Auam Coiey

PBCY 411, 0NC-ESoP

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Neuiouegeneiative uiseases impact the lives of patients anu theii families. As the biain slowly ueteiioiates,
patients lose contiol of theii bouies, thoughts, anu ultimately succumb to the uisease. An aging population
geneiates a highei inciuence of Alzheimei's uisease, Paikinson's uisease, anu othei neuiological uisoiueis.
Concuiiently, the iise of Autism Spectium uisoiueis has become an inteiesting aiea of potential ieseaich. As of
now, neuiological meuicines only tieat the symptoms anu iaiely auuiess the ioot cause - uying oi misfiiing
neuions. uetting uiugs into the biain has pioven a uifficult task because of the impeimeable bloou-biain baiiiei
(BBB). Newly uevelopeu tools ciicumvent the BBB by going thiough the nose. Intianasal-to-biain (INB) ueliveiy
pioviues a hopeful avenue to slow, tieat, anu pievent the piogiession of the uiseases of the cential neivous system
(CNS) with gieatei efficacy, less invasion anu ieuuceu toxicity. Neuical piofessionals shoulu iecognize the
uifficulty of ueliveiing uiug to the biain anu the neeu foi easiei, uiiect ioute such as nasal auministiation.
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As the contiolling oigan of the bouy, the biain is lockeu behinu two majoi uefense mechanisms. The cianium
pioviues a haiu case that limits access to only highly invasive techniques that inject uiugs thiough the skull
uiiectly into the paienchyma oi ceiebiospinal fluiu. The BBB inteinally piotects the CNS fiom potentially
uamaging foieign chemicals tiavelling thiough the blooustieam. Toxins anu potential meuications aie blockeu
fiom neuions by seveial mechanisms. Bespite the iich netwoik of bloou vessels ieaching all aieas of the biain, the
enuothelial lining of the capillaiies aie fuseu togethei with extiemely tight junctions pieventing the passage of
many molecules.
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0nly the smallest hyuiophilic molecules can entei the biain thiough the paiacellulai ioute
aiounu the tight junctions. Some small, lipophilic molecules can cioss thiough the epithelial cells via the
tianscellulai ioute.
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Piouiugs can inciease lipophilicity anu nanopaiticles can hiue polai iegions insiue a PLuA
liposome. Laigei enuogenous molecules aie selectively alloweu acioss the baiiiei thiough tianspoit pioteins, like
insulin anu tiansfeiiin, which we can use to tianspoit uiugs acioss.
1
While we can make uiugs lipophilic oi hijack
tianspoitei pioteins to cioss the membiane, P-gp efflux pumps woik to actively iemove foieign compounus. Some
uiugs can be given with P-gp inhibitois to inciease the chances of iemaining insiue the biain.
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All of these uefense
mechanisms make getting uiugs into the biain incieuibly uifficult. Inueeu, as little as 1% of an intiavenous uose
may ieach anu iemain within the CNS. The laigei uoses iequiieu leaus to toxic siue effects elsewheie in the bouy.
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To tieat the giowing pioblem of neuiouegeneiative uisoiuei, we neeu a less invasive, patient uiiecteu ioute of
auministiation that pioviues iapiu onset of action, highei biain concentiations, anu lowei systemic uistiibution
anu siue effects. uoing thiough the nose to the olfactoiy bulb pioviues each of oui iequiiements.
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The nasal cavity peifoims thiee functions foi the human bouy: waims aii, filteis laige paiticles, samples ouois. In
uiiect contact with the exteinal enviionment, the cavity is lineu with mucosal epithelium. Nucus, secieteu fiom
suiiounuing glanus, tiaps foieign bouies, while the cilia continuously push the mucus to the esophagus foi
elimination. Any nasal meuication must be absoibeu quickly oi be washeu into the stomach. When we bieathe, aii
enteis thiough the naies, past the vestibule anu into a laige nasal cavity. The empty space contains specializeu
folus, calleu conchae, which inciease the suiface aiea anu cieate tuibulence to help waim the aii on the way to the
lungs. Nost nasal spiays foi the tieatment of ihinitis taiget the infeiioi anu miuule conchae. The iich vasculatuie
in the aiea pioviues access to systemic ciiculation, but effects aie limiteu uue to nasal mucus. To taiget the CNS
howevei, specializeu INB spiays taiget the supeiioi concha to uiiectly access the olfactoiy bulb. Compiiseu of
millions of neive enuings, the olfactoiy bulb senus out those neive enuings thiough the holes in the ciibiifoim
plate to test the aii foi smells anu pioviues a pathway fiom the nasal cavity to the biain. As such, the nasal cavity is
a iaie location with open access to the neivous system. INB uiugs can bypass the uifficult BBB tieat CNS
uisoiueis.
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Coiey 2
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To ieach oui goal, INB uiugs uo not taiget the vasculatuie, but iathei the top of the nasal cavity - olfactoiy bulb
anu ciibiifoim. If absoibeu systematically, the uiug woulu still have to pass thiough the BBB ieuucing the
neuional availability anu potentially cause toxicity. INB uiugs avoiu systemic ciiculation by enteiing the biain
thiough the moie peimeable epithelial membiane above the supeiioi concha. Any INB uiug ieaches the CNS
thiough two main pathways. The epithelial pathway uses paiacellulai tianspoit aiounu the olfactoiy epithelium,
acioss the ciibiifoim plate anu into the subaichnoiu space. The CSF caiiies the uiug paiticle thioughout the biain
oi cleais into the systemic ciiculation.
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0sing the epithelial pathway iequiies a small, hyuiophilic molecule. An
olfactoiy pathway uses the neive enuings to inteinalize the uiug anu feiiy it to the olfactoiy bulb anu into the
olfactoiy iegion of the biain. These molecules must tiiggei enuocytosis to piomote tianspoit.

While easiei to ieach than thiough the bloou, the nasal cavity still possesses a numbei of factois that can affect
absoiption. As stateu befoie, small moleculai weight uiugs aie iueal as absoiption is limiteu at 1uuu ualtons. The
secietion anu iemoval of mucus can affect absoiption cleaiing uiug fiom the site of absoiption. Few enzymes exist
in the aiea, but uegiauation iemains a concein foi uiug stability, especially foi pioteins. Finally, ihinitis can altei
absoiption.
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Still, the nasal cavity iemains a valiu alteinative to auministei uiugs to the CNS, especially if the uiug
is oially ineffective, blockeu by the BBB, oi iequiies a iapiu onset of action. Seveial mouifications can piotect fiom
these piotections anu impiove INB ueliveiy.

To impiove uptake thiough the olfactoiy bulb, eithei the uiug oi the foimulation can be mouifieu. Piouiugs take
auvantage of local enzymes anu inciease lipophilicity. Excipients tiansiently open up mucosal poies to inciease
absoiptions. Chitosan is a natuial polysacchaiiue that binus to the mucosal membiane anu loosens the tight
junctions between epithelial cells allowing moie uiug to entei.
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PLuA nanopaiticles can inciease absoiption by
attaching a lectin liganu, tiiggeiing ieceptoi-meuiateu enuocytosis.
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Cuiiently, seveial uiugs aie being uesigneu
anu stuuieu to use these methous to tieat a vaiiety of CNS uisoiueis. Nouse mouels show an inciease in biain
uistiibution thiough INB ielative to noimal intiavenous auministiation, opening the uooi to potential tieatments
foi Alzheimei's uisease anu autism.
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Alzheimei's patients face a uaik uiagnosis with little positive light. Chi Zhang anu his gioup in Shanghi hope to
make the outlook a little biightei. Basic fibioblast giowth factoi (bFuF) simulates the giowth of neuions, but
iemains blockeu by the BBB. Intiavasculai ueliveiy of the peptiue shows that only 1% ieaches the biain. INB
offeis an alteinative ioute but must oveicome mucusal cleaiance anu piotein uegiauation. Incoipoiating bFuF
into PEu-PLuA nanopaiticles coateu with !"#$%&' )&*+,"-&' lectin, Zhang's gioup showeu incieaseu iesiuence
time, CNS concentiation of bFuF in Alzheimei-mouel iats anu coiiesponuing impiovement in memoiy tests. Biiect
bFuF auministiation to the biain thiough the nose uecieases plasma concentiations iesulting in fewei toxicities.
7

Each uay, moie chiluien ieceive uiagnoses of autism spectium uisoiueis, but few tieatments exist. Evuokia
Anagnostou anu hei Toionto-baseu lab want to auministei intianasal oxytocin as a potential cuie. Chiluien with
ASB have pooi social skills, tenu to peifoim iepetitive behaviois, anu have ieuuceu levels of oxytocin in the bloou.
Neuical oxytocin coulu hopefully amelioiate many autism symptoms. Because oxytocin uegiaues in the intestines
by chymotiypsin, it cannot be given oially. Intiavasculai injection of oxytocin shows positive effects, but is too
invasive foi chiluien. INB piouuceu bettei CNS uistiibution with easiei auministiation. While eaily in the piocess,
chiluien tieateu with INB oxytocin showeu piomising impiovements in autism-ielateu behaviois.
8
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uetting meuication into the biain iemains a uifficult task as many molecules fail to ieach the uesiieu uestination.
The BBB piotects the neuions but makes tieatment moie uifficult. As the population giows anu ages, moie
patients will be uiagnoseu with neuiouegeneiative uiseases, like Alzheimei's. A taigeteu nasal spiay to the
olfactoiy bulb coulu potentially uelivei theiapeutic compounus foi a vaiiety of CNS uisoiueis. INB is a iapiu acting
ioute that avoius the iestiictive BBB anu potentially toxic systemic siue effects. Noie stuuies must ueteimine the
safety of this ioute on a laigei scale anu show moie examples of efficacy. We shoulu leain moie about local siue
effects of penetiation enhanceis on an impoitant piotective membiane oi sensitivity in the nasal cavity leauing to
ihinitis. 0veiall, INB offeis a safei, less invasive ioute of auministiation uiiectly to the biain anu can potentially
help the patients with the fiightening uiseases of the CNS.
Coiey S
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