The near future of nose and brain:
There is a long history of lab experimentation designed to bypass the protective Blood Brain Barrier (BBB).
Viral delivery (Adeno), Lipid Nano Particles (e.g. with PEG), and Intranasal Delivery are three enthusiastic approaches. Two got unfettered worldwide access; the third is currently being promoted.
The nose offers direct access to the brain via the olfactory epithelium and cribiform plate.
Decades of lab testing have focused on the goal of ‘bypassing the Blood Brain Barrier’, sacrificing animals soon after administration to judge success by “bypass-or-not.” Brain changes […inflammation, barrier integrity, epigenetic change, toxicity, neurodegeneration…] and damage to organs beyond the study’s interest may not be critically and cautiously evaluated.
Aerosolized nose-to-brain vaccines is another cluster of enthusiasm. Aerosol encounters can be applied beyond control, consent, or awareness of people receiving them.
Articles listed here are a narrow, haphazard example of hundreds of similar publications, paved with enthusiastic intentions.
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1929:
Report to the Committee on Vaccination on an Anatomical Investigation into the Routes by which Infections may pass from the Nasal Cavities into the Brain
Clark, W. E. Le G. Reports on Public Health and Medical Subjects. Ministry of Health 1929 No.54 pp.27
“Clark found that instillations of … potassium ferro-cyanide and iron ammonium citrate into each nostril of rabbits gained the surface of the brain within an hour, the solution reaching the subarachnoid spaces over the surface of the brain by way of the perineural sheaths of the olfactory nerves. The evidence showed that the spaces of these perineural sheaths were continuous above with the subarachnoid spaces and extended peripherally along the peripheral fibres of the olfactory nerves to the olfactory sensory epithelium. It was also found that material might pass from the nasal to the intracranial cavity via the blood vessels piercing the cribiform plate.”
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SARS-CoV-2 Receptors and Entry Genes Are Expressed in the Human Olfactory Neuroepithelium and Brain
Fodoulian L. et al. 2020. https://doi.org/10.1016/j.isci.2020.101839
“SARS-CoV-2 receptors ACE2 and TMPRSS2 are expressed in olfactory neuroepithelia
A subset of neuronal and non-neuronal cells in the brain transcribe ACE2”
“Reports indicate an association between COVID-19 and anosmia, as well as the presence of SARS-CoV-2 virions in the olfactory bulb. … We found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2) and for the virus internalization enhancer TMPRSS2.
… It is critical to determine whether this virus disposes of a niche to replicate just under the cribriform plate of the ethmoid bone, a structure with large holes through which olfactory neuron axonal projections directly contact the olfactory bulb and offer a potential gateway to the brain. This latter, if expressing SARS-CoV2 receptors, could in turn become infected.”
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In Vitro Evaluation of Nasal Aerosol Depositions: An Insight for Direct Nose to Brain Drug Delivery
Maaz A, Blagbrough IS, De Bank PA. Pharmaceutics. 2021 Jul 14;13(7):1079. doi: 10.3390/pharmaceutics13071079
“… Effective drug delivery to brain tissues is still a great challenge due to complex anatomical and physiological barriers that selectively limit the entry of drugs into the brain. To work towards overcoming these challenges, recent advancements in the field of nanoparticle-based drug delivery have demonstrated promising results for nanotherapies in the possible treatment of CNS disorders [1]. … the blood–brain barrier (BBB), which protects the brain from the entry of toxic substances, is a crucial obstacle for therapeutics to access the CNS.
… The olfactory region is the uppermost region in the nasal cavity exclusively connecting the external environment to the brain, unimpeded by the BBB. Over the last few decades, intranasal administration has emerged as an attractive non-invasive and direct route for the therapeutics to enter the CNS bypassing the BBB …
Figure 1: … “The olfactory mucosa (yellow) is located next to the cribriform plate at the skull base ... Nasally transmitted substances can cross the cribriform plate via different pathways to enter the brain. … Reproduced from [13], MDPI, 2018.”
… Three main pathways are involved: an epithelial pathway via the olfactory epithelium and neuronal pathways via olfactory and trigeminal nerves. … Drugs could then be transported via the olfactory epithelium intracellularly along the nerve axons or across the olfactory mucosa, transcellularly through the cells as well as paracellularly through the gaps between the cells [13]. In addition to delivery to the olfactory region of the brain, drugs can also find their way to the brainstem via the trigeminal nerve, which extensively innervates the respiratory mucosa in the nasal cavity. …”
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Insights into direct nose to brain delivery: current status and future perspective
Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Drug Deliv. 2014 Mar;21(2):75-86. doi: 10.3109/10717544.2013.838713.
“… Intranasal drug delivery is emerging as a reliable method to bypass the blood-brain barrier (BBB) and deliver a wide range of therapeutic agents including both small and large molecules, growth factors, viral vectors and even stem cells to the brain ...”
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Recent patents review on intranasal administration for CNS drug delivery.
Jogani V, Jinturkar K, Vyas T, Misra A. Recent Pat Drug Deliv Formul. 2008;2(1):25-40. doi: 10.2174/187221108783331429.
“…Approximately, 100% of large molecule drugs and >98% of small molecule drugs do not cross the blood-brain barrier (BBB). … Intranasal drug delivery is one of the important delivery options for brain targeting … Many patents have been filed in recent past … ”
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Intranasal drug delivery for brain targeting.
Vyas TK, Shahiwala A, Marathe S, Misra A. Curr Drug Deliv. 2005 Apr;2(2):165-75. doi: 10.2174/1567201053586047.
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Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.
Pardeshi CV, Belgamwar VS.Expert Opin Drug Deliv. 2013 Jul;10(7):957-72. doi: 10.1517/17425247.2013.790887.
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Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa.
Gänger S, Schindowski K. Pharmaceutics. 2018 Aug 3;10(3):116. doi: 10.3390/pharmaceutics10030116.
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Cell-Penetrating Peptide-Modified Block Copolymer Micelles Promote Direct Brain Delivery via Intranasal Administration.
Kanazawa, T., Taki, H., Tanaka, K. et al. Pharm Res 28, 2130–2139 (2011). https://doi.org/10.1007/s11095-011-0440-7
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Nose-to-brain drug delivery mediated by polymeric nanoparticles: influence of PEG surface coating.
de Oliveira Junior ER et al. Drug Deliv Transl Res. 2020 Dec;10(6):1688-1699. doi: 10.1007/s13346-020-00816-2.
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2012: Novel Mucoadhesive Polymers for Nasal Drug Delivery
Anand U, Feridooni T, and Agu RU. 2012. http://dx.doi.org/10.5772/52560
“… Formulation strategies … to improve the absorption of drugs through the nasal route ... work by attaching themselves to the mucus layer and thus preventing clearance of the drug delivery system…. PEG polymers… readily penetrate nasal mucus. The deployment of polymeric particles with improved sinus mucus penetration capability should encourage the commercial development of new generations of nanoparticle-based intranasal drug delivery systems [46].”
PEG: Figure 2: Mechanisms of mucoadhesion by Lectins (A), Thiomers (B), Alginate Poly ethylene glycol acrylate (C)
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PEG is an ingredient in the mRNA vaccines:
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Exhilarating, Non-Invasive, and Herbal
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Exhilarating prospects:
Convolutions in the rendition of nose to brain therapeutics from bench to bedside: Feats & fallacies
Honey Goel, Vinni Kalra, Sant Kumar, Verma Sunil, Kumar Dubey, Ashok Kumar Tiwary. 2022. https://doi.org/10.1016/j.jconrel.2021.12.009
“Novel paradigms for the repurposing of conventional biomolecules by assessing their particle engineering characteristics purveys exhilarating prospects in the [Nose-to-Brain] N2B therapeutics…
… Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro‑leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. …”
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Non-invasive
Intranasal Drug Delivery: A Non-Invasive Approach for the Better Delivery of Neurotherapeutics
Kumar H, Mishra G, Sharma AK, Gothwal A, Kesharwani P, Gupta U. Pharm Nanotechnol. 2017;5(3):203-214. doi: 10.2174/2211738505666170515113936.
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For those of us interested in natural herbal health and reduced toxicity…..
A Patent Review on Nanotechnology-Based Nose-to-Brain Drug Delivery
Singh R, Brumlik C, Vaidya M, Choudhury A. Recent Pat Nanotechnol. 2020;14(3):174-192. doi: 10.2174/1872210514666200508121050.
“Surface modified nanoparticles can greatly improve drug transport and bioavailability of drugs, particularly higher molecular weight drugs…. Nanoformulations of herbal drugs could increase drug bioavailability and reduce toxicity. …”
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Not beating around the bush
Brain pharmacokinetics of neurotoxin-loaded PLA nanoparticles modified with chitosan after intranasal administration in awake rats.
Zhang X, Liu L, Chai G, Zhang X, Li F.Drug Dev Ind Pharm. 2013 Nov;39(11):1618-24. doi: 10.3109/03639045.2012.727828.PMID: 24087853
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Strategies to facilitate or block nose-to-brain drug delivery
Martins, P. P., Smyth, H. D. C., & Cui, Z. (2019). doi:10.1016/j.ijpharm.2019.118635
“… A scarcely studied topic in this emerging field is how to inhibit or block nose-to-brain delivery, which can be important when local and systemic delivery are needed, but brain delivery is not desired. An example of this scenario is the intranasal administration of vaccines. For example, upon intranasal immunization with FluMist, the live attenuated influenza viruses may reach the brain with unknown but potentially harmful clinical effects (FDA 2009, 2017). …”
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Articles quoted here are for non-commercial educational purposes only; refer to the copyrights of the owners.