Recent progress in the intranasal PLGA-based drug delivery for neurodegenerative diseases treatment

Document Type : Review Article


1 Department of Biology, Payame Noor University, Tehran, Iran

2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of medical sciences, Tehran, Iran

3 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

4 Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

5 Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

6 Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

7 Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran

8 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran


One of the most challenging problems of the current treatments of neurodegenerative diseases is related to the permeation and access of most therapeutic agents to the central nervous system (CNS), prevented by the blood-brain barrier (BBB). Recently, intranasal (IN) delivery has opened new prospects because it directly delivers drugs for neurological diseases into the brain via the olfactory route. Recently, PLGA-based nanocarriers have attracted a lot of interest for IN delivery of drugs. This review gathered clear and concise statements of the recent progress of the various developed PLGA-based nanocarriers for IN drug delivery in brain diseases including Alzheimer’s, Parkinson’s, brain tumors, ischemia, epilepsy, depression, and schizophrenia. Subsequently, future perspectives and challenges of PLGA-based IN administration are discussed briefly. 


Main Subjects

1. Fonseca LC, Lopes JA, Vieira J, Viegas C, Oliveira CS, Hartmann RP, et al. Intranasal drug delivery for treatment of Alzheimer’s disease. Drug Deliv Transl Res 2021; 11: 411-425.
2. Ahmadi F, Jorre H, Hadipour E, Rezaei E, Tayarani-Najaran Z, Salmasi Z. A comparative study of neuroprotective effects of human adipose and dental pulp derived stem cells on hypoxic SH-SY5Y cells exposed to CoCl2. J Maz Univ Med Sci 2022; 31: 1-13.
3. Kumar A, Pandey AN, Jain SK. Nasal-nanotechnology: revolution for efficient therapeutics delivery. Drug Deliv 2016; 23: 671-683.
4. Mignani S, Shi X, Karpus A, Majoral J-P. Non-invasive intranasal administration route directly to the brain using dendrimer nanoplatforms: An opportunity to develop new CNS drugs. Eur J Med Chem 2021; 209: 112905.
5. Emad NA, Ahmed B, Alhalmi A, Alzobaidi N, Al-Kubati SS. Recent progress in nanocarriers for direct nose to brain drug delivery. J Drug Deliv Sci Technol 2021; 64: 102642.
6. Agrawal M, Saraf S, Saraf S, Antimisiaris SG, Chougule MB, Shoyele SA, et al. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release 2018; 281: 139-177.
7. Costa C, Moreira J, Amaral M, Lobo JS, Silva AC. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. J Control Release 2019; 295: 187-200.
8. Zhi K, Raji B, Nookala AR, Khan MM, Nguyen XH, Sakshi S, et al. PLGA nanoparticle-based formulations to cross the blood–brain barrier for drug delivery: From R&D to cGMP. Pharmaceutics 2021; 13: 500.
9. Spindler LM, Feuerhake A, Ladel S, Günday C, Flamm J, Günday-Türeli N, et al. Nano-in-micro-particles consisting of PLGA nanoparticles embedded in chitosan microparticles via spray-drying enhances their uptake in the olfactory mucosa. Front Pharmacol 2021; 12.
10. Ebrahimian M, Shahgordi S, Yazdian-Robati R, Etemad L, Hashemi M, Salmasi Z. Targeted delivery of galbanic acid to colon cancer cells by PLGA nanoparticles incorporated into human mesenchymal stem cells. Avicenna J Phytomed 2022; 12.
11. Astete CE, Sabliov CMJJoBS, Polymer Edition. Synthesis and characterization of PLGA nanoparticles. J Biomater Sci Polymer Edn 2006; 17: 247-289.
12. Cunha A, Gaubert A, Latxague L, Dehay B. PLGA-based nanoparticles for neuroprotective drug delivery in neurodegenerative diseases. Pharmaceutics 2021; 13: 1042.
13. Kumari A, Yadav SK, Yadav SCJC, biointerfaces sB. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 2010; 75: 1-18.
14. Bouissou C, Rouse J, Price R, Van der Walle CJPr. The influence of surfactant on PLGA microsphere glass transition and water sorption: remodeling the surface morphology to attenuate the burst release. Pharm Res 2006; 23: 1295-1305.
15. Ruhe PQ, Hedberg EL, Padron NT, Spauwen PH, Jansen JA, Mikos AGJJ. rhBMP-2 release from injectable poly (DL-lactic-co-glycolic acid)/calcium-phosphate cement composites. J Bone Joint Surg Am 2003; 85: 75-81.
16. Shahabadi N, Moshiri M, Roohbakhsh A, Imenshahidi M, Hashemi M, Amin F, et al. A dose‐related positive effect of inhaled simvastatin‐loaded PLGA nanoparticles on paraquat‐induced pulmonary fibrosis in rats. Basic Clin Pharmacol Toxicol 2022; 131: 251-261.
17. Allison SD. Effect of structural relaxation on the preparation and drug release behavior of poly (lactic-co-glycolic) acid microparticle drug delivery systems. J Pharm Sci 2008; 97: 2022-2035.
18. Mohamed F, van der Walle CFJJops. Engineering biodegradable polyester particles with specific drug targeting and drug release properties. J Pharm Sci 2008; 97: 71-87.
19. Del Amo L, Cano A, Ettcheto M, Souto EB, Espina M, Camins A, et al. Surface functionalization of plga nanoparticles to increase transport across the bbb for alzheimer’s disease. Appl Sci 2021; 11: 4305.
20. Nosrati R, Abnous K, Alibolandi M, Mosafer J, Dehghani S, Taghdisi SM, et al. Targeted SPION siderophore conjugate loaded with doxorubicin as a theranostic agent for imaging and treatment of colon carcinoma. Sci Rep 2021; 11: 13065.
21. Bharadwaj VN, Tzabazis AZ, Klukinov M, Manering NA, Yeomans DC. Intranasal administration for pain: Oxytocin and other polypeptides. Pharmaceutics 2021; 13: 1088.
22. Bonaccorso A, Musumeci T, Serapide MF, Pellitteri R, Uchegbu IF, Puglisi G. Nose to brain delivery in rats: Effect of surface charge of rhodamine B labeled nanocarriers on brain subregion localization. Colloids Surf B Biointerfaces 2017; 154: 297-306.
23. Craparo EF, Musumeci T, Bonaccorso A, Pellitteri R, Romeo A, Naletova I, et al. Mpeg-plga nanoparticles labelled with loaded or conjugated rhodamine-b for potential nose-to-brain delivery. Pharmaceutics 2021; 13.
24. Baranowska-Wójcik E, Szwajgier D. Alzheimer’s disease: review of current nanotechnological therapeutic strategies. Expert Rev Neurother 2020; 20: 271-279.
25. Rouhi N, Akhgari A, Orouji N, Nezami A, Rahimzadegan M, Kamali H. Recent progress in the graphene-based biosensing approaches for the detection of Alzheimer’s biomarkers. J Pharm Biomed Anal 2023; 222: 115084.
26. Mohapatra D, Jena S, Prusty S, Sahu P. Biomarkers of Alzheimer’s disease: A review. Syst Rev Pharm 2020; 11.
27. Hashemi M, Haghgoo Z, Yazdian-Robati R, Shahgordi S, Salmasi Z, Abnous K. Improved anticancer efficiency of Mitoxantrone by Curcumin-loaded PLGA nanoparticles targeted with AS1411 aptamer. Nanomedicine J 2021; 8.
28. Mathew A, Fukuda T, Nagaoka Y, Hasumura T, Morimoto H, Yoshida Y, et al. Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer’s disease. PLoS one 2012; 7: e32616.
29. Hathout RM, El-Ahmady SH, Metwally AA. Curcumin or bisdemethoxycurcumin for nose-to-brain treatment of Alzheimer disease? A bio/chemo-informatics case study. Nat Prod Res 2018; 32: 2873-2881.
30. Zhang L, Yang S, Wong LR, Xie H, Ho PC-L. In vitro and in vivo comparison of curcumin-encapsulated chitosan-coated Poly(lactic-co-glycolic acid) nanoparticles and Curcumin/Hydroxypropyl-β-Cyclodextrin Inclusion complexes administered intranasally as therapeutic strategies for Alzheimer’s disease. Mol Pharmaceutics 2020; 17: 4256-4269.
31. Dhas N, Mehta T. Intranasal delivery of chitosan decorated PLGA core /shell nanoparticles containing flavonoid to reduce oxidative stress in the treatment of Alzheimer’s disease. J Drug Deliv Sci Technol 2021; 61.
32. Yan L, Wang H, Jiang Y, Liu J, Wang Z, Yang Y, et al. Cell-penetrating peptide-modified PLGA nanoparticles for enhanced nose-to-brain macromolecular delivery. Macromol Res 2013; 21: 435-441.
33. Zhang C, Chen J, Feng C, Shao X, Liu Q, Zhang Q, et al. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer’s disease. Int J Nanomedicine 2014; 461: 192-202.
34. Muntimadugu E, Dhommati R, Jain A, Challa VGS, Shaheen M, Khan W. Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer’s disease. Eur J Pharm Sci 2016; 92: 224-234.
35. Akel H, Ismail R, Katona G, Sabir F, Ambrus R, Csóka I. A comparison study of lipid and polymeric nanoparticles in the nasal delivery of meloxicam: Formulation, characterization, and in vitro evaluation. Int J Nanomedicine 2021; 604.
36. Rompicherla SKL, Arumugam K, Bojja SL, Kumar N, Rao CM. Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease. Naunyn Schmiedebergs Arch Pharmacol 2021; 394: 1737-1755.
37. Meng Q, Wang A, Hua H, Jiang Y, Wang Y, Mu H, et al. Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease. Int J Nanomedicine 2018; 13: 705-718.
38. Shamarekh KS, Gad HA, Soliman ME, Sammour OA. Development and evaluation of protamine-coated PLGA nanoparticles for nose-to-brain delivery of tacrine: In vitro and in vivo assessment. J Drug Deliv Sci Technol 2020; 57.
39. Nanaki SG, Spyrou K, Bekiari C, Veneti P, Baroud TN, Karouta N, et al. Hierarchical porous carbon-PLLA and PLGA Hybrid nanoparticles for intranasal delivery of galantamine for Alzheimer’s disease therapy. Pharmaceutics 2020; 12: 227.
40. Jia L, Nie X-q, Ji H-m, Yuan Z-x, Li R-s. Multiple-coated PLGA nanoparticles loading triptolide attenuate injury of a cellular model of Alzheimer’s disease. Biomed Res Int 2021; 2021.
41. Olanow CW, Stocchi F. Levodopa: a new look at an old friend. Mov Disord 2018; 33: 859-866.
42. Paik J. Levodopa inhalation powder: A review in Parkinson’s disease. Drugs 2020; 80: 821-828.
43. Tran TN, Vo TNN, Frei K, Truong DD. Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. J Neural Transm 2018; 125: 1109-1117.
44. Acharya S, Meenambiga S. Nanotechnology in Parkinson’s disease: A review. Res J Pharm Technol 2020; 13: 1967-1971.
45. Kamali H, Nosrati R, Malaekeh-Nikouei B. Chapter 1 - Nanostructures and their associated challenges for drug delivery. In: Kesharwani P, Jain NK, editors. Hybrid Nanomaterials for Drug Delivery: Woodhead Publishing; 2022. p. 1-26.
46. Gambaryan PY, Kondrasheva IG, Severin ES, Guseva AA, Kamensky AA. Increasing the efficiency of Parkinson’s disease treatment using a poly(lactic-co-glycolic acid) (PLGA) based L-DOPA delivery system. Exp Neurobiol 2014; 23: 246-252.
47. Arisoy S, Sayiner O, Comoglu T, Onal D, Atalay O, Pehlivanoglu B. In vitro and in vivo evaluation of levodopa-loaded nanoparticles for nose to brain delivery. Pharm Dev Technol 2020; 25: 735-747.
48. Patil GB, Surana SJ. Fabrication and statistical optimization of surface engineered PLGA nanoparticles for naso-brain delivery of ropinirole hydrochloride: In-vitro-ex-vivo studies. J Biomater Sci Polym Ed 2013; 24: 1740-1756.
49. Chatzitaki AT, Jesus S, Karavasili C, Andreadis D, Fatouros DG, Borges O. Chitosan-coated PLGA nanoparticles for the nasal delivery of ropinirole hydrochloride: In vitro and ex vivo evaluation of efficacy and safety. Int J Nanomedicine 2020; 589.
50. Wen Z, Yan Z, Hu K, Pang Z, Cheng X, Guo L, et al. Odorranalectin-conjugated nanoparticles: Preparation, brain delivery and pharmacodynamic study on Parkinson’s disease following intranasal administration. J Control Release 2011; 151: 131-138.
51. Wen Z, Yan Z, He R, Pang Z, Guo L, Qian Y, et al. Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration. Drug Deliv 2011; 18: 555-561.
52. Li X, Su J, Kamal Z, Guo P, Wu X, Lu L, et al. Odorranalectin modified PEG–PLGA/PEG–PBLG curcumin-loaded nanoparticle for intranasal administration. Drug Dev Ind Pharm 2020; 46: 899-909.
53. Bi CC, Wang AP, Chu YC, Liu S, Mu HJ, Liu WH, et al. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment. Int J Nanomedicine 2016; 11: 6547-6559.
54. Ahmad N. Rasagiline-encapsulated chitosan-coated PLGA nanoparticles targeted to the brain in the treatment of Parkinson’s disease. J Liq Chromatogr Relat Technol 2017; 40: 677-690.
55. Sekerdag E, Lüle S, Bozdağ Pehlivan S, Öztürk N, Kara A, Kaffashi A, et al. A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles. J Control Release 2017; 261: 187-198.
56. Chu L, Wanga A, Ni L, Yan X, Song Y, Zhao M, et al. Nose-to-brain delivery of temozolomide-loaded plga nanoparticles functionalized with anti-epha3 for glioblastoma targeting. Drug Deliv 2018; 25: 1634-1641.
57. Sousa F, Dhaliwal HK, Gattacceca F, Sarmento B, Amiji MM. Enhanced anti-angiogenic effects of bevacizumab in glioblastoma treatment upon intranasal administration in polymeric nanoparticles. J Control Release 2019; 309: 37-47.
58. Ferreira NN, Granja S, Boni FI, Prezotti FG, Ferreira LMB, Cury BSF, et al. Modulating chitosan-PLGA nanoparticle properties to design a co-delivery platform for glioblastoma therapy intended for nose-to-brain route. Drug Deliv Transl Res 2020; 10: 1729-1747.
59. Ullah I, Chung K, Bae S, Li Y, Kim C, Choi B, et al. Nose-to-brain delivery of cancer-targeting Paclitaxel-loaded nanoparticles potentiates antitumor effects in malignant glioblastoma. Mol Pharmaceutics 2020; 17: 1193-1204.
60. Zhang Y, Sun C, Zhang Q, Deng Y, Hu X, Chen P. Intranasal delivery of Paclitaxel encapsulated nanoparticles for brain injury due to glioblastoma. J Appl Biomater Funct Mater 2020; 18: 2280800020977170.
61. Jani P, Suman S, Subramanian S, Korde A, Gohel D, Singh R, et al. Development of mitochondrial targeted theranostic nanocarriers for treatment of gliomas. J Drug Deliv Sci Technol 2021; 64.
62. Hosseini SM, Golaghaei A, Nassireslami E, Naderi N, Pourbadie HG, Rahimzadegan M, et al. Neuroprotective effects of lipopolysaccharide and naltrexone co-preconditioning in the photothrombotic model of unilateral selective hippocampal ischemia in rat. Acta Neurobiol Exp 2019; 79: 73-85.
63. Wang L, Xu L, Du J, Zhao X, Liu M, Feng J, et al. Nose-to-brain delivery of borneol modified tanshinone IIA nanoparticles in prevention of cerebral ischemia/reperfusion injury. Drug Deliv 2021; 28: 1363-1375.
64. Hao R, Sun B, Yang L, Ma C, Li S. RVG29-modified microRNA-loaded nanoparticles improve ischemic brain injury by nasal delivery. Drug Deliv 2020; 27: 772-781.
65. Xiao XY, Zhu YX, Bu JY, Li GW, Zhou JH, Zhou SP. Evaluation of neuroprotective effect of Thymoquinone nanoformulation in the rodent cerebral ischemia-reperfusion model. Biomed Res Int 2016; 2016.
66. El-Zaafarany GM, Soliman ME, Mansour S, Cespi M, Palmieri GF, Illum L, et al. A tailored thermosensitive PLGA-PEG-PLGA/emulsomes composite for enhanced oxcarbazepine brain delivery via the nasal route. Pharmaceutics 2018; 10.
67. Musumeci T, Serapide MF, Pellitteri R, Dalpiaz A, Ferraro L, Dal Magro R, et al. Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents. Eur J Pharm Sci 2018; 133: 309-320.
68. Nigam K, Kaur A, Tyagi A, Nematullah M, Khan F, Gabrani R, et al. Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. Drug Deliv Transl Res 2019; 9: 879-890.
69. Shah P, Dubey P, Vyas B, Kaul A, Mishra AK, Chopra D, et al. Lamotrigine loaded PLGA nanoparticles intended for direct nose to brain delivery in epilepsy: pharmacokinetic, pharmacodynamic and scintigraphy study. Artif Cells Nanomed Biotechnol 2021; 49: 511-522.
70. Ahmad N, Ahmad R, Alrasheed RA, Almatar HMA, Al-Ramadan AS, Amir M, et al. Quantification and evaluations of catechin hydrate polymeric nanoparticles used in brain targeting for the treatment of epilepsy. Pharmaceutics 2020; 12.
71. Kaur S, Manhas P, Swami A, Bhandari R, Sharma KK, Jain R, et al. Bioengineered PLGA-chitosan nanoparticles for brain targeted intranasal delivery of antiepileptic TRH analogues. Chem Eng J 2018; 346: 630-639.
72. Ahmad N, Ahmad R, Al Qatifi S, Alessa M, Al Hajji H, Sarafroz M. A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy. BMC Chem 2020; 14: 10.
73. Shah P, Sarolia J, Vyas B, Wagh P, Ankur K, Kumar MA. Plga nanoparticles for nose to brain delivery of clonazepam: Formula-tion, optimization by 32 factorial design, in vitro and in vivo evaluation. Curr Drug Deliv 2021; 18: 805-824.
74. Tong GF, Qin N, Sun LW. Development and evaluation of Desvenlafaxine loaded PLGA-chitosan nanoparticles for brain delivery. Saudi Pharm J 2017; 25: 844-851.
75. Cayero-Otero MD, Gomes MJ, Martins C, Álvarez-Fuentes J, Fernández-Arévalo M, Sarmento B, et al. In vivo biodistribution of venlafaxine-PLGA nanoparticles for brain delivery: Plain vs. functionalized nanoparticles. Expert Opin Drug Deliv 2019; 16: 1413-1427.
76. Seju U, Kumar A, Sawant KK. Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: In vitro and in vivo studies. Acta Biomater 2011; 7: 4169-4176.
77. Chen J, Zhang C, Liu Q, Shao X, Feng C, Shen Y, et al. Solanum tuberosum lectin-conjugated PLGA nanoparticles for nose-to-brain delivery: In vivo and in vitro evaluations. J Drug Target 2012; 20: 174-184.
78. Piazza J, Hoare T, Molinaro L, Terpstra K, Bhandari J, Selvaganapathy PR, et al. Haloperidol-loaded intranasally administered lectin functionalized poly(ethylene glycol)–block-poly(d,l)-lactic-co-glycolic acid (PEG–PLGA) nanoparticles for the treatment of schizophrenia. Eur J Pharm Sci 2014; 87: 30-39.
79. Piazza JE, Zhu C, Ravi Selvaganapathy P, Hoare TR, Jain SB, Hossain F, et al. A novel intranasal spray device for the administration of nanoparticles to rodents. J Med Devices Trans ASME 2015; 9.