine improves behavioral discrepancies in a rat model of scopolamine-induced dementia.Front. Neurosci.202417126767510.3389/fnins.2023.1267675 38323121
     [Google Scholar]
  71. MokarramiS. JahanshahiM. ElyasiL. BadelisarkalaH. KhaliliM. Naringin prevents the reduction of the number of neurons and the volume of CA1 in a scopolamine-induced animal model of Alzheimer’s disease (AD): A stereological study.Int. J. Neurosci.2024134436437110.1080/00207454.2022.2102981 35861379
     [Google Scholar]
  72. JinhuaW. Ursolic acid: Pharmacokinetics process in vitro and in vivo, a mini review.Arch. Pharm. (Weinheim)20193523180022210.1002/ardp.201800222 30663087
     [Google Scholar]
  73. SunQ. HeM. ZhangM. Ursolic acid: A systematic review of its pharmacology, toxicity and rethink on its pharmacokinetics based on PK-PD model.Fitoterapia202014710473510.1016/j.fitote.2020.104735 33010369
     [Google Scholar]
  74. XiaY. WeiG. SiD. LiuC. Quantitation of ursolic acid in human plasma by ultra performance liquid chromatography tandem mass spectrometry and its pharmacokinetic study.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.2011879221922410.1016/j.jchromb.2010.11.037 21169069
     [Google Scholar]
  75. SatheR.Y. BharatamP.V. Drug-dendrimer complexes and conjugates: Detailed furtherance through theory and experiments.Adv. Colloid Interface Sci.202230310263910.1016/j.cis.2022.102639 35339862
     [Google Scholar]
  76. YaoW. SunK. MuH. Preparation and characterization of puerarin–dendrimer complexes as an ocular drug delivery system.Drug Dev. Ind. Pharm.20103691027103510.3109/03639041003610799 20545508
     [Google Scholar]
  77. LuongD. KesharwaniP. DeshmukhR. PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery.Acta Biomater.201643142910.1016/j.actbio.2016.07.015 27422195
     [Google Scholar]
  78. ChanphaiP. BekaleL. SanyakamdhornS. PAMAM dendrimers in drug delivery: loading efficacy and polymer morphology.Can. J. Chem.201795989189610.1139/cjc‑2017‑0115
     [Google Scholar]
/content/journals/cpa/10.2174/0115734129300077240813063934
Loading
Pharmacokinetic Assessments of Ursolic Loaded-dendrimer Complex
Current Pharmaceutical Analysis 20, 538 (2024); https://doi.org/10.2174/0115734129300077240813063934
/content/journals/cpa/10.2174/0115734129300077240813063934
/content/journals/cpa/10.2174/0115734129300077240813063934
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): controlled release; dendrimer functionalization; drug release kinetics; drug-dendrimer complex; hydrophobic drug delivery; nanocarrier systems; nanoprecipitation; nanotechnology; oral bioavailability; PAMAM G0 dendrimers; targeted drug delivery; zeta potential

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test