Research J. Pharm. and Tech.

16(12): December 2023

ISSN 0974-3618 (Print) www.rjptonline.org

0974-360X (Online)

REVIEW ARTICLE

Applications of Polymeric Nanoparticle in Nose to Brain Drug Delivery

Sunena*, Sumit Kumar1, Sulekha2, Deepali Tomar3, Dinesh Kumar4, Vimal Kishore5
*
School of Pharmaceutical Sciences, Om Sterling Global University, Hisar - 125001, Haryana, India.
1
Department of Pharmaceutical Sciences, Central University of Haryana,
Jant-Pali Mahendergarh - 123031, Haryana, India.
2
Geeta Institute of Pharmacy, Geeta University, Panipat - 132145, Haryana, India.
3
Lala Birkha Ram College of Pharmacy, Golpura, Panchkula, Haryana, India.
4
Atam Institute of Pharmacy, Om Sterling Global University.
5
Dr. A.P.J. Abdul Kalam University, Indore Madhya Pradesh, India.
*Corresponding Author E-mail: sunaina.garhwal@gmail.com
ABSTRACT: studied for the therapy of various brain disorders as
The primary goal of developing novel formulations is well as the process of nanoparticle transport.
to effectively deliver the drug the at the target site. A
desirable, non-invasive method of enhancing
medication penetration or delivering innovative drug
or gene carriers into the brain is nose-to-brain
administration. The main benefit of intranasal
medication administration is that it avoids the blood-
brain barrier and targets drug molecules directly to
the brain. Due to their difficulty in crossing the
blood-brain barrier, big molecular weight and
hydrophilic compounds can also be transported to the
brain by this drug delivery channel. By speeding the
administration of treatments at the target site and
preventing systemic adverse effects, intranasal
delivery to the brain is helpful in treating many
neurological disorders. Potential drug delivery
systems, the drug-encapsulated polymeric
nanoparticles can convey a sizable amount of
medication from the nose to brain. The advantages of
polymeric nanoparticles-mediated nose to brain
targeting are discussed in this paper. Additionally, it Graphical Abstract: Benefits of polymeric
provides an overview of the polymeric nanoparticles nanoparticles in nose to brain drug delivery

KEYWORDS: Intranasal, Blood-brain-barrier, Neurological disorders, Polymeric nanoparticles, Brain

targeting, Non-invasive.

1. INTRODUCTION:
The intranasal pathway is a non-invasive opportunity to
the oral and parenteral direction to supply medications
to the Brain. This approach can reduce a drug's systemic
Received on 25.01.2023 Modified on 01.07.2023
negative outcomes through bypassing the blood-brain
Accepted on 24.11.2023 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(12):6087-6094. barrier1,2. Through nasal administration, the medicine
DOI: 10.52711/0974-360X.2023.00988 either enters the systemic circulation over the nasal
6087
 Research J. Pharm. and Tech. 16(12): December 2023
mucosa or directly enters the brain via the olfactory and
trigeminal nerves3. Since many years ago, intranasal
administration of medicines to the central nervous
system (CNS) has been intensively researched. Strokes,
migraines, brain tumors, and other CNS illnesses have
all been treated to great success using this method. Due
to mucociliary clearance, the amount of medicine that
enters the central nervous system through direct nasal
transport is very low, necessitating the usage of effective
drug delivery systems. Novel drug delivery methods,
ordinarily drug-loaded nanoparticles, have lately been
advanced to enhance nose-to-brain delivery4. In the
creation of nanoparticles, polymers are crucial because
they offer high drug encapsulation effectiveness, greater
absorption, better solubility, and high permeability. The
fact that polymeric nanoparticles utilized for drug
administration are biocompatible, biodegradable, and
have non-immunogenic qualities is their most significant
advantage5. Additionally, cutting-edge methods like
mucoadhesive polymeric nanoparticles enhance
olfactory contact to overcome mucociliary clearance and
upsurge the drug concentration that reaches the brain6.
In nose to brain applications, mucoadhesive polymers
like chitosan and its modified derivatives would be the
potential carrier. Chitosan is widely employed in the
nasal administration of several CNS-acting medications
as well as other therapies like proteins and hormones
like insulin, etc. since it also acts as a permeation
enhancer7. The transfer of nanoparticles from the nose to
the brain and their numerous uses in treating neuronal
issues is outlined in this paper.
2. Drug delivery pathways from nose to CNS:
The delivery of medicinal chemicals to the brain to treat
CNS illnesses has been researched via drug transport
through the olfactory mucosa8-11. For extremely
important drugs with limited blood-brain permeability,
such as neuropeptides used to treat Alzheimer's or
Parkinson's disease and for immediate pain relief, the
olfactory transfer pathway may be advantageous12. The
trigeminal neural pathway and olfactory receptor
neurons are used in direct nose to brain medication
delivery.
The nasal cavity is directly connected to the central
nervous system (CNS) through the trigeminal and
olfactory nerves, respectively13-14. The respiratory and
olfactory segments make up the majority of the nasal
cavity. For drugs to go straight from the nose to the
brain, these are the most practical portions. Intranasal
drug delivery quickly travels from the upper nasal cavity
to the brain via the olfactory nerve pathways
extracellularly1,15. The olfactory bulbs get a substantial
quantity of drug from this conduit16,17. Other sensory
nerve known as the trigeminal nerve present in the
6088
olfactory epithelium also take part in drug delivery from
nose to brain. The trigeminal nerve (cranial nerve V) is
attached to the pons and the cribriform plate thru axons
of the bipolar neurons, allowing perivascular transport to
the dual brain areas and the spinal cord1,18.
2.1 Intranasal drug delivery to CNS: Possible
transport mechanism for nanoparticles:
Either transcellular (inside the epithelial cell) or
paracellular (between the epithelial cells) processes are
used for drug transport across the nasal epithelium.
2.1.1 Transcellular transport/Endocytosis:
By way of endocytic uptake to the olfactory bulb, the
olfactory sensory neurons (OSN) perform transcellular
trafficking. It has been claimed that the OSN has
without delay carried many big molecules, which
include albumin, horseradish peroxidase (HRP), wheat
germ agglutinin-horseradish peroxidase (WGAHRP),
and rhabdoviruses, to the olfactory bulb 19-23. Numerous
molecular approaches, along with clathrin-mediated,
caveolin-mediated, macropinocytosis, caveolin-
impartial, and phagocytosis, are involved in endocytosis
transport24. The best transport system is the clathrin-
mediated endocytic pathway, but the fundamental
mechanism that causes cellular internalisation of
nanoparticles is still not fully understood 25. Particle size
is a significant factor that starts cellular internalisation
of nanoparticles. According to certain investigations,
particle sizes between 200 and 1000 nm trigger
caveolin-mediated uptake whereas those smaller than 20
nm promote clathrin-mediated uptake26. Surface charge
and particle concentration over the cells are additional
factors that influence the internalisation route of
nanoparticles27, 28.
2.1.2 Paracellular transport/transcytosis:
To reach the lamina propria, transport that is
extracellular or paracellular must pass via the
sustentacular cells. Only tiny drug molecules can pass
through the paracellular route, which is made up of
hydrophilic channels and tight junctional complexes
joining the epithelial cells. As tight junctions are
typically impermeable to molecules with a
hydrodynamic radius greater than 4-8nm, the largest
molecular size for paracellular drug transport in nasal
epithelial cells has been estimated to be 1000 Da, which
limits the movement of molecules larger than this to
pass between neighboring cells29. Consequently, it's far
believed that drug distribution from the nostril to the
brain occurs transcellularly (via epithelial cell) for
nanoparticles larger than around 20nm. Chitosan acts
with the aid of its ability to translocate the junctional
proteins, ZO-1 and claudins, from the cell membrane to
the cytosol and functionally regulate the tight junction
 Research J. Pharm. and Tech. 16(12): December 2023

protein, ZO-1, via adjustments in protein kinase C via olfactory nerves to the brain via several endocytic
activity30,31. Intracellular transport is a slow procedure, routes due to their small size. P-gp efflux proteins carry
requiring numerous hours, but extracellular transport is drug-encapsulated nanoparticles outside of cells while
rapid and feature rapid onset of action13,32. protecting them from biological, chemical, and/or
3. Rationale of nanoparticles in nose to brain drug physical destruction. As a result, the drug would be
delivery: more readily available in the CNS. By releasing tight
Nanoparticles provide greater nasal mucosa penetration junctions, they also make it easier to distribute
and extended residence times33. Nanoparticles are a medications through the nose, enhancing drug
common colloidal component that has numerous distribution across the mucosal barrier. Nanoparticles
advantages, such as higher bioavailability, systemic that are bio adhesive or mucoadhesive are frequently
balance, high drug loading capability, lengthy blood used because they improve drug bioavailability at the
circulation instances, and selective organ/tissue target location by reducing mucociliary clearance,
distribution with longer half-life. Nasal sprays and drops extending residence duration through mucoadhesive
primarily based on nanoparticles have these days gone interactions with nasal mucosa5. Table 1 provides a
through extensive formulations to improve the summary of the polymeric nanoparticles-based
efficiency of nasal delivery. Drug transport to the CNS formulations created for the various drugs that target the
through oral routes is difficult because of the blood- nose to brain.
brain barrier (BBB), which restricts the admission of
many compounds into the brain. The BBB is a
specialized barrier that divides cerebrospinal fluid from
blood. It's far made up of endothelial cells joined by
means of tricky tight junctions, and it prevents the entry
of big, hydrophilic molecules like peptides and proteins
into the brain. If administered orally, protein and peptide
molecules are likewise quickly broken down by
gastrointestinal enzymes or the liver cytochromes,
therefore nasal administration may be a superior
option12,34. According to a number of studies35, the
nanoparticulate drug delivery systems seem to be a
potential brain-targeting method. It is still unclear
exactly how nanoparticles transfer drugs from the nose
to the brain. The drug-loaded nanoparticles are transport
via paracellular, transcellular, and olfactory neuronal Figure: 1 Major transport mechanisms of nanoparticles from nose
pathways are depicted in Fig. 14. to brain: (A) olfactory paracellular pathway; (B) olfactory
transcellular pathway and (C) olfactory neural pathway.
Nanoparticles may be able to travel between cells and
Table: 1 Nose to brain drug delivery of various drugs through polymeric nanoparticles
Drug Pharmacological use Polymers used References
Olanzapine Antipsychotic Chitosan 36
Risperidone Antipsychotic, Alzheimer's Disease Polycarbophil and chitosan 37
Didanosine Antiretroviral Drug Chitosan 38
Olanzapine Antipsychotic PLGA 39
Gallic acid Alzheimer's Disease, Antioxident Chitosan 40
Thymoquinone Anti-cancer Chitosan 41
Rivastigmine Dementia Chitosan 42
Bromocriptine Parkinson's disease, Neuroletic malignant syndrome, Type 2 Chitosan 43
Diabetes
Ropinirole Parkinson's disease Chitosan 44
Ziprasidone Antipsychotic Chitosan 45
Venalfixine Antidepressant Chitosan 46
Tizanidine Centrally acting muscle relaxcent Thiolated chitosan 47
HBV surface antigen Hepatitis B N, N, N Trimethyl chitosan 48
Ondansetron Chemotherapy induced emesis Lecithin and Poloxamer 188 49
Insulin Neurodegenerative diseases PLGA 50
Sumatriptan Antimigrane Chitosan 51
Cyclobenzaprine Muscle relaxant Thiolated chitosan 52
Lecuine enkephalin Neurotransmitter in pain management N- trimethyl chitosan 53

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 Research J. Pharm. and Tech. 16(12): December 2023

NAP peptide Neuroprotective agent Lactoferrin modified PEG Co- 54

PCL
Venalfixine Antidepressant Alginate 55
Midazolam Sedative PLGA 56
Ropinirole Parkinson's disease Chitosan 57
Paclitaxel Anti- Cancer PLGA 58
Resveratrol Dietary Supplement Deacetylated gellan gum 59
Quetiapine fumarate Antipsychotic Transcutol P, PEG 400, Emalex 60
LWIS 10
Quetiapine fumarate Antipsychotic Chitosan 61
Aripiprazole Antipsychotic Poly(caprolactone) 62
Tarenflurbil Anti - Alzheimer's Poly(lactide- co- glycolide) 63
Neuropeptide Neuroprotective agent Gelatin 64
Substance P
Selegiline Anti-Depressant Thiolated Chitosan 65
Diazepam Sedative hypnotic PLGA 66
Rasagiline Parkinson's disease Chitosan glutamate 67
Desvenlafaxine Anti-Depressant PLGA-chitosan 68
Huperzine A Alzheimer's Disease, N-trimethylated chitosan 69
Temozolomide Glioblastoma PLGA 70
Galantamine Alzheimer's Disease, Thiolated Chitosan 71
Melatonin Glioblastoma. Polycaprolactone 72
Paclitaxel Glioblastoma PLGA 73

4. Polymer used in constituting nanoparticles drug shipping76.PEG–PLA or PEG–PLGA nanoparticles

designed as drug carriers and Surface modification
of polymeric nanoparticles for brain targeting:
Most widely used polymers for nanoparticles used in
nose to brain delivery are classified broadly in two
categories summarized in Table 2.
Table2: Polymers used in nanoparticles fabrication for nose to
brain drug delivery
Natural Synthetic Polymers
Polymers
• Chitosan • Polylactide (PLA)
• Gelatin • Poly(lactide co - glycolide) PLGA
• Sodium • Poly (ƹ-caprolactone) PCL
Aginate • Poly acrylates & Polymethacrylates
• Albumin (Eudragit)
• Poly lactide- poly(ethylene glycol) PLA -
PEG
• Poly(lactide- co - glycolide) - poly(ethylene
glycol) PLGA -PEG
• Poly (ƹ-caprolactone) - poly(ethylene
glycol) PCL -PEG
Lectins are proteins or glycoproteins extracted from
plants, able to understand and bind with quite specific
glycan arrays of glycosylated lipids and proteins present
at the surface of different cellular sorts. Studies
suggested, wheat germ agglutinin (WGA) obtained from
Triticum vulgare–horseradish peroxidase conjugate can
bind with the mobile surface of olfactory sensory cells,
undergo adsorptive endocytosis and anterograde axonal
delivery, and reached in the olfactory bulb at
concentrations more than the ones acquired through i.v.
management of the same conjugate74,75. Some different
lectins, inclusive of Solanum tuberosum lectin (STL),
Ulex europeus agglutinin I (UEA I), and odorranalectin
(OL) have been additionally studied for the nose to brain
6090
have been conjugated to those lectins improved brain
focused on as compared to non-centered nano Proteins
or glycoproteins derived from flora called lectins are
able to detect and interact with extremely specialized
glycan arrays of glycosylated lipids and proteins
observed on the floor of many cellular types. In keeping
with studies, Triticum vulgare-horseradish peroxidase
conjugate's wheat germ agglutinin (WGA) can bind to
the floor of olfactory sensory cells, go through
adsorptive endocytosis and anterograde axonal transport,
and attain higher concentrations in the olfactory bulb
than whilst the identical conjugate is administered
intravenously74,75.Different lectins had been investigated
for nose-to-brain drug transport, consisting of Solanum
tuberosum lectin (STL), Ulex europeus agglutinin I
(UEA I), and odorranalectin (OL)76. In comparison to
non-focused lectins, PEG-PLA or PEG-PLGA
nanoparticles have been attached to those lectins to
increase the brain concentration. In spite of having many
advantages, lectins are critically restricted by using the
opportunity of toxicity and immunogenicity77. Some
cationic amino acid sequences known as cellular-
penetrating peptides (CPPs) have the ability to penetrate
cell membranes and flow into the intracellular region,
improving penetration through the nasal mucosa. In
view that lactoferrin (Lf), an iron-binding cationic
glycoprotein of the transferrin circle of relatives, is
appreciably expressed on the floor of respiration
epithelial cells as well as on neurons and brain
endothelial cells, it has been hired as a focused-on
ligand of nanocarriers78,79.
5. Applications of polymeric nanoparticles fornose to
brain drug delivery in various brain disorders:
 Research J. Pharm. and Tech. 16(12): December 2023
Variousdrugs loaded nanoparticles have been
investigated for CNS targeting through nasalolfactory
pathway.
5.1 Migraine and pain: The more effective alternative
migraine therapy approach involves direct nasal drug
delivery. By quickly reaching the CNS, it provides quick
relief while avoiding the severe gastrointestinal side
effects brought on by oral medication. When treating
migraine episodes, intranasal sprays of zolmitriptan had
a higher bioavailability and faster absorption than oral
tablets80. Additionally, zolmitriptan micellar
nanocarriers have a significant potential for brain
targeting due to their improved permeability across nasal
mucosa81. Formigraine treatment, rizatriptan nano-
emulsion-based intranasal administration enhances
bioavailability and brain tissue deposition82.
Nasaldelivery of zolmitriptan-loaded thiolated chitosan
nanoparticles for the treatment of migraines was also
investigated and found significant83,84.
5.2 Psychotic disorders: A non-invasive and quick-
acting treatment option for psychotic individuals is the
nasal route. Intranasal haloperidol is a superior
alternative to intravenous or intramuscular haloperidol
for the treatment of psychosis85. Buspirone administered
via the intranasal route is preferable for the treatment of
anxiety because it goes through significant presystemic
metabolism. Clonazepam was also investigated for nose
to brain transfer in patients with status epilepticus86.
5.3 Neurodegenerative diseases: For the treatment of
brain stroke in animal models, intranasal administration
of insulin-like growth component IGF-I, deferoxamine,
and erythropoietin were investigated. According to
reviews, intranasal management of IGF-I can quickly
cause pharmacological effects inside the brain and spinal
cord by way of heading off the blood-brain barrier and
visiting through olfactory and trigeminal nerve
pathways87. In this study, the kinetics of brain
penetration and bioavailability of two tacrine
formulations—a mucoadhesive microemulsion and a
solution—were evaluated. In comparison to the solution,
the mucoadhesive formulation of tacrine was shown to
have a 2-fold greater bioavailability88. Galantamine-
loaded mucoadhesive polymeric nanoparticles were
discovered to be more efficient than solutions when
tested in vivo on mice and in vitro via nasal mucosa,
respectively72,89. Significant enhancement of
bioavailability in brain was observed by rasagiline
loaded nanoparticles direct nose to brain targeting in
Parkinson's disease therapy. Therefore, administering
rasagiline via the nasal route will be a promising way to
avoid the first pass effect and increases its
bioavailability90,91.Intranasal delivery of metoclopramide
6091
hydrochloride was in-vivo investigated in rats suggested
that the mucoadhesive metoclopramide prolong the
residence time in nasal cavity from approximately 10
(ordinary solution) to 52 minutes92.
5.5 Drug addictions: In individuals being treated for
severe drug addictions, intranasal delivery of
diamorphine is a better therapeutic alternative than
intravenous diamorphine. Due to the higher stigma
associated with needle-related issues, intranasal
distribution is a less intrusive strategy than existing
intravenous therapy93. According to reports, methadone
is more quickly absorbed and has a better bioavailability
when administered by the nose94
5.6 Sedation and preanesthetic: An efficient and
painless method for administering sedatives and
preanesthetic drugs is intranasal administration. Fast
acting medications without sedation include midazolam,
fentanyl, and sufentanyl95,96. Intranasal administration of
anxiolytics has also been proposed as a superior
alternative to intravenous delivery.
5.7 Brain tumor: Because it is challenging for
chemotherapy medicines to get across the blood-brain
barrier and reach the brain, brain tumors are among the
most challenging malignancies to diagnose and treat.
The majority of chemotherapeutic drugs used in clinical
settings, including doxorubicin, paclitaxel, cisplatin,
methotrexate, and carmustine, are unable to pass
theBBB97-98. Due to their ability to target tumor cells
specifically, nanoparticles have become the ideal
method for delivering cytostatic medicines for the
treatment of cancer99-101.
CONCLUSION:
There are several advantages to intranasal administration
to the brain over traditional drug delivery methods in a
variety of neurological conditions. By determining the
precise dose and using in-vivo methods to assess the
bioavailability of medications that cannot pass the blood
brain barrier or have low oral bioavailability, intranasal
administration can be made more realistically useful.
Drugs may be addressed from the nose to the brain in a
therapeutic range using cutting-edge drug delivery
techniques like nanoparticles. Due to their improved
ability to pass through the olfactory epithelium,
polymeric nanoparticles are being extensively
researched for nose to brain medication delivery. Drug
delivery methods including nanoparticles have
significant difficulties in terms of stability and safety
standards. Future nasal routes for treating many brain
illnesses may be feasible non-invasive options if
effective and reliable nanoparticulate delivery systems
are developed.
 Research J. Pharm. and Tech. 16(12): December 2023
DECLARATION OF INTEREST:
The authors were addressing no conflicts of interest.
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