Nanomedicine Journal

Nanomedicine Journal

The use of nanocarriers for drug delivery through the blood-brain barrier

Document Type : Review Paper

Authors
Raissa Alves da Conceicao 1
João Vitor Vicente da Silva 2
Livia Deris Prado 3
Beatriz Ferreira C. Patrício 2
1 Faculty of Pharmacy, Federal University of Rio de Janeiro, RJ, Brazil
2 Postgraduate Program in Molecular and Cell Biology, Biomedical Institute, Federal University of State of Rio de Janeiro, RJ, Brazil
3 Institute of Drug Technology, Farmanguinhos/FIOCRUZ, RJ, Brazil
10.22038/nmj.2025.78717.1934
Abstract
Due to its importance, the central nervous system (CNS) is protected by the blood‒brain barrier (BBB), a multicellular structure that controls the passage of molecules and ions and acts as a barrier for toxins and pathogens. However, the BBB represents an obstacle to achieving the delivery of therapeutic substances into the nervous system to treat neurological diseases. Strategies such as modulation, bypass of the BBB, and changes in the physical–chemical parameters of drugs can be used to enhance permeation. However, all of these methods have some drawbacks, and another growing strategy involves the use of drug nanocarrier systems. This review identifies the main nanocarriers administered orally or parenterally to increase BBB permeation. The literature describes the use of polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles, dendrimers, nanostructured lipid carriers, inorganic nanoparticles, nanoemulsions, and hybrid systems. However, polymers are widely applied. Ligand conjugation represents a common strategy for increasing cellular uptake, and the mechanisms involved are receptor-mediated and adsorptive-mediated transcytosis. Despite the potential and promising data for applying this strategy to treat CNS diseases, no commercial nanoformulations with these characteristics are available to treat CNS diseases.
Keywords
Drug delivery systems
Nanoparticles vectorization
Nanotechnology
Blood-brain barrier
Brain
  1. Cardoso AM, Guedes JR, Cardoso AL, Morais C, Cunha P, Viegas AT, et al. Recent Trends in Nanotechnology Toward CNS Diseases: Lipid-Based Nanoparticles and Exosomes for Targeted Therapeutic Delivery. 2016;130:1-40.
  2. Harilal S, Jose J, Parambi DGT, Kumar R, Unnikrishnan MK, Uddin MS, et al. Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules. Brain Res Bull. 2020;160:121–140.
  3. Huang Z, Wong LW, Su Y, Huang X, Wang N, Chen H, et al. Blood-brain barrier integrity in the pathogenesis of Alzheimer’s disease. Front Neuroendocrinol. 2020;59:100857.
  4. Jäkel S, Dimou L. Glial cells and their function in the adult brain: A journey through the history of their ablation. Front Cell Neurosci. 2017;11:1–17.
  5. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: An overview: Structure, regulation, and clinical implications. Neurobiol Dis. 2004;16(1):1–13.
  6. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13–25.
  7. Wager TT, Hou X, Verhoest PR, Villalobos A. Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery. ACS Chem Neurosci 2016;7(6):767–775.
  8. Li G, Shao K, Umeshappa CS. Recent progress in blood-brain barrier transportation research. Elsevier Ltd. 2019;33-51.
  9. Sun M, Lee J, Chen Y, Hoshino K. Studies of nanoparticle delivery with in vitro bio-engineered microtissues. Bioact Mater. 2020;5(4):924–937.
  10. Alberts B, Bray D, Hopkin K, Johnson A, Lewis J, Raff M, et al. Essential cell biology. 3rd ed. Porto Alegre: Artmed; 2011.
  11. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013;19(12):1584–1596.
  12. GBD Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459–480.
  13. Satarker S, Nampoothiri M. Involvement of the nervous system in COVID-19: The bell should toll in the brain. Life Sci. 2020;262:118568.
  14. Nuzzo D, Picone P. Potential neurological effects of severe COVID-19 infection. Neurosci Res. 2020;158:1–5.
  15. Spandana KMA, Bhaskaran M, Karri VVSNR, Natarajan J. A comprehensive review of nano drug delivery system in the treatment of CNS disorders. J Drug Deliv Sci Technol. 2020;57:101628.
  16. Lochhead JJ, Yang J, Ronaldson PT, Davis TP. Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders. Front Physiol. 2020;11:1–17.
  17. Fisher DG, Price RJ. Recent advances in the use of focused ultrasound for magnetic resonance image-guided therapeutic nanoparticle delivery to the central nervous system. Front Pharmacol. 2019;10:1–14.
  18. Brunton LL, Chabner BA, Knollmann BC. The Pharmacological Basis of Therapeutics. 12th ed. Porto Alegre: AMGH; 2012.
  19. Mangas-Sanjuan V, González-Alvarez M, Gonzalez-Alvarez I, Bermejo M. Drug penetration across the blood-brain barrier: An overview. Ther Deliv. 2010;1(4):535–562.
  20. Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics. 2018;10(3):116.
  21. Samaridou E, Alonso MJ. Nose-to-brain peptide delivery – The potential of nanotechnology. Bioorganic Med Chem. 2018;26(10):2888–2905.
  22. Gupta M, Lee HJ, Barden CJ, Weaver DF. The Blood-Brain Barrier (BBB) Score. J Med Chem. 2019;62(21):9824–9836.
  23. Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Adv Drug Deliv Rev. 2013;65(1):36–48.
  24. Florek J, Caillard R, Kleitz F. Evaluation of mesoporous silica nanoparticles for oral drug delivery-current status and perspective of MSNs drug carriers. Nanoscale. 2017;9(40):15252–15277.
  25. Venditti I. Morphologies and functionalities of polymeric nanocarriers as chemical tools for drug delivery: A review. J King Saud Univ - Sci. 2019;31(3):398–411.
  26. Bhardwaj V, Kaushik A, Khatib ZM, Nair M, McGoron AJ. Recalcitrant issues and new frontiers in nano-pharmacology. Front Pharmacol. 2019;10:1–9.
  27. Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR. Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. Nanomedicine. 2019;14(1):93–126.
  28. Nicolas J, Mura S, Brambilla D, Mackiewicz N, Couvreur P. Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Chem Soc Rev. 2013;42(3):1147–235.
  29. Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51.
  30. Sanità G, Carrese B, Lamberti A. Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization. Front Mol Biosci. 2020;7:1–20.
  31. Idrees H, Zaidi SZJ, Sabir A, Khan RU, Zhang X, Hassan SU. A review of biodegradable natural polymer-based nanoparticles for drug delivery applications. Nanomaterials 2020;10(10):1–22.
  32. Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016;116(4):2602–2663.
  33. Saralkar P, Arsiwala T, Geldenhuys WJ. Nanoparticle formulation and in vitro efficacy testing of the mitoNEET ligand NL-1 for drug delivery in a brain endothelial model of ischemic reperfusion-injury. Int J Pharm. 2020;578:119090.
  34. Nowak M, Brown TD, Graham A, Helgeson ME, Mitragotri S. Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow. Bioeng Transl Med. 2020;5(2):1–11.
  35. Kieseier BC, Arnold DL, Balcer LJ, Boyko AA, Pelletier J, Liu S, et al. Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. Mult Scler J. 2015;21(8):1025–1035.
  36. Johnson KP. Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2012(4);12:371–384.
  37. Ottenbrite RM, Javan R. Biological Structures. Encycl. Condens. Matter Phys. 2005; 99–108.
  38. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: An overview of biomedical applications. J Control Release. 2012;161(2):505–522.
  39. Lei C, Davoodi P, Zhan W, Chow PKH, Wang CH. Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue. J Pharm Sci. 2019;108(5):1736–1745.
  40. Meng XY, Huang AQ, Khan A, Zhang L, Sun XQ, Song H, et al. Vascular endothelial growth factor-loaded poly-lactic-co-glycolic acid nanoparticles with controlled release protect the dopaminergic neurons in Parkinson’s rats. Chem Biol Drug Des 2020;95(6):631–639.
  41. Parmar A, Jain A, Uppal S, Mehta SK, Kaur K, Singh B, et al. Anti-proliferate and apoptosis triggering potential of methotrexate-transferrin conjugate encapsulated PLGA nanoparticles with enhanced cellular uptake by high-affinity folate receptors. Artif Cells, Nanomedicine Biotechnol. 2018;46(sub2):704–719.
  42. Zybina A, Anshakova A, Malinovskaya J, Melnikov P, Baklaushev V, Chekhonin V, et al. Nanoparticle-based delivery of carbamazepine: A promising approach for the treatment of refractory epilepsy. Int J Pharm. 2018;547(1-2):10–23.
  43. Fernandes C, Martins C, Fonseca A, Nunes R, Matos MJ, Silva R, et al. PEGylated PLGA Nanoparticles As a Smart Carrier to Increase the Cellular Uptake of a Coumarin-Based Monoamine Oxidase B Inhibitor. ACS Appl Mater Interfaces. 2018;10(46):39557–39569.
  44. Dhas N, Mehta T. Cationic biopolymer functionalized nanoparticles encapsulating lutein to attenuate oxidative stress in effective treatment of Alzheimer’s disease: A non-invasive approach. Int J Pharm. 2020;586:119553.
  45. Shen J, Zhao Z, Shang W, Liu C, Zhang B, Zhao L, et al. Ginsenoside Rgl nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction. Int J Nanomedicine. 2017;12:6477–6486.
  46. Gevorgyan S, Rossi E, Cappelluti MA, Tocchio A, Martello F, Gerges I, et al. Photocrosslinked poly(amidoamine) nanoparticles for central nervous system targeting. Colloids Surfaces B Biointerfaces. 2017;151:197–205.
  47. Ammar HO, Ghorab MM, Mahmoud AA, Higazy IM. Lamotrigine loaded poly-ɛ-(D,L-lactide-co-caprolactone) nanoparticles as brain delivery system. Eur J Pharm Sci 2018;115:77–87.
  48. da Silveira EF, Ferreira LM, Gehrcke M, Cruz L, Pedra NS, Ramos PT, et al. 2-(2-Methoxyphenyl)-3-((Piperidin-1-yl)ethyl)thiazolidin-4-One-Loaded Polymeric Nanocapsules: In Vitro Antiglioma Activity and In Vivo Toxicity Evaluation. Cell Mol Neurobiol. 2019;39:783–797.
  49. Lahkar S, Das MK. Surface-modified polycaprolactone nanoparticles for the brain-targeted delivery of nevirapine. J Nanoparticle Res. 2020;22(5):109.
  50. Peviani M, Capasso Palmiero U, Cecere F, Milazzo R, Moscatelli D, Biffi A. Biodegradable polymeric nanoparticles administered in the cerebrospinal fluid: Brain biodistribution, preferential internalization in microglia and implications for cell-selective drug release. Biomaterials. 2019;209:25–40.
  51. Jahansooz F, Hosseinzade BE, Zarmi AH, Hadi F, Hojjati SMM, Shahpasand K. Dopamine-loaded poly (butyl cyanoacrylate) nanoparticles reverse behavioral deficits in Parkinson’s animal models. Ther Deliv 2020;11(6):387–399.
  52. Bilia AR, Nardiello P, Piazzini V, Leri M, Bergonzi MC, Bucciantini M, et al. Successful brain delivery of andrographolide loaded in human albumin nanoparticles to TgCRND8 mice, an Alzheimer’s disease mouse model. Front Pharmacol. 2019;10:1–13.
  53. Feczkó T, Piiper A, Ansar S, Blixt FW, Ashtikar M, Schiffmann S, et al. Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy. J Control Release. 2019;293:63–72.
  54. Guccione C, Oufir M, Piazzini V, Eigenmann DE, Jähne EA, Zabela V, et al. Andrographolide-loaded nanoparticles for brain delivery: Formulation, characterisation and in vitro permeability using hCMEC/D3 cell line. Eur J Pharm Biopharm. 2017;119:253–263.
  55. Pradhan D, Tambe V, Raval N, Gondalia P, Bhattacharya P, Kalia K, et al. Dendrimer grafted albumin nanoparticles for the treatment of post cerebral stroke damages: A proof of concept study. Colloids Surfaces B Biointerfaces. 2019;184:110488.
  56. Ruan C, Liu L, Lu Y, Zhang Y, He X, Chen X, et al. Substance P-modified human serum albumin nanoparticles loaded with paclitaxel for targeted therapy of glioma. Acta Pharm Sin B. 2018;8(1):85–96.
  57. Zhang S, Asghar S, Yang L, Hu Z, Chen Z, Shao F, et al. Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting. Int J Pharm. 2020;575:119002.
  58. Sánchez-López E, Ettcheto M, Egea MA, Espina M, Calpena AC, Folch J, et al. New potential strategies for Alzheimer’s disease prevention: pegylated biodegradable dexibuprofen nanospheres administration to APPswe/PS1dE9. Nanomedicine Nanotechnology, Biol Med. 2017;13(3):1171–1182.
  59. Caban-Toktas S, Sahin A, Lule S, Esendagli G, Vural I, Karlı Oguz K, et al. Combination of Paclitaxel and R-flurbiprofen loaded PLGA nanoparticles suppresses glioblastoma growth on systemic administration. Int J Pharm. 2020;578:119076.
  60. Li H, Tong Y, Bai L, Ye L, Zhong L, Duan X, et al. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int J Biol Macromol. 2018;107:204–211.
  61. Cano A, Ettcheto M, Chang JH, Barroso E, Espina M, Kühne BA, et al. Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer’s disease mice model. J Control Release. 2019;301:62–75.
  62. Guo Q, Xu S, Yang P, Wang P, Lu S, Sheng D, et al. A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer’s disease mice. J Control Release. 2020;320:347–362.
  63. Boussahel A, Ibegbu DM, Lamtahri R, Maucotel J, Chuquet J, Lefranc B, et al. Investigations of octylglyceryl dextran-graft-poly (lactic acid) nanoparticles for peptide delivery to the brain. Nanomedicine 2017;12(8):879–892.
  64. Chen EM, Quijano AR, Seo YE, Jackson C, Josowitz AD, Noorbakhsh S, et al. Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors. Biomaterials 2018;178:193–203.
  65. Hu X, Yang F, Liao Y, Li L, Zhang L. Cholesterol-PEG comodified poly (N-butyl) cyanoacrylate nanoparticles for brain delivery: In vitro and in vivo evaluations. Drug Deliv 2017;24(1):121–132.
  66. Di Mauro PP, Cascante A, Vilà PB, Gómez-Vallejo V, Llop J, Borrós S. Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma. Int J Pharm. 2018;553(1-2):169–185.
  67. Shi XX, Miao WM, Pang DW, Wu JS, Tong QS, Li JX, et al. Angiopep-2 conjugated nanoparticles loaded with doxorubicin for the treatment of primary central nervous system lymphoma. Biomater Sci. 2020;8(5):1290–1297.
  68. Wiley SE, Murphy AN, Ross SA, Van Der Geer P, Dixon JE. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc Natl Acad Sci. 2007;104(13):5318–5323.
  69. Song H, Wei M, Zhang N, Li H, Tan XC, Zhang YJ, et al. Enhanced permeability of blood-brain barrier and targeting function of brain via borneol-modified chemically solid lipid nanoparticle. Int J Nanomedicine. 2018;13:1869–79.
  70. Sánchez-López E, Ettcheto M, Egea MA, Espina M, Cano A, Calpena AC, et al. Memantine loaded PLGA PEGylated nanoparticles for Alzheimer’s disease: In vitro and in vivo characterization. J Nanobiotechnology. 2018;16:1–16.
  71. Sezigen S, Esim O, Sarper M, Savaser A. In vitro evaluation of two different types of obidoxime-loaded nanoparticles for cytotoxicity and blood-brain barrier transport. Toxicol Lett. 2020;330:53–58.
  72. Torchilin VP. Micellar nanocarriers: Pharmaceutical perspectives. Pharm Res. 2007;24:1–16.
  73. Plapied L, Duhem N, des Rieux A, Préat V. Fate of polymeric nanocarriers for oral drug delivery. Curr Opin Colloid Interface Sci. 2011;16(3):228–237.
  74. Borgå O, Lilienberg E, Bjermo H, Hansson F, Heldring N, Dediu R. Pharmacokinetics of Total and Unbound Paclitaxel After Administration of Paclitaxel Micellar or Nab-Paclitaxel: An Open, Randomized, Cross-Over, Explorative Study in Breast Cancer Patients. Adv Ther. 2019;36:2825–2837.
  75. Simon JA. Estradiol in micellar nanoparticles: The efficacy and safety of a novel transdermal drug-delivery technology in the management of moderate to severe vasomotor symptoms. Menopause J North Am Menopause Soc. 2006;13(2):222–231.
  76. Li Y, Baiyang L, Leran B, Zhen W, Yandong X, Baixiang D, et al. Reduction-responsive petoz-ss-pcl micelle with tailored size to overcome blood–brain barrier and enhance doxorubicin antiglioma effect. Drug Deliv. 2017;24(1):1782–1790.
  77. Xiang Y, Duan X, Feng L, Jiang S, Deng L, Shen J, et al. tLyp-1-conjugated GSH-sensitive biodegradable micelles mediate enhanced pUNO1-hTRAILa/curcumin co-delivery to gliomas. Chem Eng J. 2019;374:392–404.
  78. Yin Y, Wang J, Yang M, Du R, Pontrelli G, McGinty S, et al. Penetration of the blood-brain barrier and the anti-tumour effect of a novel PLGA-lysoGM1/DOX micelle drug delivery system. Nanoscale. 2020;12(5):2946–2960.
  79. Zou D, Wang W, Lei D, Yin Y, Ren P, Chen J, et al. Penetration of blood–brain barrier and antitumor activity and nerve repair in glioma by doxorubicin-loaded monosialoganglioside micelles system. Int J Nanomedicine. 2017;12:4879–4889.
  80. Li J, Du Y, Jiang Z, Tian Y, Qiu N, Wang Y, et al. Y1 receptor ligand-based nanomicelle as a novel nanoprobe for glioma-targeted imaging and therapy. Nanoscale. 2018;10(13):5845–5851.
  81. Ren Y, Zhan C, Gao J, Zhang M, Wei X, Ying M, et al. A D-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells. Mol Pharm. 2018;15(2):592–601.
  82. Niu J, Wang L, Yuan M, Zhang J, Chen H, Zhang Y. Dual-targeting nanocarrier based on glucose and folic acid functionalized pluronic P105 polymeric micelles for enhanced brain distribution. J Drug Deliv Sci Technol. 2020;57:101343.
  83. Tian Y, Mi G, Chen Q, Chaurasiya B, Li Y, Shi D, et al. Acid-Induced Activated Cell-Penetrating Peptide-Modified Cholesterol-Conjugated Polyoxyethylene Sorbitol Oleate Mixed Micelles for pH-Triggered Drug Release and Efficient Brain Tumor Targeting Based on a Charge Reversal Mechanism. ACS Appl Mater Interfaces. 2018;10(50):43411–43428.
  84. Guo X, Wu G, Wang H, Chen L. Pep-1&borneol–Bifunctionalized Carmustine-Loaded Micelles Enhance Anti-Glioma Efficacy Through Tumor-Targeting and BBB-Penetrating. J Pharm Sci. 2019;108(5):1726–1735.
  85. Lv L, Li X, Qian W, Li S, Jiang Y, Xiong Y, et al. Enhanced Anti-Glioma Efficacy by Borneol Combined With CGKRK-Modified Paclitaxel Self-Assembled Redox-Sensitive Nanoparticles. Front Pharmacol. 2020;11:1–11.
  86. Dong S, He J, Sun Y, Li D, Li L, Zhang M, et al. Efficient Click Synthesis of a Protonized and Reduction-Sensitive Amphiphilic Small-Molecule Prodrug Containing Camptothecin and Gemcitabine for a Drug Self-Delivery System. Mol Pharm. 2019;16(9):3770–3779.
  87. Lu L, Zhao X, Fu T, Li K, He Y, Luo Z, et al. An iRGD-conjugated prodrug micelle with blood-brain-barrier penetrability for anti-glioma therapy. Biomaterials. 2020;230.
  88. Liu H, Zhao X, Liang S, Fan L, Li Z, Zhang Y, et al. Amphiphilic Endomorphin-1 derivative functions as self-assembling nanomedicine for effective brain delivery. Chem Pharm Bull. 2019;67(9):977–984.
  89. Agwa MM, Abdelmonsif DA, Khattab SN, Sabra S. Self- assembled lactoferrin-conjugated linoleic acid micelles as an orally active targeted nanoplatform for Alzheimer’s disease. Int J Biol Macromol. 2020;162:246–261.
  90. Ding J, Sun Y, Li J, Wang H, Mao S. Enhanced blood–brain barrier transport of vinpocetine by oral delivery of mixed micelles in combination with a message guider. J Drug Target. 2017;25(6):532–540.
  91. Lu Y, Li C, Chen Q, Liu P, Guo Q, Zhang Y, et al. Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke. Adv Mater. 2019;31(21):1–12.
  92. Li M, Liu G, Wang K, Wang L, Fu X, Lim LY, et al. Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage. J Nanobiotechnology 2020;18:1–19.
  93. Batrakova E, Lee S, Li S, Venne A, Alakhov V, Kabanov A. Fundamental relantionships between the composition of Pluronic Block Copolymers and their hypersensitization effect in MDR cancer cells. Pharm Res. 1999;16:1373–1379.
  94. Uchegbu IF, Schätzlein AG, Cheng WP, Lalatsa A, editors. Fundamentals of Pharmaceutical Nanoscience. Springer-Verlag New York. 2013.
  95. Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev. 2012;64:213–222.
  96. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4(2):145–160.
  97. Barenholz Y. Doxil® - The first FDA-approved nano-drug: Lessons learned. J Control Release. 2012;160(2):117–134.
  98. Lao J, Madani J, Puértolas T, Álvarez M, Hernández A, Pazo-Cid R, et al. Liposomal Doxorubicin in the Treatment of Breast Cancer Patients: A Review. J Drug Deliv. 2013;2013(1):1–12.
  99. Fassas A, Anagnostopoulos A. The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia. Leuk Lymphoma. 2005;46(6):795–802.
  100. Akinc A, Maier MA, Manoharan M, Fitzgerald K, Jayaraman M, Barros S, et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat Nanotechnol. 2019;14(12):1084–1087.
  101. Yang T, Ferrill L, Gallant L, McGillicuddy S, Fernandes T, Schields N, et al. Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: A potent approach to treat amyotrophic lateral sclerosis. Eur J Pharm Sci. 2018;120:30–39.
  102. Lopalco A, Cutrignelli A, Denora N, Lopedota A, Franco M, Laquintana V. Transferrin functionalized liposomes loading dopamine HCl: Development and permeability studies across an In vitro model of human blood-brain barrier. Nanomaterials 2018;8(3):178.
  103. Gurturk Z, Tezcaner A, Dalgic AD, Korkmaz S, Keskin D. Maltodextrin modified liposomes for drug delivery through the blood-brain barrier. Medchemcomm 2017;8(6):1337–1345.
  104. Kuo YC, Chen CL, Rajesh R. Optimized liposomes with transactivator of transcription peptide and anti-apoptotic drugs to target hippocampal neurons and prevent tau-hyperphosphorylated neurodegeneration. Acta Biomater. 2019;87:207–222.
  105. Han W, Yin G, Pu X, Chen X, Liao X, Huang Z. Glioma targeted delivery strategy of doxorubicin-loaded liposomes by dual-ligand modification. J Biomater Sci Polym Ed. 2017;28(15):1695–1712.
  106. Liu S, Zhang S meng, Ju R jun, Xiao Y, Wang X, Song X li, et al. Antitumor efficacy of Lf modified daunorubicin plus honokiol liposomes in treatment of brain glioma. Eur J Pharm Sci 2017;106:185–197.
  107. Fu Q, Zhao Y, Yang Z, Yue Q, Xiao W, Chen Y, et al. Liposomes actively recognizing the glucose transporter GLUT1 and integrin αvβ3 for dual-targeting of glioma. Arch Pharm (Weinheim). 2019;352(2):1800219.
  108. Shaw TK, Mandal D, Dey G, Pal MM, Paul P, Chakraborty S, et al. Successful delivery of docetaxel to rat brain using experimentally developed nanoliposome: A treatment strategy for brain tumor. Drug Deliv. 2017;24(1):346–357.
  109. Lakkadwala S, Singh J. Dual Functionalized 5-Fluorouracil Liposomes as Highly Efficient Nanomedicine for Glioblastoma Treatment as Assessed in an In Vitro Brain Tumor Model. J Pharm Sci. 2018;107(11):2902–2913.
  110. Wang Y, Ying X, Xu H, Yan H, Li X, Tang H. The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals. Int J Nanomedicine. 2017;12:1369–1384.
  111. Omarch G, Kippie Y, Mentor S, Ebrahim N, Fisher D, Murilla G, et al. Comparative in vitro transportation of pentamidine across the blood-brain barrier using polycaprolactone nanoparticles and phosphatidylcholine liposomes. Artif Cells, Nanomedicine Biotechnol 2019;47(1):1428–1436.
  112. Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: From concepts to clinic. Crit Rev Ther Drug Carrier Syst. 2009;26(6):523–580.
  113. Pardeike J, Hommoss A, Müller RH. Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. Int J Pharm. 2009;366(1-2):170–184.
  114. Beloqui A, Solinís MÁ, Rodríguez-Gascón A, Almeida AJ, Préat V. Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine Nanotechnology, Biol Med. 2016;12(1):143–161.
  115. Loureiro JA, Andrade S, Duarte A, Neves AR, Queiroz JF, Nunes C, et al. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules 2017;22(2):1–16.
  116. Ramalingam P, Ganesan P, Prabakaran DS, Gupta PK, Jonnalagadda S, Govindarajan K, et al. Lipid Nanoparticles Improve the Uptake of α-Asarone Into the Brain Parenchyma: Formulation, Characterization, In Vivo Pharmacokinetics, and Brain Delivery. AAPS PharmSciTech. 2020;21.
  117. Graverini G, Piazzini V, Landucci E, Pantano D, Nardiello P, Casamenti F, et al. Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloids Surfaces B Biointerfaces. 2018;161:302–13.
  118. Arduino I, Depalo N, Re F, Dal Magro R, Panniello A, Margiotta N, et al. PEGylated solid lipid nanoparticles for brain delivery of lipophilic kiteplatin Pt(IV) prodrugs: An in vitro study. Int J Pharm. 2020;583:119351.
  119. Bao Y, Zhang S, Chen Z, Chen AT, Ma J, Deng G, et al. Synergistic Chemotherapy for Breast Cancer and Breast Cancer Brain Metastases via Paclitaxel-Loaded Oleanolic Acid Nanoparticles. Mol Pharm. 2020;17(4):1343–1351.
  120. Kadari A, Pooja D, Gora RH, Gudem S, Kolapalli VRM, Kulhari H, et al. Design of multifunctional peptide collaborated and docetaxel loaded lipid nanoparticles for antiglioma therapy. Eur J Pharm Biopharm. 2018;132:168–179.
  121. Huang R, Zhu Y, Lin L, Song S, Cheng L, Zhu R. Solid Lipid nanoparticles enhanced the neuroprotective role of Curcumin against epilepsy through activation of Bcl-2 family and P38 MAPK pathways. ACS Chem Neurosci. 2020;11(13):1985–1995.
  122. Pashirova TN, Braïki A, Zueva I V., Petrov KA, Babaev VM, Burilova EA, et al. Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection. J Control Release. 2018;290:102–11.
  123. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Stearic acid based, systematically designed oral lipid nanoparticles for enhanced brain delivery of dimethyl fumarate. Nanomedicine. 2017;12(23):2607–2621.
  124. Gandomi N, Varshochian R, Atyabi F, Ghahremani MH, Sharifzadeh M, Amini M, et al. Solid lipid nanoparticles surface modified with anti-Contactin-2 or anti-Neurofascin for brain-targeted delivery of medicines. Pharm Dev Technol. 2017;22(3):426–435.
  125. Lahkar S, Kumar Das M. Surface modified kokum butter lipid nanoparticles for the brain targeted delivery of nevirapine. J Microencapsul. 2018;35(7-8):680–694.
  126. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Enhanced Brain Delivery of Dimethyl Fumarate Employing Tocopherol-Acetate-Based Nanolipidic Carriers: Evidence from Pharmacokinetic, Biodistribution, and Cellular Uptake Studies. ACS Chem Neurosci. 2017;8(4):860–865.
  127. Martinelli C, Battaglini M, Battaglini M, Pucci C, Gioi S, Caracci C, et al. Development of Nanostructured Lipid Carriers for the Delivery of Idebenone in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay. ACS Omega. 2020;5(21):12451–12466.
  128. Wu Y, Song X, Kebebe D, Li X, Xue Z, Li J, et al. Brain targeting of Baicalin and Salvianolic acid B combination by OX26 functionalized nanostructured lipid carriers. Int J Pharm. 2019;571:118754.
  129. Guo P, Si M, Wu D, Xue HY, Hu W, Wong HL. Incorporation of docosahexaenoic acid (DHA) enhances nanodelivery of antiretroviral across the blood-brain barrier for treatment of HIV reservoir in brain. J Control Release. 2020;328:696–709.
  130. Eleraky NE, Omar MM, Mahmoud HA, Abou-Taleb HA. Nanostructured lipid carriers to mediate brain delivery of Temazepam: Design and in vivo study. Pharmaceutics. 2020;12(5):451.
  131. Lee CC, MacKay JA, Fréchet JMJ, Szoka FC. Designing dendrimers for biological applications. Nat Biotechnol. 2005;23(12):1517–1526.
  132. Sharma R, Kambhampati SP, Zhang Z, Sharma A, Chen S, Duh EI, et al. Dendrimer mediated targeted delivery of sinomenine for the treatment of acute neuroinflammation in traumatic brain injury. J Control Release. 2020;323:361–375.
  133. Sharma R, Kim SY, Sharma A, Zhang Z, Kambhampati SP, Kannan S, et al. Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation. Bioconjug Chem. 2017;28(11):2874–2886.
  134. Gothwal A, Nakhate KT, Alexander A, Ajazuddin A, Gupta U. Boosted Memory and Improved Brain Bioavailability of Rivastigmine: Targeting Effort to the Brain Using Covalently Tethered Lower Generation PAMAM Dendrimers with Lactoferrin. Mol Pharm. 2018;15(10):4538–4549.
  135. Han S, Zheng H, Lu Y, Sun Y, Huang A, Fei W, et al. A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer. J Drug Target. 2018;26(1):86–94.
  136. Lu Y, Han S, Zheng H, Ma R, Ping Y, Zou J, et al. A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system. Int J Nanomedicine. 2018;13:5937–5952.
  137. Shi X, Ma R, Lu Y, Cheng Y, Fan X, Zou J, et al. iRGD and TGN co-modified PAMAM for multi-targeted delivery of ATO to gliomas. Biochem Biophys Res Commun. 2020;527(1):117–123.
  138. Al-Azzawi S, Masheta D, Guildford AL, Phillips G, Santin M. Dendrimeric poly(Epsilon-lysine) delivery systems for the enhanced permeability of flurbiprofen across the blood-brain barrier in Alzheimer’s disease. Int J Mol Sci. 2018;19(10):1–18.
  139. Aswathanarayan JB, Vittal RR. Nanoemulsions and Their Potential Applications in Food Industry. Front Sustain Food Syst. 2019;3:1–21.
  140. Gupta A, Eral HB, Hatton TA, Doyle PS. Nanoemulsions: Formation, properties and applications. Soft Matter. 2016;12(11):2826–2841.
  141. Harun SN, Nordin SA, Gani SSA, Shamsuddin AF, Basri M, Basri H Bin. Development of nanoemulsion for efficient brain parenteral delivery of cefuroxime: Designs, characterizations, and pharmacokinetics. Int J Nanomedicine. 2018;13:2571–2584.
  142. Karami Z, Saghatchi Zanjani MR, Rezaee S, Rostamizadeh K, Hamidi M. Neuropharmacokinetic evaluation of lactoferrin-treated indinavir-loaded nanoemulsions: remarkable brain delivery enhancement. Drug Dev Ind Pharm. 2019;45(5):736–744.
  143. Tan SF, Kirby BP, Stanslas J, Basri H Bin. Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability. J Pharm Pharmacol. 2017;69(11):1447–1457.
  144. Hong L, Li X, Bao Y, Duvall CL, Zhang C, Chen W, et al. Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol. Eur J Pharm Sci. 2019;133:160–166.
  145. Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. 2011;60(6):910–920.
  146. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368(9533):387–403.
  147. Madni A, Tahir N, Rehman M, Raza A, Mahmood MA, Khan MI, et al. Hybrid nano-carriers for potential drug delivery. Adv Technol Deliv Ther. 2017; 53–87.
  148. Gao C, Wang Y, Sun J, Han Y, Gong W, Li Y, et al. Neuronal mitochondria-targeted delivery of curcumin by biomimetic engineered nanosystems in Alzheimer’s disease mice. Acta Biomater. 2020;108:285–299.
  149. Gao C, Chu X, Gong W, Zheng J, Xie X, Wang Y, et al. Neuron tau-targeting biomimetic nanoparticles for curcumin delivery to delay progression of Alzheimer’s disease. J Nanobiotechnology. 2020;18:1–23.
  150. Chai Z, Hu X, Wei X, Zhan C, Lu L, Jiang K, et al. A facile approach to functionalizing cell membrane-coated nanoparticles with neurotoxin-derived peptide for brain-targeted drug delivery. J Control Release. 2017;264:102–111.
  151. Han Y, Chu X, Cui L, Fu S, Gao C, Li Y, et al. Neuronal mitochondria-targeted therapy for Alzheimer’s disease by systemic delivery of resveratrol using dual-modified novel biomimetic nanosystems. Drug Deliv. 2020;27(1):502–518.
  152. Zou L, Tao Y, Payne G, Do L, Thomas T, Rodriguez J, et al. Targeted delivery of nano-PTX to the brain tumor-associated macrophages. Oncotarget. 2016;8(4):6564–6578.
  153. Wang H, Zhu Z, Zhang G, Lin F, Liu Y, Zhang Y, et al. AS1411 Aptamer/Hyaluronic Acid-Bifunctionalized Microemulsion Co-Loading Shikonin and Docetaxel for Enhanced Antiglioma Therapy. J Pharm Sci. 2019;108(11):3684–3694.
  154. Palazzo C, Laloy J, Delvigne AS, Nys G, Fillet M, Dogne JM, et al. Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies. Eur J Pharm Sci. 2019;127:52–59.
  155. Wei X, Zhan C, Shen Q, Fu W, Xie C, Gao J, et al. A D-peptide ligand of nicotine acetylcholine receptors for brain-targeted drug delivery. Angew Chemie - Int Ed. 2015;127(10):3066-3070.
  156. Lafon M. Rabies virus receptors. J Neurovirol. 2005;11:82–87.
  157. Mukherjee A, Waters AK, Kalyan P, Achrol AS, Kesari S, Yenugonda VM. Lipid-polymer hybrid nanoparticles as a next-generation drug delivery platform: State of the art, emerging technologies, and perspectives. Int J Nanomedicine. 2019;14:1937–1952.
  158. Wang S, Zhao C, Liu P, Wang Z, Ding J, Zhou W. Facile construction of dual-targeting delivery system by using lipid capped polymer nanoparticles for anti-glioma therapy. RSC Adv. 2018;8(1):444–453.
  159. Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59(7):645–666.
  160. Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: Past, present and future. Nat Rev Drug Discov. 2004;3(12):1023–1035.
Nanomedicine Journal
Volume 12, Issue 4
Autumn 2025
Pages 593-613