Re: BBB 통과 대뇌 약물전달... 비강내 투여 경로 탐구!!!

[문형철]

REVIEW article

Front. Drug Deliv., 11 August 2023

Sec. CNS Drug Delivery

Volume 3 - 2023 | https://doi.org/10.3389/fddev.2023.1247162

Transnasal-brain delivery of nanomedicines for neurodegenerative diseases

Neurodegenerative diseases (NDs) have become a serious global health problem as the population ages. Traditionally, treatment strategies for NDs have included oral and intravenous administration; however, the blood–brain barrier (BBB) can prevent drugs from reaching the brain, rendering the treatment incomplete and the effect unsatisfactory. Additionally, the prolonged or excessive use of drugs that can cross the BBB can damage liver and kidney function. Recent studies have shown that nose-to-brain drug delivery can noninvasively bypass the BBB, allowing drugs to enter the brain through the olfactory or trigeminal nerve pathways; additionally, nanoparticle carriers can enhance drug delivery. This review introduces drug carrier nanoparticles for nose-to-brain delivery systems, compares the advantages and disadvantages of different nanoparticles, and discusses the factors influencing nose-to-brain nanomedicine delivery and enhancement strategies. We also summarize nose-to-brain delivery and nanomedicines for treating NDs, the current challenges of this approach, and the future promise of nanomedicine-based ND treatment.

신경퇴행성 질환(NDs)은 인구 고령화로 인해 심각한 글로벌 건강 문제로 부상했습니다. 전통적으로 NDs의 치료 전략은 경구 투여와 정맥 투여를 포함해 왔으나, 혈액-뇌 장벽(BBB)이 약물이 뇌에 도달하는 것을 차단해 치료가 불완전하고 효과가 미흡할 수 있습니다. 또한 BBB를 통과할 수 있는 약물의 장기적 또는 과도한 사용은 간과 신장 기능을 손상시킬 수 있습니다.

최근 연구에서는

비강-뇌 약물 전달이

비침습적으로 BBB를 우회해 약물이 후각 또는 삼차신경 경로를 통해

뇌로 들어갈 수 있음을 보여주었습니다.

또한 나노입자 운반체는 약물 전달을 향상시킬 수 있습니다.

이 리뷰는

비강-뇌 전달 시스템용 약물 운반체 나노입자를 소개하고,

다양한 나노입자의 장단점을 비교하며,

비강-뇌 나노의약품 전달 및 향상 전략에 영향을 미치는 요인을 논의합니다.

또한 신경퇴행성 질환(ND) 치료를 위한 코에서 뇌로의 전달 및 나노의약품을 요약하고,

이 접근법의 현재 과제, 나노의약품 기반 ND 치료의 미래 전망을 논의합니다

1 Introduction

Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and sensorineural hearing loss (SNHL) are neurodegenerative diseases (NDs) caused by the accumulation of misfolded proteins inside and outside cells, and by the deformation or loss of neurons (Teleanu et al., 2022). As the global population ages, the preval‎ence of neurodegenerative diseases is expected to rise (Noble and Burns, 2010). According to the World Health Organization, 57.4 million people worldwide were living with neurodegenerative diseases in 2019 and this number is expected to rise to 153 million by 2050 (A et al., 2022). The corresponding healthcare costs have increased with the increasing preval‎ence of NDs, significantly impacting patients, families, and society.

NDs cause neurological and psychiatric symptoms depending on the area of the brain affected, mainly progressive motor dysfunction and cognitive impairment. Pharmacological agents are the main means of treating these disorders, traditionally via oral and intravenous administration; however, therapeutic efficacy is hampered by the blood–brain barrier (BBB). The BBB is a unique microvascular system in the brain that regulates the movement of ions, molecules, and cells between the blood and the brain (Profaci et al., 2020). Although the BBB protects the brain from toxins and pathogens, it also poses a serious obstacle to delivering therapeutic drugs, with 98% of small molecules and almost all large molecules unable to cross the BBB. Other factors to be considered during the delivery of drugs to the brain via the circulatory pathway include minimal peripheral exposure, first-pass metabolism, plasma protein binding, and rapid elimination (Tan et al., 2020).

Numerous methods for delivering drugs to the brain have been reported recently. In contrast to conventional drug delivery via the circulatory pathways, intranasal drug delivery bypasses the BBB and targets the brain directly (Perteghella et al., 2021). Since the drug does not reach non-targeted sites, the systemic side effects and dose are reduced. Better bioavailability of the drug is obtained through intranasal administration, as it avoids first-pass metabolism and overcomes incomplete absorption in the gastrointestinal tract (Homayun et al., 2019). This noninvasive approach facilitates self-administration, especially for patients with motor disorders, nausea, impaired gastrointestinal function, and salivary gland dysfunction (Hoekman et al., 2020). Intranasal delivery results in a higher drug concentration than oral administration at the same dose (Bicker et al., 2020).

Nanoparticles are emerging drug delivery vehicles that resolve various obstacles in the drug delivery process. Nanoparticles can protect the delivered drug from degradation by biological or chemical factors in the nasal environment and from the effects of efflux proteins and release and modulate the drug faster, which is advantageous in emergencies and long-term dosing situations. In addition, nanoparticles can facilitate targeted drug transport, thus increasing the efficiency and controllability of nose-to-brain delivery (Bicker et al., 2020).

There are few studies on the nose-to-brain delivery of nanomedicines to the brain for treating NDs. Most current studies are animal experiments; thus, these approaches are far from translation into clinical applications. While nose-to-brain delivery has advantages and limitations, few studies have investigated the limitations and how to overcome them.

Therefore, here, we review the different nose-to-brain delivery pathways and compare the advantages and disadvantages of different nanocarriers. In addition, we summarize the strategies and methods for nose-to-brain delivery for treating NDs and discuss the challenges and potential directions for intranasal nanomedicine delivery.

1. 서론

알츠하이머 병(AD), 파킨슨 병(PD), 헌팅턴 병(HD), 감각신경성 난청(SNHL)은 세포 내외에서 변형된 단백질의 축적 및 신경 세포의 변형 또는 손실로 인해 발생하는 신경퇴행성 질환(ND)입니다(Teleanu et al., 2022). 전 세계 인구 고령화에 따라 신경퇴행성 질환의 유병률은 증가할 것으로 예상됩니다(Noble and Burns, 2010). 세계보건기구(WHO)에 따르면 2019년 전 세계에서 신경퇴행성 질환을 앓고 있는 사람은 5,740만 명이었으며, 이 숫자는 2050년까지 1억 5,300만 명으로 증가할 것으로 예상됩니다(A et al., 2022). 신경퇴행성 질환의 유병률 증가와 함께 의료 비용도 증가해 환자, 가족, 사회에 심각한 영향을 미치고 있습니다.

신경퇴행성 질환은 뇌의 영향을 받은 부위에 따라 신경학적 및 정신적 증상을 유발하며, 주로 진행성 운동 장애와 인지 기능 저하가 주요 증상입니다. 약물 치료는 이러한 질환의 주요 치료 방법으로, 전통적으로 경구 투여나 정맥 투여를 통해 이루어져 왔습니다. 그러나 혈액-뇌 장벽(BBB)은 치료 효과에 장애를 초래합니다. BBB는 뇌 내의 독특한 미세혈관 시스템으로, 혈액과 뇌 사이의 이온, 분자, 세포의 이동을 조절합니다(Profaci et al., 2020). BBB는 뇌를 독소와 병원체로부터 보호하지만, 치료 약물의 전달에 심각한 장애물을 제공합니다. 소분자의 98%와 거의 모든 대분자는 BBB를 통과하지 못합니다. 혈관 경로를 통해 뇌에 약물을 전달할 때 고려해야 할 다른 요인에는 주변 노출 최소화, 첫 번째 통과 대사, 혈장 단백질 결합, 빠른 배설 등이 있습니다(Tan et al., 2020).

최근 뇌로 약물을 전달하는 다양한 방법이 보고되었습니다.

순환 경로를 통한 전통적인 약물 전달과 달리,

비강 내 약물 전달은 BBB를 우회하여

뇌를 직접 표적화합니다 (Perteghella et al., 2021).

약물이 비표적 부위에 도달하지 않기 때문에

전신 부작용과 용량이 감소됩니다.

비강 투여는

첫 번째 통과 대사 및 위장관에서의 불완전한 흡수를 회피하여

약물의 생체 이용률을 향상시킵니다(Homayun et al., 2019).

이 비침습적 접근 방식은

운동 장애, 구토, 위장관 기능 장애, 타액선 기능 장애를 가진 환자들에게

자가 투여를 용이하게 합니다(Hoekman et al., 2020).

비강 투여는

동일한 용량에서 경구 투여보다 약물 농도가 더 높습니다(Bicker et al., 2020).

나노입자는 약물 전달 과정의 다양한 장애물을 해결하는 신흥 약물 전달체입니다. 나노입자는 비강 환경에서의 생물학적 또는 화학적 요인에 의한 약물 분해로부터 약물을 보호하고 배출 단백질의 영향을 차단하며 약물을 더 빠르게 방출하고 조절할 수 있어 응급 상황이나 장기 투여 상황에서 유리합니다. 또한 나노입자는 표적 약물 전달을 촉진하여 코에서 뇌로의 전달 효율성과 제어성을 향상시킬 수 있습니다(Bicker et al., 2020).

뇌신경 장애(NDs) 치료를 위한 뇌로의 나노의약품 전달에 대한 연구는 제한적입니다. 현재 대부분의 연구는 동물 실험에 국한되어 있어 임상 적용으로의 전환은 아직 멀었습니다. 코에서 뇌로의 전달은 장점과 한계를 모두 가지고 있지만, 이러한 한계와 극복 방법을 조사한 연구는 거의 없습니다.

따라서 본 연구에서는 다양한 코에서 뇌로의 전달 경로를 검토하고 다양한 나노 캐리어의 장단점을 비교합니다. 또한 ND 치료를 위한 코에서 뇌로의 전달 전략과 방법을 요약하고, 비강 내 나노의약품 전달의 도전 과제와 잠재적 방향을 논의합니다.

2 Route of nose-to-brain delivery

2.1 Anatomy of the nasal cavity

The nasal epithelium can be divided into three regions based on the cell types present: the nasal vestibule, the respiratory epithelium, and the olfactory epithelium (Lofts et al., 2022). The nasal vestibule is the most anterior part of the nasal cavity. The small surface area and low vascularization of the nasal vestibule make drug absorption negligible. The respiratory epithelium is located in the posterior part of the nasal vestibule. Since the respiratory epithelium has a surface area of approximately 130 cm2, accounts for 90% of the nasal area, and is extensively vascularized, it is considered the primary site for drug delivery. The ophthalmic and maxillary nerves, which are branches of the trigeminal nerve, innervate this region; thus, drugs can be delivered to the brain via the trigeminal pathway. The olfactory epithelium is located in the upper posterior part of the nasal cavity, with an area of approximately 10 cm2, accounting for 10% of the entire nasal epithelium. Olfactory sensory neurons (OSNs) are responsible for the perception and transmission of odor information to the brain via the olfactory pathway, which comprises OSNs, the lamina propria, and the olfactory bulb that projects to various brain regions. This pathway is a direct route for drug delivery to the brain. Since the lamina propria of the olfactory epithelium also houses the maxillary nerve, therapeutic drugs can be delivered to the brain via the trigeminal pathway.

2 코에서 뇌로의 전달 경로

2.1 코 동굴의 해부학

코 상피는 존재하는 세포 유형에 따라

세 가지 지역으로 나눌 수 있습니다:

코 전정,

호흡 상피, 그리고

후각 상피 (Lofts et al., 2022).

the nasal vestibule,

the respiratory epithelium, and

the olfactory epithelium

1. 비강 전방부는

비강 동굴의 가장 앞쪽 부분입니다.

비강 전방부의 작은 표면적과 낮은 혈관 분포로 인해

약물 흡수량은 미미합니다.

2. 호흡 상피는

비강 전방부의 후방 부분에 위치합니다.

호흡 상피는

약 130 cm²의 표면적을 차지하며 비강 면적의 90%를 차지하고

광범위하게 혈관화되어 있어 약물 전달의 주요 부위로 간주됩니다.

삼차신경의 분지인 안구신경과 상악신경이 이 부위를 신경 분포하며,
따라서 약물은 삼차신경 경로를 통해 뇌로 전달될 수 있습니다.

3. 후각 상피는

비강 상부 후방부에 위치하며,

약 10cm²의 면적을 차지하며 전체 비강 상피의 10%를 차지합니다.

후각 감각 신경세포(OSNs)는

후각 경로를 통해 냄새 정보를 뇌로 전달하는 역할을 합니다.

이 경로는 OSNs, 점막하층, 그리고 다양한 뇌 부위로 투사되는 후각 구로 구성됩니다.

이 경로는 약물을 뇌로 전달하는 직접적인 경로입니다.

후각 상피의 점막하층에는 상악 신경도 존재하기 때문에,

삼차 신경 경로를 통해 치료 약물을 뇌로 전달할 수 있습니다.

2.2 Drug delivery pathway through the nasal cavity to the brain

Drugs can reach the brain via indirect and direct pathways after reaching the sieve plate via the nasal mucosa (Bicker et al., 2020). In the indirect pathway, some drugs are absorbed into the vascular or lymphatic systems, enter the systemic circulatory system and reach the brain through the BBB. In the direct pathway, drugs bypass the BBB through the nasal mucosa and are directly connected to the nerves in the brain and spinal cord and delivered through the neural pathways (olfactory and trigeminal). After drugs are delivered to the brain, they disperse via intracellular or extracellular delivery mechanisms. Intracellular delivery refers to the entry and exit of drugs into and out of neurons by cytokinesis or receptor-mediated transport, mainly through axons, which leads to the central nervous system (CNS). The drug is then further dispersed by fluid movement (Kashyap and Shukla, 2019). Extracellular delivery involves the drug crossing the nasal epithelium to the lamina propria, where neurons are located. Then, the drug is transported along neuronal axons through the overall flow transport process via perineural channels, through which the drug can be transported from one neuron to another. Drug delivery via the nasal cavity involves olfactory and trigeminal nerve pathways, vascular pathways, cerebrospinal fluid, and lymphatics (Figure 1).

2.2 비강을 통해 뇌로 전달되는 약물 전달 경로

약물은

비강 점막을 통해 체망판에 도달한 후

간접 및 직접 경로를 통해 뇌에 도달할 수 있습니다 (Bicker et al., 2020).

Drugs can reach the brain via indirect and direct pathways after reaching the

sieve plate via the nasal mucosa.

간접 경로에서는

일부 약물이 혈관이나 림프계에 흡수되어

체내 순환계로 들어가 BBB를 통해 뇌에 도달합니다.

직접 경로에서는

약물이 비강 점막을 통해 BBB를 우회하여

뇌와 척수의 신경과 직접 연결되어

신경 경로(후각 및 삼차신경)를 통해 전달됩니다.

약물이 뇌에 전달된 후에는

세포 내 또는 세포 외 전달 메커니즘을 통해 확산됩니다.

 After drugs are delivered to the brain,

they disperse via intracellular or extracellular delivery mechanisms.

Intracellular delivery refers to the entry and exit of drugs into and out of neurons by

cytokinesis or receptor-mediated transport,

mainly through axons, which leads to the central nervous system (CNS).

The drug is then further dispersed by

fluid movement

세포 내 전달은

cytokinesis이나 수용체 매개 운반을 통해

약물이 신경 세포 내로 들어가고 나가는 과정을 의미하며,

주로 축삭을 통해 중추 신경계(CNS)로 전달됩니다.

약물은

이후 체액의 움직임을 통해 추가로 확산됩니다(Kashyap and Shukla, 2019).

세포외 전달은

약물이 비강 상피를 통해 신경이 위치한 점막하층으로 이동하는 것을 포함합니다.

이후 약물은 신경 축삭을 따라

전체 유동 전달 과정을 통해 전달되며,

이 과정에서 약물은 신경 간 전달 경로를 통해

한 신경세포에서 다른 신경세포로 전달될 수 있습니다.

비강을 통한 약물 전달은

후각 신경과 삼차 신경 경로, 혈관 경로, 뇌척수액, 림프계 등을 통해

이루어집니다(그림 1).

FIGURE 1

FIGURE 1. Anatomy of the human nasal cavity and four nose-to-brain delivery pathways. Created with BioRender.com.

2.2.1 Olfactory nerve pathway

Drugs are transported across the sieve plate via the olfactory nerve to the olfactory bulb in the brain (Lofts et al., 2022). The drug concentration in the olfactory epithelium positively correlates with its concentration in the olfactory bulb (Cunha et al., 2017). A study indicated that DL-3-n-butylphthalide applied to the nasal mucosa are able to enter the brain regions through the olfactory nerve pathway, olfactory epithelium pathway and bloodstream, making it possible for central nervous diseases treatment (Zhao et al., 2017). Drugs can also be ingested by cytokinesis or passive diffusion and axonally transported to the olfactory bulb and other brain regions. Metal salts, such as aluminium salt (Das et al., 2021), and those with the relevant receptor (wheat germ agglutinin conjugated to horseradish peroxidase, WGA–HRP) are delivered in this way (Shu et al., 2019).

2.2.1 후각 신경 경로

약물은 후각 신경 через 체판(sieve plate)을 통해

의 후각 구역(olfactory bulb)으로 운반됩니다(Lofts et al., 2022).

후각 상피(olfactory epithelium) 내 약물 농도는

후각 구역 내 농도와 양의 상관관계를 보입니다(Cunha et al., 2017).

한 연구에서 DL-3-n-butylphthalide를 비강 점막에 적용했을 때,

이 약물은 후각 신경 경로, 후각 상피 경로 및 혈류를 통해 뇌 부위로 들어갈 수 있으며,

이는 중추 신경계 질환 치료가 가능함을 보여주었습니다(Zhao et al., 2017).

약물은

포 분열이나 수동 확산으로 흡수되어

축삭을 통해 후각 구와 다른 뇌 부위로 운반될 수 있습니다.

알루미늄 염(Das et al., 2021)과 관련 수용체(밀 배아 응집소와 과산화수소 효소 결합체, WGA–HRP)를 가진 금속 염은 이 방식으로 전달됩니다(Shu et al., 2019).

2.2.2 Trigeminal nerve pathway

The CNS innervates the respiratory and olfactory epithelium through the trigeminal nerve (Patel, 2017). Drugs can be transported to the brain via these two sites, and the delivery mechanism is similar to that of the olfactory neural pathway. IGF-I was the first drug to be delivered intranasally via the trigeminal nerve pathway (Thorne et al., 2004) and was observed in the trigeminal branches and ganglia. In addition, another study also found a high concentration of the drug in the caudal medulla after intranasal administration, demonstrating that drugs can be delivered via the trigeminal pathway after intranasal administration (Charlton et al., 2008).

2.2.2 삼차 신경 경로

중추 신경계는

삼차 신경을 통해 호흡 및 후각 상피를 신경 분포합니다 (Patel, 2017).

약물은

이 두 부위를 통해 뇌로 운반될 수 있으며,

전달 메커니즘은 후각 신경 경로와 유사합니다.

IGF-I는 삼차신경 경로를 통해 비강 내 투여된 첫 번째 약물로(Thorne et al., 2004), 삼차신경 분지와 신경절에서 관찰되었습니다. 또한 다른 연구에서도 비강 내 투여 후 뇌간 후부에서 약물의 높은 농도가 관찰되어, 비강 내 투여 후 삼차신경 경로를 통해 약물이 전달될 수 있음을 보여주었습니다(Charlton et al., 2008).

2.2.3 Vascular pathways

Blood from the branches of the maxillary, facial, and ophthalmic arteries and the carotid artery supplies the nasal cavity (Patel, 2017), and drugs delivered through this pathway mainly act on the respiratory epithelial area, which has a large surface area and abundant blood vessels (Lofts et al., 2022). As with intravenous administration, after the drug enters the circulation, it is partially metabolized by the liver and kidneys, degraded by plasma proteases, and bound by plasma proteins; some absorbed drugs do not cross the BBB, reducing the dose that reaches the CNS. Small lipophilic drugs are more likely to cross the BBB than large molecules, such as peptides and proteins (Patel, 2017).

2.2.3 혈관 경로

상악동, 안면동, 안구동 동맥의 분지와

경동맥에서 공급되는 혈액이

비강을 공급합니다(Patel, 2017),

maxillary, facial, and ophthalmic arteries

이 경로를 통해 전달된 약물은

넓은 표면적과 풍부한 혈관을 가진

호흡 상피 부위에 주로 작용합니다(Lofts et al., 2022).

정맥 내 투여와 마찬가지로 약물이 순환계에 들어가면

간과 신장에서 부분적으로 대사되며,

혈장 프로테아제에 의해 분해되고

혈장 단백질에 결합됩니다.

일부 흡수된 약물은 BBB를 통과하지 않아

CNS에 도달하는 용량이 감소합니다.

작은 지용성 약물은 펩타이드나 단백질과 같은 큰 분자보다

BBB를 통과할 가능성이 높습니다(Patel, 2017).

2.2.4 Pathways involving cerebrospinal fluid and lymphatics

The nasal lymphatics are connected to the cerebrospinal fluid, and there are perineurial spaces in the olfactory nerve through which drugs can enter the CNS directly (Wang et al., 2023). A study has found that intranasal administration can promote the absorption of drugs in Nao-Qing microemulsion and achieve fast effect (Li et al., 2015).

2.2.4 뇌척수액 및 림프계 관련 경로

비강 림프계는

뇌척수액과 연결되어 있으며,

후각 신경의 주변 신경막 공간을 통해 약물이 CNS로 직접 들어갈 수 있습니다(Wang et al., 2023).

연구 결과, 비강 내 투여는

Nao-Qing 미세유화액의 약물 흡수를 촉진하고

빠른 효과를 달성할 수 있음을 보여주었습니다(Li et al., 2015).

2.3 Safety of nose-to-brain administration

2.3.1 Toxicity

Most NDs require long-term treatment; thus, toxicity is a concern, including the toxicity of the drug and excipients related to the formulation, such as preservatives, surfactants, and mucoadhesives. Repeated delivery of the drug to the nasal cavity can cause nasal pruritus, nasal bleeding, reduced or altered sense of smell and taste, sinusitis, and nasal epithelial damage (Musumeci et al., 2019). Some drugs also alter ciliary beating frequency (e.g., atropine) (Ukai et al., 1985) and inhibit ciliary motility (e.g., ketamine) (Feldman et al., 2021), and enhancing long-term patient compliance is a challenge that requires further eval‎uation.

2.3.2 Inappropriate drug use by patients

Due to the small surface area of the olfactory epithelium and the large area of the respiratory epithelium, the inappropriate administration of drugs that act on the neural pathway can lead to absorption in the highly vascularized respiratory area, reducing the absorption of drugs through the nasal pathways and increasing the circulatory side effects (Lofts et al., 2022). The development of appropriate drug delivery devices and patient education is necessary.

2.3.3 Airway hazards

Air enters the airway via nasal breathing in most mammals, including humans. Therefore, treatment of NDs via nose-to-brain administration can interfere with the patient’s normal breathing pattern. For adults, nasal resistance accounts for half of the airway resistance; thus, even a slight change in nasal resistance from the drug can cause dramatic changes in breathing. In addition, due to drug toxicity, repeated use can cause rhinitis, which endangers the patient’s breathing safety. Moreover, nasal circulation can help hydrate the airway surface, and the two nasal cavities can take turns assuming air conditioning and mucus removal functions, jeopardizing the patient’s airway safety if the two nasal cavities are administered unequal doses (White et al., 2015). Therefore, developing individualized protocols to minimize airway hazards is extremely important.

2.3 코에서 뇌로의 투여 안전성

2.3.1 독성

대부분의 ND는 장기 치료가 필요하므로

독성이 주요 문제로 제기됩니다.

이는 약물 자체의 독성뿐만 아니라

제형에 포함된 보존제,

계면활성제,

점막 부착제 등 부형제의 독성도 포함됩니다.

약물을 코에 반복적으로 투여하면

코 가려움증, 코 출혈, 후각 및 미각의 감소 또는

변화, 부비동염, 코 점막 손상 등이 발생할 수 있습니다 (Musumeci et al., 2019).

일부 약물은

섬모 박동 빈도를 변화시키기도 합니다(예: 아트로핀) (Ukai et al., 1985)

또는 섬모 운동을 억제하기도 합니다(예: 케타민) (Feldman et al., 2021),

장기적인 환자 순응도를 향상시키는 것은

추가 평가가 필요한 과제입니다.

2.3.2 환자의 부적절한 약물 사용

후각 상피의 작은 표면적과 호흡 상피의 넓은 면적 때문에 신경 경로를 작용하는 약물의 부적절한 투여는 혈관이 풍부한 호흡 부위로의 흡수 증가를 초래할 수 있습니다. 이는 비강 경로를 통한 약물 흡수 감소와 순환계 부작용 증가를 유발합니다(Lofts et al., 2022). 적절한 약물 전달 장치 개발과 환자 교육이 필요합니다.

2.3.3 기도 위험

대부분의 포유류, 특히 인간은 코를 통해 공기를 흡입하여 기도로 공기가 들어갑니다. 따라서 코에서 뇌로 약물을 투여하는 ND 치료는 환자의 정상적인 호흡 패턴을 방해할 수 있습니다. 성인 경우 코 저항이 기도 저항의 절반을 차지하므로, 약물로 인한 코 저항의 작은 변화만으로도 호흡에 극적인 변화가 발생할 수 있습니다. 또한 약물 독성으로 인해 반복 사용은 비염을 유발할 수 있으며, 이는 환자의 호흡 안전을 위협합니다. 또한 비강 순환은 기도 표면을 습윤시키는 데 도움을 주며, 두 개의 비강은 공기 조절과 점액 제거 기능을 번갈아 수행합니다. 두 비강에 불균등한 용량이 투여될 경우 환자의 기도 안전이 위협받을 수 있습니다 (White et al., 2015). 따라서 기도의 위험을 최소화하기 위한 개별화된 프로토콜을 개발하는 것이 매우 중요합니다.

3 Treatment for central nervous system disease

3.1 Nanocarriers for nose-to-brain drug delivery

Drug delivery systems deliver a certain dose to a target site in the body and maintain the drug concentration in that area at a dose appropriate for the duration of the treatment (Moritz and Geszke-Moritz, 2022). Nanocarriers are loaded with drugs to achieve this purpose and to deliver drugs to the brain efficiently, where they are selectively released to the target site via transport to specific cells and tissues, avoiding side effects caused by systemic exposure; nanocarriers also help drugs cross the BBB and provide neuroprotection (Figure 2) (Wen et al., 2021). Therefore, various nanocarriers have been investigated for nose-to-brain drug delivery systems (Riccardi et al., 2021; Correia et al., 2022), including organic or inorganic nanostructures. Polymeric nanoparticles, lipid nanoparticles, micelles, nanoemulsions, nanogels, cell-penetrating peptides and exosomes belong to organic nanostructures. Inorganic nanoparticles consist of inorganic matter (Figure 3). Here, we summarize these nanocarriers and compare their advantages and disadvantages (Table 1).

3 중추 신경계 질환의 치료

3.1 코에서 뇌로 약물을 전달하는 나노 캐리어

약물 전달 시스템은 신체의 목표 부위에 특정 용량을 전달하고 치료 기간 동안 해당 부위의 약물 농도를 적절한 용량으로 유지합니다 (Moritz 및 Geszke-Moritz, 2022). 나노캐리어는 이 목적을 달성하기 위해 약물을 탑재하며, 뇌로 약물을 효율적으로 전달하여 특정 세포 및 조직으로의 운반을 통해 표적 부위에 선택적으로 방출되도록 합니다. 이 과정에서 전신 노출로 인한 부작용을 피하며, 나노캐리어는 약물이 혈액-뇌 장벽(BBB)을 통과하도록 돕고 신경 보호 효과를 제공합니다(그림 2) (Wen et al., 2021). 따라서 코에서 뇌로 약물을 전달하는 시스템에 다양한 나노캐리어가 연구되었습니다(Riccardi et al., 2021; Correia et al., 2022), 유기 또는 무기 나노구조를 포함합니다. 폴리머 나노입자, 지질 나노입자, 미셀, 나노에멀션, 나노겔, 세포 침투 펩타이드 및 엑소좀은 유기 나노구조물에 속합니다. 무기 나노입자는 무기 물질로 구성되어 있습니다(그림 3). 여기서는 이러한 나노캐리어를 요약하고 장단점을 비교합니다(표 1).

FIGURE 2

FIGURE 2. Nanocarriers for drug delivery to the brain across the blood-brain barrier. Reproduced with permission (Wen et al., 2021). Copyright 2021, Science advances.

FIGURE 3

FIGURE 3. Nanocarriers for nose-to-brain drug delivery. Created with BioRender.com.

TABLE 1

TABLE 1. Comparison of the advantages and disadvantages of nanocarriers for nose-to-brain drug delivery.

3.1.1 Polymer-based nanocarriers

Polymer-based nanocarriers can be optimally combined with drugs and are very stable (Patel et al., 2012). They can be loaded with larger drug levels than single-molecule carriers. In addition to delivering drugs, polymers can potentially deliver nucleic acids, proteins, and diagnostic reagents (Fahmy et al., 2007; Demento et al., 2009; Woodrow et al., 2009). Several researchers utilized Polylactic-co-glycolic acid (PLGA) nanoparticles to load with siRNA and lead to efficient and sustained gene silencing (Woodrow et al., 2009). Additionally, Polymer-based nanocarriers can be modified with ligands, and many are safe for long-term use in humans (Patel et al., 2012). For example, modified chitosan is often used to treat neurological diseases (Manek et al., 2020). Polymer-based nanocarriers modified with nanoparticles can protect the drug from chemical or enzymatic degradation, making it easier for the active molecule to reach the target site, thus increasing therapeutic efficacy (Tosi et al., 2008). Polymer-based nanocarriers modified with nanoparticles can facilitate drug targeting and enhance therapeutic effects (Tosi et al., 2008). Treating polymer surfaces with appropriate ligands can reduce toxicity and avoid rapid clearance in vivo (Zhou et al., 2018). Polyalkylcyanoacrylate (PACA) is one of the most common NP modifications for delivery to the CNS (Vauthier et al., 2007). PLGA and polylactic acid (PLA) are the most commonly used polymers (Mirhadi et al., 2018). PLA and PLGA have been approved for clinical use in humans; their degradation products are readily removed in the body, and they do not produce inflammatory reactions (Dechy-Cabaret et al., 2004). Chitosan nanoparticles can easily cross the BBB due to their large positive charge (Yu et al., 2019). However, polymers often exhibit instantaneous rather than sustained drug release (Correia et al., 2022). In addition, the high cost and mass production difficulties associated with some polymers make them difficult to apply in the market (Fernandes et al., 2021).

3.1.2 Lipid nanoparticles

Lipid nanoparticles are nanocarriers that can deliver and store different lipophilic drugs (Briuglia et al., 2015). The materials used for their fabrication are simple and widely available; thus, these nanoparticles are easy to produce industrially (Fernandes et al., 2021; Correia et al., 2022). They can be prepared without organic solvents, are easily degraded and removed, and have better biocompatibility, exhibiting a higher safety profile than polymeric nanoparticles. The ability of lipid nanoparticles to encapsulate drugs is superior to other approaches and allows controlled drug release over a longer period (Naseri et al., 2015). However, lipid nanoparticles are unstable and susceptible to degradation by environmental factors, including unsuitable storage temperatures and pH and exposure to light or oxygen (Liu et al., 2015). Additionally, it is difficult to package highly water-soluble substances and achieve instantaneous drug release with lipid nanoparticles (Campardelli et al., 2016).

3.1.3 Micelles

Nanomicelles, comprising polar and nonpolar molecules, are erelatively dense spherulitic structure, and drug were entrapped within nanomicelles (Lofts et al., 2022). The surfactant determines micelle size; generally, micelles are smaller than other nanocarriers. However, regarding human drug delivery, micelle cytocompatibility is low, and the dose of the delivered drug and potential surfactant toxicity determines the ease of fabrication. Poly (ethylene glycol)-block-poly (D, L-lactide) (PEG–PLA) micelles can deliver baicalein to the brain via the nose for the treatment of NDs caused by oxidative stress and inflammation (Zhang et al., 2020). In addition, hydroxytyrosol micelles protect against Parkinson-related oxidative stress in vitro (Mursaleen et al., 2021).

3.1.4 Nanoemulsions

Nanoemulsions are drug carriers made using liquid lipids with a similar structure to lipid nanoparticles (Bonferoni et al., 2019) that can be made into a spray for easy intranasal administration (Makidon et al., 2010). Nanoemulsions can also incorporate components that adhere to the nasal mucosa (Bahadur et al., 2020), leading to increased bioavailability in nanoemulsion-mediated intranasal drug delivery, prolonging the retention time and facilitating nose-to-brain drug delivery in the olfactory and trigeminal nerve pathways (Bonferoni et al., 2019). Some nanoemulsions can also be absorbed directly into the lymphatic system, avoiding first-pass metabolism to improve bioavailability (Singh et al., 2017). Several nanoemulsions are beneficial in neurodegeneration, including nimodipine, curcumin, resveratrol, selegiline, and rivastigmine (Pangeni et al., 2014; Pathak et al., 2014; Kumar et al., 2016; Bonferoni et al., 2019). However, there are obvious drawbacks to using nanoemulsions in humans, such as lower biocompatibility than lipid nanoparticles and the potential toxicity of core surfactants; thus, it must be ensured that the product is nontoxic (Singh et al., 2017). The preparation of nanoemulsions usually requires a large volume of surfactant to stabilize the droplets; however, when passing through a biofilm, the surfactant can fluidize, making the emulsion ineffective for use in the human body.

3.1.5 Nanogels

Nanogels are crosslinked polymer networks with high hydration, deformability, and loading capacity and can release drugs over a longer period, thus prolonging the treatment (Lofts et al., 2022). Nanogels have been widely used to deliver various drugs and diagnostic reagents (Neamtu et al., 2017) and release oligonucleotides, proteins, low molecular weight drugs, and other small molecules after dissolution in water (Song et al., 2015; Neamtu et al., 2017). Nanogel products are nontoxic in living organisms. Poly (N-vinylpyrrolidone)-based (Picone et al., 2018) and carboxylated poly (N-vinyl pyrrolidone) (Picone et al., 2016) nanogels have been used to treat NDs; these nanogels transport drugs from the nose to the brain via olfactory and trigeminal nerve pathways. However, unstable bonds were incorporated into the crosslinked polymer network to make the nanogels degradable, making the inherently reductive nanogels sensitive to acidic conditions (Tahara and Akiyoshi, 2015; Neamtu et al., 2017) and susceptible to degradation during nose-to-brain drug delivery. In addition, the safety of the excipients of nanogels for intranasal administration to nasal epithelial cells is unclear (Aderibigbe, 2018).

3.1.6 Cell-penetrating peptides

Cell-penetrating peptides (CPPs) can form complexes with selected drugs for intranasal drug delivery (Sharma et al., 2016), penetrate cell membranes, and transfer into cells, thus increasing drug biocompatibility. CPPs can help drugs to cross physiological barriers, such as the BBB and nasal mucosa (Zhang et al., 2016). CPPs can also be combined with nanomedicines to increase their targeting, enhancing delivery efficiency (Douat et al., 2015). Cyclic adenosine monophosphate (CAMP), PEP-1-Paraoxonase 1 (PEP-1-PON1), K16 Apolipoprotein E (K16ApoE), transactivator of transcription (TAT), and other CPPs can effectively improve drug delivery for treating NDs (Xie et al., 2020). However, CPPs are prone to internal degradation when exposed to the blood because their peptide nature is unstable (Kristensen et al., 2016); thus, drug degradation via the indirect pathway is less efficient as an insufficient drug concentration is targeted to the localization site. In addition, CPPs can enter almost all cells in the body, which is harmful. Similarly, CPPs are widely distributed in many cellular tissues, reducing the drug concentration at the indicated site and reducing efficiency.

3.1.7 Exosomes

Exosomes are special drug carriers comprising cell-secreted single lipid membrane vesicles that can easily move from 1 cell to another (Lässer et al., 2011). The fusion process observed in R18-labeled exosomes and PKH-67-labeled cells revealed that exosomes bind to target cells via membrane receptors and fuse directly with the plasma membrane or release their contents by endocytosis, thus resulting in very high biocompatibility (Parolini et al., 2009). Adding curcumin to exosomes increases its biocompatibility, thereby increasing the efficiency of drug delivery to the brain (Sun et al., 2010). Exosomes can also enhance the drug retention time in the nasal mucosa, increasing bioavailability (Zhuang et al., 2011). Exosomes can cross the BBB to deliver nucleic acids, such as miRNA and siRNA. Modified exosomes have been used to deliver exogenous siRNA to brain tissue in AD mice via the intravenous route (Alvarez-Erviti et al., 2011). Exosomes are also widely used to treat NDs, and exosomes from N2a cells or human cerebrospinal fluid can reduce the accumulation of intracellular β-amyloid (Aβ) through surface proteins, such as cellular prion protein (PrPC), which can play a role in AD treatment (An et al., 2013). Exosomes can deliver gamma interferon (IFN-γ) stimulated dendritic cells to the CNS, improving myelin regeneration (Pusic et al., 2021). Sphingolipid metabolizing enzymes can modulate exosomes to direct conformational changes in Aβ and promote the uptake of Aβ by microglia to reduce Aβ levels in the AD brain (Yuyama et al., 2012). Exosomes isolated from adipose-derived stem cells (ADSCs) contain high levels of neutral endopeptidase (NEP) (Katsuda et al., 2013), which eliminates Aβ (Iwata et al., 2001), and rat neural stem cells have high levels of cystatin C, which can nourish the brain and nerves (Taupin et al., 2000). Exosomes delivered via the nose encapsulate synaptic proteins and are released in response to high neuronal activity or stimulation by oxidative stress, promoting neuronal growth and neuronal survival and keeping neurons free from oxidative stress (Wang et al., 2011). In addition, exosomes loaded with catalase delivered to the brain have neuroprotective effects and may be effective for treating NDs (Haney et al., 2015). Intranasal delivery of human-induced pluripotent stem cell–derived exosomes to the brain has been shown to yield better bioavailability than the intravenous route in mice (Gu et al., 2022), and this approach facilitated easier clinical acceptance. In conclusion, exosomes are a promising drug carrier; however, achieving high selectivity for target cells is challenging (Jiang L. et al., 2019).

3.1.7 엑소좀

엑소좀은

세포가 분비하는 단일 지질 막 소포로 구성된 특수한 약물 운반체로,

한 세포에서 다른 세포로 쉽게 이동할 수 있습니다 (Lässer et al., 2011). R

18로 표지된 엑소좀과 PKH-67로 표지된 세포에서 관찰된 융합 과정은 엑소좀이 표적 세포의 막 수용체를 통해 결합한 후 직접적으로 세포막과 융합하거나 내포작용을 통해 내용물을 방출함으로써 매우 높은 생체적합성을 나타냅니다(Parolini et al., 2009). 엑소좀에 커큐민을 추가하면 생체 적합성이 증가하여 뇌로의 약물 전달 효율이 향상됩니다(Sun et al., 2010). 엑소좀은 비강 점막에서의 약물 유지 시간을 연장하여 생체 이용률을 향상시킵니다(Zhuang et al., 2011). 엑소좀은 BBB를 통과하여 miRNA 및 siRNA와 같은 핵산을 전달할 수 있습니다. 수정된 엑소좀은 AD 마우스에서 정맥 내 투여를 통해 뇌 조직에 외인성 siRNA를 전달하는 데 사용되었습니다(Alvarez-Erviti et al., 2011). 엑소좀은 ND 치료에도 널리 사용되며, N2a 세포나 인간 뇌척수액에서 유래한 엑소좀은 세포 표면 단백질(예: 세포 프리온 단백질(PrPC))을 통해 세포 내 β-아밀로이드(Aβ) 축적을 감소시켜 AD 치료에 역할을 할 수 있습니다(An et al., 2013). 엑소좀은 감마 인터페론(IFN-γ)로 자극받은 ден드리틱 세포를 중추신경계(CNS)로 전달하여 미엘린 재생 개선에 기여합니다(Pusic et al., 2021). 스핑고리피드 대사 효소는 엑소좀을 조절하여 Aβ의 구조 변화를 유도하고 미세아교세포의 Aβ 흡수를 촉진하여 AD 뇌에서의 Aβ 수준을 감소시킵니다(Yuyama et al., 2012). 지방 유래 줄기세포(ADSCs)에서 분리된 엑소좀은 중성 엔도펩티다제(NEP)를 고농도로 함유합니다(Katsuda et al., 2013), 이는 Aβ를 제거합니다(Iwata et al., 2001), 그리고 쥐 신경 줄기세포는 뇌와 신경에 영양을 공급하는 시스타틴 C를 고농도로 함유합니다(Taupin et al., 2000). 코를 통해 전달된 엑소좀은 시냅스 단백질을 포함하며, 높은 신경 활동이나 산화 스트레스 자극에 반응하여 방출되어 신경 성장과 신경 생존을 촉진하며 신경 세포를 산화 스트레스로부터 보호합니다(Wang et al., 2011). 또한 뇌에 전달된 카탈라아제 함유 엑소좀은 신경 보호 효과를 나타내며 ND 치료에 효과적일 수 있습니다(Haney et al., 2015). 인간 유도 만능 줄기세포(hIPSC)에서 유래한 엑소좀을 뇌에 비강 내 투여하는 방법은 쥐에서 정맥 내 투여보다 더 높은 생체 이용률을 보여주었습니다(Gu et al., 2022), 이 접근법은 임상적 수용성을 높이는 데 기여했습니다. 결론적으로, 엑소좀은 유망한 약물 전달체이지만, 표적 세포에 대한 높은 선택성을 달성하는 것은 도전 과제입니다(Jiang L. et al., 2019).

3.1.8 Inorganic nanoparticles

Inorganic nanoparticles are composed of different inorganic materials, such as silica and metal oxides, that are uniform in size, easy to produce, and more stable in structure than organic materials (Kim et al., 2019). Among them, mesoporous silica nanoparticles, which are inorganic nanoparticles used to deliver drugs, can provide greater holding space, better biocompatibility, and easier-to-impose surface functionalization for brain-targeted transport (Alexander et al., 2019). These nanoparticles can diffuse better than others in the brain, facilitating drug distribution (Fahmy et al., 2019). However, inorganic nanoparticles are toxic to humans, drug release is difficult to control, and complete clearance from the body is difficult (Yang et al., 2010).

3.2 Methods for nose-to-brain delivery

It is necessary to increase the exposure time between the drug and the nasal mucosa and to target the drug effectively to specific regions via the nose to maximize the therapeutic efficacy of nose-to-brain drug delivery.

3.2.1 Promoting mucoadhesion

Mucoadhesion can be divided into two steps. First, the two surfaces are in close contact, and consolidation results in firm binding (Smart, 2005). The prolonged retention time of nanocarriers at the absorption site typically increases the bioavailability of the carried drug. Therefore, the mucoadhesion of nanomedicines may facilitate nasal absorption and increase the retention time of the drug in the brain, and the frequency of drug administration by the patient can be reduced.

In addition to the adherence of drugs to mucosal surfaces conferred by different nanocarriers, nasal microspheres can be combined with nanocarriers to achieve better mucoadhesion (Gangane et al., 2020). Nasal microspheres enter the nasal cavity and contain cations that bind to the nasal secretion and undergo spontaneous gelation in the nasal cavity, prolonging residence time. Polymers combined with microspheres can obtain better results, and hydroxypropyl beta-cyclodextrin (HP-CD) polymer microspheres of chitosan or sodium alginate inhibit hippocampal oxidative stress and apoptosis and counteract Ab-induced neurotoxic effects in AD (Yalcin et al., 2016). Lectin-functionalized microspheres enhance retention and show a twofold efficiency increase in nasal mucoadhesion compared with non-functionalized microspheres (Gao et al., 2021). Nasal powders also achieve mucoadhesion (Figure 4) (Kiss et al., 2022). Recent studies have shown that chitosan–cysteine adducts made with the anti-Parkinson’s disease drug levodopa methyl ester hydrochloride increase mucoadhesion by forming disulfide bonds and show better adhesion effects than deacetylated chitosan powders (Kiss et al., 2022). However, this approach has not been studied in animal models.

FIGURE 4

FIGURE 4. Thiol chitosan-cysteine as a suitable mucoadhesion excipient for nasal dry powder. Reproduced with permission (Kiss et al., 2022). Copyright 2022, Elsevier.

3.2.2 Stimulus-responsive drug carriers

Stimulus-responsive carriers are a class of drug delivery systems that change physicochemical properties in response to a specific stimulus (Sheng et al., 2019). These changed properties can be adapted to the nasal environment to facilitate nose-to-brain drug delivery. In situ hydrogels have been formulated with the anti-AD drug nasal timosaponin BII via temperature or ionic stimulation (Figure 5) (Chen et al., 2020); the temperature and ionic environment in the nasal cavity stabilized the drug, significantly increasing the retention time. An in situ gel loaded with the anti-AD drug tacrine prepared by the thermosensitive polymer Pluronic F-127 increased the retention time in the nasal cavity and absorption in the brain (Qian et al., 2014). A composite gel loaded with the anti-AD drug rivastigmine tartrate facilitated absorption better than regular gel (Salatin et al., 2017). In situ preparation of a thermoreversible nasal gel adhered to the nasal mucosa carrying Parkinson’s disease drugs increases the adhesion effect and protects the nasal mucosa more than in normal nasal drug delivery (Rao et al., 2017). A thermosensitive gel used in lecithin–chitosan hybrid nanoparticles loaded with pyridoxine for treating PD improved the therapeutic effect of nasal brain delivery (Uppuluri et al., 2021). In addition, cubic phase in situ nasal gels based on mucoadhesion are expected to be new vehicles for nose-to-brain drug delivery for NDs (Patil et al., 2019). However, a study of levodopa-configured thermoreversible gels for PD showed that highly viscous gels are detrimental to drug absorption in the nasal cavity (Sharma et al., 2014). Therefore, gel safety needs to be further investigated.

FIGURE 5

FIGURE 5. Temperature/ion dual-sensitive in situ hydrogel of nasal timosaponin BII. Reproduced with permission (Chen et al., 2020). Copyright 2020, Elsevier.

3.2.3 Targeted ligand functionalized nanocarriers

Modifying the nanocarrier surface with targeting ligands after covalent modification can optimize the delivery of nanocarriers. The first targeting ligand used as a nanocarrier was wheat germ agglutinin (WGA), mainly on the surface of the olfactory epithelium (Schwab et al., 1978). One study revealed that after intranasal administration, WGA-modified nanoparticles, compared to unmodified nanoparticles, were more abundant in the brain (Gao et al., 2007). Furthermore, tracking the location of these nanocarriers in the brain revealed particularly high accumulation at the olfactory bulb, suggesting that they mainly target the olfactory pathway (Liu et al., 2012). In addition to using WGA as a targeting ligand for nanoparticles, many lectins have been shown to modify the surface of nanocarriers to facilitate nose-to-brain delivery, such as Eggplant tuber lectin, fluorescent probes, and basic fibroblast growth factor (bFGF) (Lundh et al., 1989; Chen et al., 2012; Zhang et al., 2014). The glycoprotein lactoferrin (Lf), the ligand of the lactoferrin receptor (LfR) is highly expressed in brain neurons and is the most commonly used nanocarrier-targeting ligand (Huang et al., 2008). In addition, Lf-functionalized nanoparticles have a stronger neuroprotective effect than other nanoparticles (Liu et al., 2013). Several other ligands are also used to modify nanoparticles, including rabies virus glycoprotein (RVG29) and inorganic nanoparticles (Gallardo-Toledo et al., 2020; Hao et al., 2020).

4 Factors influencing the intranasal administration of drugs into the brain

Drug delivery to the brain via intranasal administration, whether through indirect or direct routes, requires an effective drug dose to reach and cross the mucosal and epithelial of the nasal cavity (Bicker et al., 2020). Effectively overcoming this difficulty is the key to successful drug delivery. Various factors influence the intranasal administration of drugs, including the drug selected, the therapeutic indication, the individual population, and the delivery device (Misra and Kher, 2012). Nevertheless, these factors cannot be separated from the nature of the drug itself and the state of the nasal cavity. Therefore, this section discusses these two aspects in the selection of appropriate nanocarriers.

4.1 Properties of the nanocarriers4.1.1 Size and morphology

Molecular weight is the main limiting factor for drug absorption (Ozsoy et al., 2009), and there is an inverse relationship between the drug particle size and the degree of effective nasal absorption of that drug (Henkin, 2010). Nanocarriers <200 nm can usually deliver drugs to the brain via extracellular pathways, and nanocarriers 20–100 nm are easily transported via extracellular pathways and along axons, where the permeability of 20-nm drugs is twice as high as that of 100-nm drugs (Brooking et al., 2001). In addition, nanoparticles with larger sizes are cleared by sneezing (Gänger and Schindowski, 2018). The drug morphology also affects absorption in the nasal cavity; cyclic particles are more readily absorbed than linear particles (McMartin et al., 1987), and polymorphic forms are better solubilized, thus easily passing through biological membranes (Morissette et al., 2004).

4.1.2 Surface charge

Drugs with a cationic surface charge can be more easily administered through the nasal cavity (Tan et al., 2020). On the one hand, this surface charge can disrupt tight junctions for better transport through extracellular pathways. On the other, nasal secretions, as many anionic links, can attract drug binding for better transport.

4.1.3 Lipophilicity

Drug surface chemistry determines the main transport pathway. Although a few hydrophilic properties exist, the nasal mucosa are mainly lipophilic. The use of lipophilic drugs (e.g., lipid nanoparticles) can better aid intracellular transport (Figure 6) (Agrawal et al., 2020b), while hydrophilic drugs can aid extracellular transport (Clementino et al., 2021). Usually, when a drug’s lipophilicity increases, the drug’s dose penetrating the nasal mucosa increases.

FIGURE 6

FIGURE 6. Extensive use of lipid nanoparticles in neurodegenerative diseases. Reproduced with permission (Agrawal et al., 2020b). Copyright 2020, Elsevier.

4.2 Physiological factors of the nasal cavity4.2.1 Mucosal mucociliary clearance and cilia movement

Nasal mucociliary clearance (MCC) is an important physiological mechanism for the nasal clearance of foreign bodies, including bacteria, dust, allergens, and secretions. The rate of MCC is 1–2 mm/h in the anterior inferior turbinate and 8–10 mm/h in the posterior inferior turbinate (Jones, 2001). Thus, placing the drug in the anterior inferior turbinate can increase drug delivery efficiency. MCC can completely clear liquid formulations in 12 min (Shaikh et al., 2011), and swallowing can drain the formulation from the nasopharynx to below; thus, drug can be lost from liquid formulations and affect the gastrointestinal tract. Within a certain range, as the temperature increases, the mucosal cilia movement also increases, and at ∼24 °C, the MCC decreases, facilitating drug retention and absorption (Corbo et al., 1990).

4.2.2 Intranasal secretions

The nasal mucosa and submucosal glands secrete mucus that is continuously present on the nasal mucosa in a bilayer and has a thickness of approximately 5 µm (Arora et al., 2002), with an aqueous layer at the bottom, in which the epithelial cilia move, and a viscous gel layer at the top, in which the gel-like surface follows the cilia forward. The viscosity of the secretion determines the drug retention time, and the composition of the secretion determines the ease of drug dissolution. Nasal secretions comprise 90% water, with the rest comprising mucin, salts, proteins, and lipids (Arora et al., 2002). Drugs with similar physicochemical properties to nasal secretions aid absorption, and studies have shown increased absorption of drugs when aqueous analogs are given intranasally (Kao et al., 2000). Reportedly, changes in the viscosity of secretions can affect cilia movement and alter the drug retention time, affecting drug absorption (Mortazavi and Smart, 1994); for example, anionic drugs enhance mucus gelation more so than neutral or cationic drugs, thereby increasing drug retention and enhancing absorption.

4.2.3 Nasal cycle

It has been shown that the nasal cycle occurs less frequently at night than in the daytime (Merkus et al., 1998). As a result, cilia movement of the nasal mucosa is reduced at night, as is the secretion production and clearance rate, influencing drug absorption.

4.3 Pathological states

Nasal diseases, such as acute and chronic rhinitis, allergic rhinitis, drug rhinitis, and nasal polyposis, usually alter the normal physiological state of the nasal mucosa, resulting in insufficient or excessive mucus secretion, swelling or drying of the mucosa, altering the conditions of drug absorption, leading to reduced drug absorption (Gizurarson, 1993). In addition, pruritus and sneezing caused by rhinitis can exacerbate this effect, and drug administration is greatly diminished in these states. Nasal secretions are acidic, and when the pKa of the drug is higher than the pH of the nasal secretions, the drug does not ionize but exists intact and is more easily absorbed (Huang et al., 1985). Infections can change the pH of nasal secretions. For example, chronic bronchitis can increase the pH of nasal secretions to 7.8, affecting the drug’s pH and thereby ionizing the drug and limiting absorption (Adler et al., 1972). The ideal pH of the nasal secretions for drug delivery is 4.5–6.5; the drug can somewhat counteract this pH change.

4.4 Nasal microbiota

The complex microbiota in the nasal cavity, including bacteria, fungi, and viruses, has a complex relationship with the host with different compositions (Dominguez-Bello et al., 2019). Nasal microbiota can affect the olfactory nerve or lymphatic drainage, leading to the occurrence and development of NDs (Bell et al., 2019). Reportedly, the nasal microbiota has both pathogenic and therapeutic effects on NDs (Xie et al., 2022). Therefore, selecting drugs compatible with the individual microbiota allows for better treatment.

4.5 Nasal immune system

Nasal mucosal epithelial cells secrete various enzymes that affect the stability of intranasal drugs, especially peptide and protein drugs, which are broken down by endopeptidases, such as serine, and exopeptidases, such as mono and diamino peptidase (Kaur et al., 2016). In addition, the nasal cavity contains immunoglobulins such as IgS, which can combine with peptide drugs to form complexes (Kakad et al., 2015), making it difficult for the drug to pass through the nasal mucosa if the size exceeds 500 nm. Therefore, it is critical to effectively package the drug to minimize the effect of the immune system on the drug.

5 Strategies for enhancing nasal-brain delivery5.1 Absorption enhancers

Tight junctions in the nasal cavity’s olfactory and respiratory epithelial regions (Ruigrok and de Lange, 2015) protect the internal mucus layer and limit the passage of drugs through the nasal mucosa. Absorption enhancers are compounds delivered via intranasal administration along with the drug and can temporarily alter the structure of the nasal mucosa, opening the tight junctions between cells, allowing easier passage, and protecting the drug from degradation (Kim et al., 2020). In addition, the lipophilic and cationic properties of the drug can better expand the effect of crossing the nasal mucosa. Enterotoxin is a good absorption enhancer but may cause side effects, such as tissue damage and reduced cilia movement, which can be reduced using surfactants, protease inhibitors, and tight junction modifiers (Ghadiri et al., 2019). Cationic polymers such as chitosan and its derivatives can act on the nasal mucosal barrier to alter tight junctions, thus improving drug absorption (Ghadiri et al., 2019). Surfactants such as bile salts, nonionic surfactants, phospholipids, and fatty acid salts can better help drugs cross the nasal mucosa by filtering out membrane proteins, opening tight junctions, or preventing enzymatic drug degradation (Ghadiri et al., 2019). Encapsulation of the impermeable drug flurbiprofen in nanoparticles can lead to the better passage of drugs for AD through the endothelial cell monolayer, reducing Aβ42 levels and modulating γ-secretase activity (Meister et al., 2013).

Notably, CPPs can promote biomolecular and cellular internalization (Said Hassane et al., 2010), which would be an interesting strategy for promoting drug uptake. Transactivated transcription (TAT) peptides deliver siRNA to the rodent brain via olfactory nerve pathways to treat AD (Kim et al., 2016). CCPs with hydrophobic (stearate) or hydrophilic (polyethylene glycol) modifications can target relevant drugs to different sites of action in the brain via olfactory pathways (Kanazawa et al., 2017).

5.2 Enzyme inhibitors

The nasal mucosa contains various enzymes that target and degrade delivered drugs, including transferases, carboxylesterases, and peptidases (Agrawal et al., 2020a). Amylosucrase inhibits aminopeptidase, while bacitracin and puromycin inhibit the protection of leucine enkephalin from enzymatic degradation. Disodium EDTA protects β-fold disrupting peptide protection from enzymatic degradation for better treatment of AD (Laffleur and Bauer, 2021).

5.3 Prodrugs

Prodrugs are used to overcome poor solubility, poor chemical or biological stability, poor absorption, and premature metabolism by transiently modifying the binding of specific functional groups of the drug to the precursor fraction to make it favorable for nasal mucosal absorption (Tirucherai et al., 2001). When the drug passes through the nasal mucosal barrier, this transient modification can avoid drug loss and thus allow optimal drug bioavailability. Nevertheless, the side effects of prodrugs for treating AD must be considered; for example, inhibiting cholinesterase increases acetylcholine in the brain (Blanco-Silvente et al., 2017), causing diarrhea, vomiting, and nausea and affecting the cognitive aspects of the patient’s treatment (Loy and Schneider, 2006).

5.4 Vasoconstrictors

The nasal respiratory region has a high density of vascular distribution and is the main target for systemic drug delivery. The olfactory epithelium is less vascular and is the main target for nerve pathways and nose-to-brain delivery. A study on intranasal delivery of neuropeptide and hypocretin-1 showed that intranasal administration increased the drug dose delivered to the olfactory bulb after vasoconstrictor administration (e.g., phenylephrine) and decreased the amount of drug in the circulation (Dhuria et al., 2010).

5.5 Drug delivery devices

The key to the success of intranasal drug delivery targeting the brain is to maximize the deposition of the drug formulation in the olfactory epithelial. Today, the most commonly used drug delivery devices are nasal drops and pump sprays. Nasal drops diffuse widely in the nasal cavity, increasing the deposition area in the olfactory epithelial (Hardy et al., 1985); with mucoadhesion, the retention time is up to 14 min (Charlton et al., 2007). However, applying nasal drops is complex and requires good patient administration technique and proper head position (Vidgren and Kublik, 1998). Pump sprays are simple to operate and can deliver a constant and stable dose of 25–200 mL (Vidgren and Kublik, 1998). Plume and delivery angles are key determinants of deposition efficiency, with maximum deposition efficiency to the turbinate (30%–50%) occurring at a plume angle of 55–65°; an approximately 90% deposition efficiency can be achieved using a 30° delivery angle (Foo et al., 2007). A deposition of 2.5% occurred in the area corresponding to the olfactory region (Djupesland and Skretting, 2012).

Vianase is an electronic nebulizer developed by Kurve Technology in which the nebulized drug moves in a vortex chamber and maintains this motion after leaving the device, maximizing drug deposition in the olfactory region (Warnken et al., 2016). This device has been used to deliver insulin to the brain to treat AD (Craft et al., 2012) and reached the patient’s brain within 2 min. However, some pulmonary complications were observed with long-term use (Rapoport and Winner, 2006). Therefore, the safety of nasal sprays in the context of long-term treatment is unclear.

6 Nose-to-brain delivery for specific NDs

Intranasal drug delivery is becoming an effective route for treating many NDs such as AD, PD, HD, and prion diseases (Chapman et al., 2013). These diseases are usually slowly progressive (Soto and Pritzkow, 2018) and are characterized by the misfolding and accumulation of intra-and extracellular protein deposits and neuron disorders, apoptosis, or necrosis, mainly manifesting as motor, cognitive, and mental impairments. Therefore, treatment involves pharmacological agents that counteract the disease pathogenesis and symptoms. Here, we summarize the application of nanocarriers for nose-to-brain drug delivery in different NDs (Table 2).

TABLE 2

TABLE 2. Nanocarriers in neurodegenerative diseases.

6.1 Alzheimer’s disease

AD is the most common ND (Breijyeh and Karaman, 2020) and the most common cause of dementia, with a projected global preval‎ence of 150 million in the mid-21st century. The main symptoms of AD are cognitive behavioral loss, memory impairment, and impairment in daily activities. AD pathogenesis is mainly divided into positive and negative lesions. Positive lesions are mainly caused by abnormal protein accumulation inside and outside brain cells, including neurofibrillary tangles, amyloid plaques, and other deposits. Amyloid β (Aβ) protein deposition or Aβ plaque formation is one of the major biomarkers of AD, and tau is another important biomarker. Hyperphosphorylation of tau can cause neurofibrillary tangles (NFTs). Negative lesions are mainly atrophy of brain areas due to the loss of neurons and synapses. In addition, cholinergic system dysfunction and oxidative stress can cause AD. Therefore, the treatment is based on cholinesterase inhibitors, neuron death reduction, deposit accumulation prevention, and antioxidants (Figures 7, 8). Thiolated chitosan (modified) nanoparticles were fabricated using modified ionic gelation method in one study. Galantamine loaded thiolated chitosan nanoparticles were showed to lead to better efficacy than conventional oral therapies (Sunena et al., 2019). Similarly, in three other studies (Muntimadugu et al., 2016; Jiang Y. et al., 2019; Yu et al., 2020), poly (lactide-co-glycolide) or solid lipid nanoparticles loaded with tarenflurbil (TFB), Wheat germ agglutinin (WGA) -modified PEG/PLA nanoparticles loaded with miR-132 (Muntimadugu et al., 2016; Yu et al., 2020) and lactoferrin loaded uperzine A (HupA) nanoemulsion (Jiang Y. et al., 2019) showed significant benefits for AD.

FIGURE 7

FIGURE 7. Nanoparticle-encapsulated tarenflurbil for AD. Reproduced with permission (Muntimadugu et al., 2016). Copyright 2016, Elsevier.

FIGURE 8

FIGURE 8. Intranasal delivery (WGA)- nanoparticles -miR132 for AD. Reproduced with permission (Yu et al., 2020). Copyright 2023, Frontiers Media S.A.

6.2 Parkinson’s disease

PD is the second most common ND (Beitz, 2014). The main symptoms are motor disorders, such as bradykinesia, tonicity, and tremor, and some nonmotor disorders, such as cognitive impairment and behavioral disturbances. The pathogenesis of PD is the loss of dopaminergic neurons at the substantia nigra. The deposition of Lewy bodies in the brain leads to impairment of neurotransmitter systems, such as uncontrolled excitation of cholinergic neurons and γ-aminobutyric acidergic neurons of the corpus striatum, leading to dyskinesia (Figure 9) (Zhao et al., 2021). Therefore, treatment is based on supplying dopamine or restoring the dopamine transmission system with levodopa as a precursor (Figure 10) (de Oliveira Junior et al., 2020). The nanoencapsulated geraniol/ursodeoxycholic acid conjugate constructed by the researchers was proven to be an effective strategy and did not damage the structural integrity of the nasal mucosa in contrast to the pure geraniol (de Oliveira Junior et al., 2020).

FIGURE 9

FIGURE 9. STING-mediated neuroinflammation-induced apoptosis may be a novel mechanism in Parkinson’s disease. Reproduced with permission (Zhao et al., 2021). Copyright 2021, Springer Nature.

FIGURE 10

FIGURE 10. Nanoparticle-encapsulated geraniol/ursodeoxycholic acid coupling for PD. Reproduced with permission (de Oliveira Junior et al., 2020). Copyright 2020, Elsevier.

6.3 Huntington’s disease

HD is a relatively rare ND (Stoker et al., 2022). Characterized by motor deficits and cognitive decline with some psychiatric symptoms such as depression and anxiety, HD is mainly due to abnormal duplication of CAG nucleotides of the gene encoding the Huntington protein, which eventually produces abnormal protein polyglutamine (polyQ) and largely accumulates in the neurons of basal ganglia (caudate-putamen), and finally cortico-striatal dysfunction. Treatment for HD is often palliative, and neurotrophic factors are critical (Figure 11) (Passoni et al., 2020). The constructing intranasal cholesterol-loaded liposomes (IN Chol-loaded liposomes) has not been shown to improve efficacy (Passoni et al., 2020).

FIGURE 11

FIGURE 11. Cholesterol delivery by the nose-to-brain pathway for HD. Reproduced with permission (Passoni et al., 2020). Copyright 2020, American Chemical Society.

6.4 Sensorineural deafness

Sensorineural hearing loss (SNHL) is a group of neurodegenerative disorders associated with hearing loss (Park et al., 2018), the main cause of which is irreversible damage to the cochlear hair cells, ultimately leading to the decline of spiral ganglion cells. Sensorineural deafness is the main type. An interconnection between dementia (e.g., AD and other cognitive impairment disorders) and hearing loss has been demonstrated (Peters et al., 1988). Deafness is a common feature of aging- and dementia-related disorders, which are associated with central auditory pathways and brain lesions, such as reduced scavenging of oxygen free radicals, mitochondrial DNA damage, and enhanced deamidation and ubiquitination (Lindner and Helliger, 2001; Chondrogianni and Gonos, 2005; Schaar et al., 2015). One study found that these two disorders significantly increased amyloid precursor protein and phosphorylated tau in the cerebral cortex (Park et al., 2018). Therefore, in addition to specialist treatments, such as hearing aids, other medications may overlap with the treatment of AD, such as antioxidant therapy and medications to reduce neuronal death and prevent deposit accumulation. Nanohydrogel may be used for inner ear dialysis, a promising treatment for SNHL (Li et al., 2017).

7 Opportunities and challenges

The anatomical, physiological, and nasal dynamics of nasal drug delivery to the CNS remain challenging. The low volume of the nasal cavity limits the dose administered, which, combined with the mucosal ciliary clearance of the nasal cycle, largely affects the absorption rate. Various enzymes, such as proteases, endopeptidases, and carboxypeptidases, degrade drug proteins and peptides during the limited retention time of the drug. However, with the advent of nanotechnology, these unfavorable drug properties no longer limit intranasal drug delivery by modulating the delivery vehicle rather than the nature of the drug. These problems can be overcome by rational drug delivery strategies and delivery methods, and these adverse drug properties no longer limit intranasal drug delivery.

Gene therapy can achieve neuroprotection and neurorepair and ultimately correct pathogenic mechanisms rather than alleviate the symptoms of NDs (Sudhakar and Richardson, 2019). In vivo siRNA or ASO delivery is effective in animal models of neurodegenerative pathologies such as AD, PD, and HD (Sah, 2006; Sudhakar and Richardson, 2019). Viral vectors account for over 70% of all active gene therapy clinical trials; however, invasive delivery systems are required for treating neurological disorders, such as stereotaxic injection of viral vectors into the brain, which is highly impractical (Dreyer, 2011). In addition, repeated injections into multiple brain regions are unacceptable for AD, PD, and HD as these pathologies gradually spread throughout the brain. Invasive injections are inherently risky, causing bleeding and infection. The intranasal delivery of molecules from the nasal cavity to the olfactory bulb to the brain is feasible (Lochhead et al., 2015; Aly et al., 2019) and allows for the noninvasive delivery of molecules to the brain, bypassing the BBB; thus, this approach can be used to carry nonviral-vector gene therapies for NDs (Villatebeitia et al., 2015). Using nanocarriers for gene delivery allows the simple, noninvasive, and chronic administration of drugs to patients. Several studies have been conducted on nanocarrier gene delivery in recent years (Kanazawa et al., 2013; Fan et al., 2018; Sanchez-Ramos et al., 2018; Sava et al., 2020; Sava et al., 2021; Alamoudi et al., 2022; Petkova et al., 2022). Therefore, the intranasal delivery of nanocarriers will have a significant impact on the treatment of brain diseases in the future.

The efficiency of nose-to-brain delivery is mainly assessed via neural pathways located in the posterior and apical olfactory and the respiratory epithelium of the nasal cavity, which are difficult to access and deposit (Quintana et al., 2016). Furthermore, no studies have guided the use of nasal sprays as a delivery device for systemic absorption after intranasal administration, and mucosal inflammation of the nose, nasal polyps, and deviation of nasal septum affecting the deposition of sprays have not been explored.

Nanoparticles as carriers for nose-to-brain delivery of drugs must be studied in more depth for use in clinical applications, including aggregation and clearance due to nanoparticle size, resulting in toxicity with control and clearance. Similarly, the potential toxicity of nanoparticles to the nasal mucosa and brain remains unclear. Each nanocarrier’s contribution is unknown, and the co-dosing association must be studied. The selection of excipients to reduce drug toxicity also awaits study in the development of drug delivery systems.

8 Conclusion

This review compared different nanomedicines and summarized the methods, influencing factors, and strategies for enhanced delivery of nanomedicines based on nasal targeting to the brain and their relevant applications in treating NDs. After intranasal administration using appropriate methods, the therapeutic efficacy of these nanomedicines has demonstrated good results in several studies. However, the clinical application of nanotechnology delivery systems for nose-to-brain drug delivery is in the early stages of development. Conclusive studies in additional animal models (e.g., monkeys) are necessary to elucidate the appropriate characteristics that nanoparticles must possess to serve as successful nose-to-brain drug delivery vehicles to facilitate this translation to the clinic. In addition, more conclusive data on the pharmacodynamics and pharmacokinetics of the different routes and the biodistribution of biomolecules in the brain are needed.