Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs

Agrawal, Mukta; Saraf, Swarnlata; Saraf, Shailendra; Antimisiaris, Sophia G.; Chougule, Mahavir B.; Shoyele, Sunday; Alexander, Amit

doi:10.1016/j.jconrel.2018.05.011

Cited by 404 publications

(244 citation statements)

References 328 publications

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“…It is claimed to deliver the drug directly to the brain without entering into the systemic circulation. 122,123 The nasal cavity is divided into three different regions, (1) vestibular region, (2) respiratory region and (3) olfactory region. The drug or any dosage form instilled into the nasal cavity can primarily absorb through the respiratory area and enters into the systemic circulation.…”

Section: Quantum Dotsmentioning

confidence: 99%

“…Also, the drug reached/or instilled in the posterior region, ie, the olfactory region, enter directly to the brain via olfactory and trigeminal neurons. 122,124 The drug entered into the systemic circulation further needs to cross the BBB while the drug entered through intraneural pathway follows cellular transport mechanism. From the olfactory region, the drug primarily enters into the olfactory bulb via trigeminal and olfactory neurons, followed by absorption into lamina propria and then entered in the CSF.…”

Section: Quantum Dotsmentioning

confidence: 99%

“…Further, mucociliary clearance and enzymatic degradation also reduce bioavailability. 122 Thus, various novel drug delivery strategies are under investigation which coverup such limitations and improves the efficiency of the intranasal route. Nigam et al (2019) utilized PLGA nanoparticle for direct nose-to-brain delivery of lamotrigine.…”

Section: Quantum Dotsmentioning

confidence: 99%

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Recent expansions of novel strategies towards the drug targeting into the brain

Alexander¹,

Agrawal²,

Uddin³

et al. 2019

IJN

Self Cite

111

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The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.

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Section: Quantum Dotsmentioning

confidence: 99%

Section: Quantum Dotsmentioning

confidence: 99%

See 1 more Smart Citation

Recent expansions of novel strategies towards the drug targeting into the brain

Alexander¹,

Agrawal²,

Uddin³

et al. 2019

IJN

Self Cite

111

View full text Add to dashboard Cite

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“…7 Furthermore, it should be noticed that these approved drugs cannot cure or delay the progression of AD, but only improve some symptoms for a limited time. 8 Therefore, the development of new AD therapeutics agents is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Rhynchophylline Loaded-mPEG-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer’s Disease

Xu¹,

Wang²,

Xu³

et al. 2020

IJN

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Purpose: Alzheimer's disease (AD) is a growing concern in the modern society. The current drugs approved by FDA are not very promising. Rhynchophylline (RIN) is a major active tetracyclic oxindole alkaloid stem from traditional Chinese medicine uncaria species, which has potential activities beneficial for the treatment of AD. However, the application of rhynchophylline for AD treatment is restricted by the low water solubility, low concentration in brain tissue and low bioavailability. And there is no study of brain-targeting therapy with RIN. In this work, we prepared rhynchophylline loaded methoxy poly (ethylene glycol)-poly (dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPS-RIN), which coupled with Tween 80 (T80) further for brain targeting delivery (T80-NPS-RIN). Methods: Preparation and characterization of T80-NPS-RIN were followed by the detection of transportation across the blood-brain barrier (BBB) model in vitro, biodistribution and neuroprotective effects of nanoparticles. Results: The results indicated T80-NPS-RIN could usefully assist RIN to pass through the BBB to the brain. T80-NPS-RIN treatment regulated the activity of neurons in vitro. Conclusion: The presented data confirmed that rhynchophylline encapsulated mPEG-PLGA nanoparticles coated with Tween 80 could across through the BBB and exhibited efficient neuroprotective effects. The T80-NPS-RIN nanoparticles have a chance to be an alternative drug to the therapy of AD.

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“…PG itself, administered intranasally, has been used as a therapy by the Voelker 434 group to effectively inhibit respiratory syncytial virus infection (Numata et al, 2010;Numata et al, 435 2013) and influenza A virus (Numata et al, 2012). Moreover, lipid based colloidal carriers are able to 436 cross the blood brain barrier (BBB) when administered intranasally (Ganesan et al, 2018;Mittal et al, 437 2014;Patel & Patel, 2017;Tapeinos et al, 2017) and have recently been shown to be efficient drug 438 delivery vehicles in the treatment of intrinsic brain tumors (van Woensel et al, 2013) and 439 neurodegenerative diseases including Alzheimer's (Agrawal et al, 2018;Tapeinos et al, 2017) and 440 Parkinson's (Tapeinos et al, 2017;Yang et al, 2016). Given the historical difficulties in treating the 441 neurological effects of NPC disease, the development of a minimally invasive, effective treatment with 442 intrinsic ability to cross the BBB is of interest.…”

mentioning

confidence: 99%

Interaction of NPC2 protein with Lysobisphosphatidic Acid is required for normal endolysosomal cholesterol trafficking

McCauliff

Langan

et al. 2019

Preprint

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1 2 Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the 3 cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or 4 NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates by the 5 LE/LY phospholipid lysobisphosphatidic acid (LBPA) and in these studies sought to determine their 6 functional relationship in normal LE/LY cholesterol egress. Here we demonstrate that NPC2 interacts 7 directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Using its 8 precursor phosphatidylglycerol (PG), we show that PG-induced LBPA enrichment results in clearance of 9 accumulated cholesterol from NPC1-deficient cells but is ineffective in cells lacking functional NPC2. 10Together these studies reveal a heretofore unknown aspect of intracellular cholesterol trafficking, in 11 which NPC2 and LBPA function together in an obligate step of sterol egress from the LE/LY 12 compartment, which appears to be independent of NPC1. 13 egress pathway of membrane-impermeable species utilized by the NPC1 and NPC2 proteins (Goldman & 46 Krise, 2010). It has also been shown that overexpression of ABCA1 reversed lysosomal cholesterol 47

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Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs

Cited by 404 publications

References 328 publications

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

<p>Rhynchophylline Loaded-mPEG-PLGA Nanoparticles Coated with Tween-80 for Preliminary Study in Alzheimer’s Disease</p>

Interaction of NPC2 protein with Lysobisphosphatidic Acid is required for normal endolysosomal cholesterol trafficking

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