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/lp/wolters-kluwer-health/extracellular-vesicle-based-drug-delivery-system-boosts-phytochemicals-M0etoz80fs
- Publisher
- Wolters Kluwer Health
- Copyright
- Copyright © 2022 Tianjin University of Traditional Chinese Medicine.
- ISSN
- 2765-8619
- DOI
- 10.1097/hm9.0000000000000039
- Publisher site
- See Article on Publisher Site
Abstract
Neurodegenerative diseases (NDs) are a major threat to the elderly, and efficient therapy is rarely available. A group of phytochemicals has been shown to ameliorate NDs; however, poor stability, low bioavailability, and reduced drug accumulation in brain tissue limit their application in NDs. Therefore, a targeted drug delivery system is a feasible treatment strategy for NDs. Extracellular vesicles (EVs) possess many favorable bioactivities and are excellent carriers for targeting brain tissue. This review summarizes EVs as novel phytochemical carriers in ND therapy. First, we discuss the current challenges of ND therapy and the therapeutic effects of phytochemicals for NDs. Second, we highlight the ability of EVs to cross the blood-brain barrier and act as drug carriers to enhance the therapeutic efficacy of drugs for NDs. Finally, encapsulation strategies for phytochemicals in EVs are particularly reviewed, as they are critical for obtaining high loading efficacy and stable drug delivery systems. This review provides new insights into EV-based drug delivery systems for improving the therapeutic effect of phytochemicals for ND treatment. Therefore, the release rate and pharmacokinetics of phytochemicals should be well controlled to ensure the therapeutic efficacy of phytochemical-loaded EVs in the brain. Keywords: Bioavailability, Brain-targeting, Extracellular vesicle-based drug delivery system, Neurodegenerative diseases, Phytochemicals peripheral nervous system lose function, and these dis- Introduction eases affect bodily functions, such as balance, movement, Neurodegenerative diseases (NDs) are becoming a seri- talking, breathing, and heart function. ous threat owing to the growing elderly population Intensive efforts have been made to develop new drugs worldwide, and the social burden has increased in recent to treat NDs. To date, some drugs have been approved decades. The four major types of NDs are Alzheimer dis- for the treatment of NDs in clinical settings; for example, ease (AD), Parkinson disease (PD), Huntington disease donepezil, memantine, galantamine, and rivastigmine are (HD), and amyotrophic lateral sclerosis (ALS). According used for AD therapy; carbidopa, levodopa, pramipexole, [1] to a 2022 report , approximately 6.2 million Americans ropinirole for PD therapy; tetrabenazine for HD therapy; have AD, and more than 10 million people worldwide [4] and risdiplam for ALS therapy . Treatment may relieve are living with PD as of 2020. In the future, the num- some physical or mental symptoms associated with NDs; ber of patients with NDs will increase significantly. The however, there is currently no treatment to slow disease pathogenesis of NDs is complex and includes genetic, progression and no known cure. This situation requires [2] environmental, and other factors . In the progression clinicians to improve their understanding of the causes of of NDs, neuroinflammation, aggregation of misfolded NDs and develop new treatment and prevention strategies. proteins, oxidative stress, inclusion body formation, and Phytochemicals extracted from herbs such as Panax mitochondrial dysfunction are considered major causes ginseng, Eucommia ulmoides, Coptis chinensis, Ginkgo [3] in the brain . NDs occur when nerve cells in the brain or biloba L. Magnolia officinalis, Camellia sinensis, and [5] Morus alba L. are beneficial to human health . Dietary College of Food Science and Engineering, Nanjing University of fruits and vegetables also contain phytochemicals such Finance and Economics/Collaborative Innovation Center for Modern as Dioscoreae rhizoma, Curcuma longa, Zingiber offi- Grain Circulation and Safety, Nanjing, China; School of Pharmacy, cinale, Garcinia parvifolia, Vitis vinifera, and berries, Nanjing University of Chinese Medicine, Nanjing, China [6] which provide nutrition . Natural phytochemicals from * Corresponding author. Zhenzhu Zhu, College of Food Science and herbs or edible plants have been identified and charac- Engineering, Nanjing University of Finance and Economics, Nanjing, terized as having therapeutic potential for NDs in recent 210023, China, E-mail: 9120191020@nufe.edu.cn. years, and they may be less toxic than novel synthetic Copyright © 2022 Tianjin University of Traditional Chinese Medicine. [7] drugs . Their mechanisms of action in the progression This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives of NDs are complicated and include anti-oxidative, License 4.0 (CCBY-NC-ND), where it is permissible to download anti-inflammatory, anti-apoptotic, anti-aggregation, and and share the work provided it is properly cited. The work cannot be mitochondrial protection effects. In addition, the role of changed in any way or used commercially without permission from the the gut microflora in the central nervous system (CNS) journal. [8] mediates the therapeutic efficacy of phytochemicals . Acupuncture and Herbal Medicine (2022) 2:4 However, the solubility, bioavailability, targeting capa- Received 13 May 2022 / Accepted 14 September 2022 bility, and effective concentrations of phytochemicals in [9] http://dx.doi.org/10.1097/HM9.0000000000000039 the brain are major concerns . 229 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Therefore, recent studies have focused on drug delivery reach clinical trial stages are limited, especially for small systems to solve these problems. Examples of nanocarri- molecule and macromolecule drugs (peptides, antibod- [19] ers include liposomes, micelles, metal-based nanoparticles, ies, and small interfering ribonucleic acid) . and extracellular vesicles (EVs). EVs are more promising Third, the therapeutic efficacy of approved drugs is not vehicles than traditional nano drug carriers for deliver - as expected. First-generation anti-AD drugs inhibit AChE [20] ing drugs into the brain, owing to their biosafety, ability and the N-methyl-d-aspartic acid receptor . However, to cross the blood-brain barrier (BBB), targeted delivery, they did not significantly improve the state of AD but only [10] [21] and low immunogenicity . This review focuses on the slowed its progression . Subsequently, β-secretase (BACE- application of phytochemical-loaded EVs in ND therapy. 1) blockers were developed, which decreased Aβ levels in The literature review was conducted to find all published neurons and glial cells. BACE-1 blockers, when used early [22] systematic reviews on the extracellular vesicle-based drug in the course of AD, prevent disease progression . In 2019, delivery system improving phytochemicals intervention GV-971 received conditional marketing approval in China in the neurodegenerative diseases. A comprehensive sys- to improve cognitive function in mild to moderate AD by tematic literature was searched in the Web of Science, restoring the gut microbial profile to normal and reduc- [23] PubMed, SciFinder, Google scholar, and China National ing brain immune cell infiltration and inflammation . In Knowledge Infrastructure. The information on clinical tri- 2021, aducanumab was approved in the United States for [24] als and ND therapeutics were collected from the website AD treatment . However, the clinical use of GV-971 and of Food and Drug Administration (FDA) of the United aducanumab has recently been terminated owing to com- States and ClinicalTrials.gov. The literature searches most plicated reasons and problems. Immunotherapies against cover the period from January 2012 to September 2022. Aβ and tau proteins are in the advanced stages of clinical trials and have the potential to block the progression of [25] AD . In addition, preclinical models do not accurately Challenges of ND therapy [26] reflect the pathogenesis of NDs in humans , which is a In recent years, there have been many challenges in devel- challenge in clinical drug development. oping therapeutic strategies for NDs. First, the exact tar- gets of NDs remain controversial. AD is caused by the Phytochemicals for ND therapy progressive formation of senile plaques and neurofibril- lary tangles in the cerebral cortex, as well as neuronal and Phytochemicals are bioactive compounds enriched in synaptic loss. The expression of amyloid precursor protein plants. Based on their chemical structure, they are clas- (APP), acetylcholinesterase (AChE) activity, and excess sified as phenolic compounds, terpenes, carotenoids, aggregated β-amyloid (Aβ) peptides initiate the pathogenic alkaloids, nitrogen-containing compounds, and orga- [27] cascade, including the propagation of microtubule-as- nosulfur compounds . Numerous studies have demon- [11] sociated tau aggregation throughout the brain . PD is strated that phytochemicals can protect neurons from [28] caused by the progressive death of neurons in the pars dysfunction and pave the way for ND therapy . Typical compacta region of the brain and alpha-synuclein (α-syn) compounds are resveratrol, curcumin, quercetin (Que), aggregation, which causes a decrease in dopamine syn- cyanidin-3-O-glucoside (C3G), epigallocatechin-3-galate [12] thesis and Lewy body formation . HD is caused by the (EGCG), berberine (Ber), and other bioactive compounds expression of mutant huntingtin protein (mHTT) with an from plants (Figure 1). Most of these phytochemicals abnormal number of glutamine repeats in its N-terminus could directly interact with aggregation-prone proteins and is characterized by intracellular mHTT aggregates in in different NDs, such as Aβ, tau, α-syn, polyglutamine, [13] the brain . ALS is caused partly by neuronal cytoplasmic SOD1, and TDP-43, or indirectly interact with path- inclusions of the tar-deoxyribonucleic acid binding pro- ways related to ND progression in vivo. Anti-oxidative, [14] tein-43 (TDP-43) and superoxide dismutase 1 (SOD1) . anti-inflammatory, and anti-apoptotic effects and mito- Great progress has been made in the research field of NDs; chondrial protection are closely related to the neuropro- however, the key underlying molecular defects or path- tective potential of phytochemicals (Table 1). ways are unidentified. Recent studies have discovered that In AD, resveratrol exhibits anti-inflammatory effects autolysosome acidification declines in neurons before Aβ by inhibiting nucleotide-binding and oligomerization [15] deposition , which is subversive, and Aβ might not be domain-like receptor protein 3 (NLRP3) inflammasome the precise target of AD. In other words, there are no eas- activation and interleukin-1 beta (IL-1β) secretion in [29] ily measurable biomarkers to predict patient progression. the CNS . Curcumin administration reduces oxidative Second, the BBB is a major obstacle. Brain endothelial stress, which helps to destroy β-amyloid plaques and [53] cells, astrocyte end-feet, and pericytes are found in the slows the progression of AD . EGCG administration sig- brain microvasculature between the blood circulation nificantly inhibits β -secretase activity and protects against [16] system and the CNS . Endothelial tight junctions form mitochondrial damage, which is beneficial for alleviating [54] a physical barrier, and membrane transporters in the Aβ-induced neurotoxicity . C3G inhibits Aβ fibril- [17] efflux system form a transport barrier . Drugs with logenesis, disintegrates preformed fibrils, and reduces [55] molecular weights less than 400 Da and hydrogen bond amyloid cytotoxicity . Silibinin decreases Aβ deposi- numbers less than eight are allowed to pass through the tion and reduces soluble Aβ levels in the hippocampus [18] BBB . Regrettably, many drugs fail to reach the treat- by downregulating APP and BACE-1 and upregulating [56] ment site through the BBB because their predicted lipo- neprilysin in APP/PS1 (presenilin 1) mice . Oleuropein philicity (log P) or lipophilic permeability coefficient (log in olive oil has been shown to reduce neuroinflamma- D) is much higher than the actual CNS permeability of tion by inhibiting the nuclear factor kappa-B pathway, lipophilic drugs. Therefore, drugs for ND therapy that suppressing the activation of NLRP3 inflammasomes 230 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Figure 1. The structure of phytochemicals that could treat neurodegenerative diseases. Source, composition, and biological effects of EVs and random activation gene expression or high mobil- ity group protein 1 pathways, reducing total Aβ brain EVs are small membranous vesicles that are naturally levels, and enhancing BBB integrity and function, which produced and excreted by numerous cell types. EVs include [46] collectively improves memory function in AD mice . In exosomes (40 nm–120 nm), microvesicles (100 nm–1 μm), PD, Que inhibits α-syn aggregation by covalently bind- apoptotic bodies (50 nm–2 μm), and oncosomes (1 μm–10 [38] [62] ing to α-syn, preventing α-syn fibrillation . Kaempferol μm) . Exosomes are small nano-sized vesicles that have induces autophagy by increasing lysosome biogenesis [63] been studied for biomedical applications . Animal-derived and inducing the expression of transcription factor EB. exosomes can be harvested from cells or bodily fluids, and Additionally, it indirectly reduces the accumulation of plants, like animals, excrete exosome-like nanovesicles [64] α-syn or directly blocks the α-syn amyloid fibril forma- containing information molecules . Exosomes contain [57] tion to protect against α-syn–related neurotoxicity . Ber various biomolecules from donor cells, including lipids, increases autophagy-dependent degradation against the proteins, and nucleic acids. The lipid bilayer of exosomes [52] accumulation of mHTT and the formation of insoluble is enriched with sphingomyelin, gangliosides, and desat- [58] TDP-43 aggregates in HD and ALS . urated lipids, but their phosphatidylcholine and diacyl- Phytochemicals have potential as preventive and ther- glycerol proportions decrease relative to the membranes [65] apeutic compounds against NDs; however, poor bio- of their cells of origin . Proteins in exosomes include availability and low accumulated concentrations in brain major histocompatibility complex class II and tetraspanins [59] tissue limit their therapeutic efficacy in clinical trials . (CD37, CD53, CD63, CD81, and CD82), endosomal sort- Some phytochemical derivatives have been synthesized ing complex required for transport proteins, ALG-2 inter- and modified to produce BBB-permeable compounds; acting protein-X, tumor susceptibility gene 101, and heat however, phytochemical distribution, metabolism, and [66] shock chaperones (Hcs70 and Hsp90) . Nucleic acids bioactivity in the brain may change to some extent. in exosomes are predominantly long non-coding RNAs, Therefore, designing and developing targeted drug deliv- [67] microRNAs (miRNAs), and messenger RNAs . ery systems capable of crossing the BBB with more stable EVs circulate through all bodily fluids and play a major phytochemicals accumulated in the brain is critical. role in intracellular and intercellular communication because of their ability to transfer proteins and nucleic EVs for drug delivery [68] acids from one cell to another . The biological effects of exosomes mainly depend on the parent cells, such as mes- EVs are secreted by various cells and serve different func- tions. EVs in the blood circulation of the body can cross enchymal stem cells (MSCs), immunocytes, neurons, and other cell types (Figure 2), as well as blood, plasma, saliva, the BBB and enter the CNS through direct transendo- [60] [69] thelial or antiaxoplasmic transport . They regulate the milk, and urine . Among them, MSCs are the most expected source of EVs, as they serve as a bridge and link development and regeneration of neurons as well as syn- [61] aptic function . Therefore, we summarize the sources, of communication between stem cells and injured cells, promoting the communication of information between compositions, and bioactivities of EVs, which were used as drug carriers for NDs. cells, regulating immunity, and facilitating self-repair of 231 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Table 1 Major effects of phytochemicals on neurodegenerative disease progression Phytochemicals Targeted molecules Effects Disease Reference [29] Resveratrol 1) anti-oxidant; AD Yu et al. 2018 , 1) SOD, CAT, GSH↑, ROS, MDA↓; 2) ↓NLRP3, TLR4/ [30] 2) anti-inflammatory; Ladiwala et al. 2010 , NF-κB, HMGB1, ↑M2 microglia polarization; 3) 3) mitochondrial protection; Karuppagounder et al. ↓mtDNA fragmentation, ↑MMP, ↑mitophagy; 4) [31] 4) anti-apoptotic; ↓BAX/Bcl-2, ↓caspase-3/9, ↓p38, JNK; 5)↓Aβ 5) anti-aggregation effect [32] Curcumin 1) anti-oxidant; AD, PD Zhang et al. 2017 , 1) ↑GSH ↑NRF2, ↓ROS ↓MDA; 2) ↓TNF- [33] 2) anti-inflammatory; Xia et al. 2016 , α, IL-1β, IL-1α, ↓TLR4, ↑M2 microglia [34] 3) mitochondrial protection; Jiang et al. 2013 , polarization; 3) ↑MMP ↑ATP, ↑mitophagy; 4) [35] 4) anti-apoptotic; Sharma et al. 2018 ↓BAX/Bcl-2, Caspase-3/9; 5) ↓Aβ, ↓α-syn 5) anti-aggregation effect [36] Quercetin 1) ↑GSH, ↓LDH ↓ROS ↓MDA; 2) ↓TLR4, 1) anti-oxidant; AD, PD Liu et al. 2019 , [37] 2) anti-inflammatory; ↓COX-2, ↓IL-1β, IL-6, TNF-α; 3) ↑MMP, Regitz et al. 2014 , [38] 3) mitochondrial protection; ↓ultrastructural alterations; 4) ↓caspase-3, Zhu et al. 2013 , [39] 4) anti-apoptotic; ↓BAX/Bcl-2; 5) ↓ Aβ, α-syn El-Horany et al. 2016 5) anti-aggregation effect [40] Cyanidin-3-O- 1) SOD, CAT, GSH↑, ROS, MDA↓; 2) ↑MMP; 1) anti-oxidant; AD, PD Pogacnik et al. 2016 , [41] 2) anti-inflammatory; glucoside (C3G) 3) ↓COX-2, ↓IL-1β, IL-6, TNF-α; 4) Winter et al. 2017 , [42] 3) mitochondrial protection; ↓caspase-3, ↓BAX/Bcl-2; 5) ↓Aβ, α-syn Rehman et al. 2017 4) anti-apoptotic; 5) anti-aggregation effect [43] Epigallocatechin- 1) SOD, CAT, GSH↑, ROS, MDA↓; 2) ↓BAX/Bcl- 1) anti-oxidant; AD, PD Chen et al. 2018 , [44] 2) mitochondrial protection 3-galate (EGCG) 2, ↓caspase-3/9; 3) ↓mtDNA fragmentation, Šneideris et al. 2015 , [45] 3) anti-apoptotic; ↑MMP, ↑mitophagy; 4) ↓ Aβ, α-syn Xu et al. 2020 4) anti-aggregation effect [46] Oleuropein 1) anti-inflammatory; AD Abdallah et al. 2022 1) ↓NLRP3, NF-κB, HMGB1; 2) ↓Aβ 2) anti-aggregation effect [47] Kaempferol 1) ↑SOD ↑GSH ↑NRF2, ↓ROS ↓SDH ↓MDA; 2) 1) anti-oxidant; PD Filomeni et al. 2012 , [48] 2) anti-inflammatory; ↓NLRP3, ↓TNF-α, IL-1β; 3) ↑MMP ↑ATP Han et al. 2019 3) mitochondrial protection; ↑mitophagy; 4) ↓caspase-3/9, ↓JNK/p38 4) anti-apoptotic MAPK; 5) ↓α-syn 5) anti-aggregation effect [49] Berberine 1) anti-oxidant; AD, HD, Chen et al. 2020 , 1) ↓ROS, ↑NRF2-HO-1; 2) ↓IL-1β, TNF-α; [50] 2) anti-inflammatory; ALS Huang et al. 2017 , 3) ↑MMP; 4) ↓caspase-3, ↓BAX/Bcl-2; [51] 3) mitochondrial protection; Jiang et al. 2015 , 5) ↓Aβ, APP, p-tau, ↓polyQ-Htt, ↓TDP-43 [52] 4) anti-apoptotic; Chang et al. 2016 5) anti-aggregation effect α-syn: Alpha-synuclein; Aβ: Aggregated β-amyloid; AD: Alzheimer disease; ALS: Amyotrophic lateral sclerosis; APP: Amyloid precursor protein; ATP: Adenosine triphosphate; BAX/Bcl-2: B-cell lymphoma protein 2-associated X; GSH: Glutathione; IL-1α: Interleukin-1 alpha; HD: Huntington’s disease; IL-1β: Interleukin-1 beta; JNK: c-Jun N-terminal kinases; MDA: Malondialdehyde; MMP: Matrix metalloproteinases; NLRP3: Nucleotide-binding and oligomerization domain-like receptor protein 3; NRF2: Nuclear factor-erythroid 2-p45 derived factor 2; PD: Parkinson disease; ROS: Reactive oxygen species; SDH: Succinate dehydrogenase; SOD: Superoxide dismutase; TNF-α: Tumor necrosis factor alpha. [70] damaged cells . MSC-derived EVs can easily cross the natural origin and bioactive molecules within EVs influ- BBB and directly stimulate neuron regeneration. EVs from ence their therapeutic potential in brain diseases (Table 2). [60] [71] [72] neurons , astrocytes , oligodendrocytes , or microg- EVs are isolated from these cells using different isolation [73] lial cells in the CNS are released to transport proteins, techniques, including ultracentrifugation, density gradient siRNA, and miRNA to remove cellular metabolic waste, centrifugation, exosome precipitation, antibody-based regulate immune responses, and adjust neuron and glial immunoaffinity purification, tangential flow filtration, [74] cell growth, regeneration, and synaptic regulation . and nano-flow cytometry, to develop their biomedical [86] Immune cells, such as dendritic cells and macrophages, application . Isolated EVs must be evaluated for cyto- migrate to pathological areas and regulate the inflam- toxicity and immunogenicity before being used in vivo. [75] matory response . Breast milk naturally secretes EVs that contain high levels of immune-related miRNAs that EVs as drug carriers can be transferred to infants and exert immunomodula- [76] tory effects . Studies have shown that EVs from cow EVs have many advantages as drug carriers, including milk have significant anti-inflammatory, tolerogenic, and innate stability, low immunogenicity, and tissue barrier [77] [87] anti-apoptotic effects in various settings . Plant-derived permeability . First, EVs protect cargo from acidic EVs, mainly isolated from vegetables, fruits, grains, and environments and enzyme degradation because of their [88] herbs, have emerged in recent years owing to their ease double membrane . Nanometer-sized EVs also circu- of acquisition, large production, and non-immunogenic- late in the body for a long time to maintain their func- [78] ity . In recent decades, several plant-derived EVs have tions. Owing to their cell origin, exosomes can avoid been registered in clinical trials, including grapes, ginger, phagocytosis or degradation by macrophages, thereby [79] and aloe-derived exosomes . EVs in various intercellular avoiding endosomal degradation of drugs. Second, EVs processes are involved in the pathology of NDs, and their are generally obtained from the patient’s recipient cells 232 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Figure 2. Sources and composition of exosomes, and their potential as drug carriers to cross the blood-brain barrier in the central nervous system. [91] to eliminate potential immune complications and ensure and receptor-mediated transcytosis . Exosomes might that EV recognition in clinical trials is similar to that of be degraded by lysosomes or their content released into [89] their recipient cells . Third, EVs could cross tissue bar- the cytoplasm through a back fusion event or trafficking riers, including the intestinal barrier and BBB. Therefore, from the multivesicular body to the plasma membrane as [92] EVs are excellent drug delivery candidates. neo formed intraluminal vesicles in the receiving cell . As the BBB is one of the major obstacles in treating Efficient drug loading into EVs is critical for suc- NDs, it is important to understand how EVs interact with cessful therapies. There are two methods for encap- the BBB. EVs secreted by brain cells can cross the BBB into sulating cargos into EVs: endogenous and exogenous the bloodstream, and circulating EVs can cross the BBB drug-loading methods (Figure 3). In the endogenous [90] into the brain . To date, exosomes and receiving cells drug-loading method, desired cargos are incubated interact in five ways: recognition by a protein G-coupled with cells that can produce EVs, relying on the nat- receptor on the cell surface, adhesion and fusion to the ural mechanisms of EVs to package natural com- [93] cell surface, micropinocytosis, non-specific or lipid rafts, pounds into EVs . EVs possess an aqueous core and 233 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com Table 2 Extracellular vesicles derived from different cells for neurodegenerative disease treatment EV source Models Disease Outcomes Reference [80] Mouse bone marrow APP/PS1 mice AD Wang et al. 2018 Aβ-induced iNOS expression suppressed derived–MSCs [81] Human bone marrow– 6-Hydroxydopamine-induced rat PD Dopaminergic neurons increased, recovery of Teixeira et al. 2017 derived MSCs motor performance outcomes [82] Human adipose–derived R6/2 mice-derived neuronal HD mHTT aggregates decreased, mitochondrial Lee et al. 2016 stem cells stem cells for HD model dysfunction and cell apoptosis reduced [83] Murine adipose–derived SOD1 transgenic mice ALS Motor performance improved, glial cells Bonafede et al. 2020 stem cells activation decreased [84] Neuro 2A (N2a) cells APP mouse AD Aβ deposition–mediated synaptotoxicity in the Chang et al. 2013 hippocampus reduced [85] Astrocytes Full-length HTT 140Q KI mice HD mHTT aggregation-induced cellular toxicity Hong et al. 2017 reduced Aβ: β-amyloid; AD: Alzheimer disease; ALS: Amyotrophic lateral sclerosis; APP/PS1: Amyloid precursor protein/presenilin 1; HD: Huntington’s disease; mHTT: Mutant huntingtin protein; MSCs: Mesenchymal stem cells; PD: Parkinson disease; SOD1: Superoxide dismutase 1. a lipophilic shell formed by the lipid bilayer, which the lipid bilayer of the EV membrane via hydrophobic allows them to store and dissolve hydrophobic and interactions. Successful drug loading has been reported [98] [99] hydrophilic compounds through non-specific binding for curcumin and doxorubicin . [94] interactions . This is a relatively simple strategy for Drug loading of hydrophilic natural compounds constructing drug delivery systems because of the cage- can be manipulated by electroporation, ultrasound, [95] like internal structures of EVs . Drug-loaded EVs are freeze or thaw cycles, and saponin permeabilization. [96] released by heat, hypoxia, and other stimuli . The Electroporation is usually used to load nucleic acids first step in the exogenous drug-loading method is the into EVs and for transfection with commercially avail- [100] isolation of EVs, and the desired cargo is then loaded able reagents . Ultrasonic treatment increased drug into the EVs using mechanical approaches. Simple load capacity and supported the release of EVs excreted [100] incubation, sonication, electroporation, freeze or thaw by macrophages . This strategy requires an isola- cycles, saponin permeabilization, and mechanical tion method that produces high yields of purified exo- extrusion have been employed to encapsulate drugs in somes free of impurities. Moreover, this method may [97] [101] exosomes . Exogenous drug-loading techniques dif- compromise functionality and the physicochemical fer depending on the solubility of the desired cargo. properties of drug molecules may affect the stability [94] Hydrophobic compounds are relatively easy to load and bioactivity of EVs . Exogenous drug loading was because they interact by mixing and incubating with used to co-incubate anthocyanidins with mature bovine Figure 3. Encapsulation strategies of drugs into exosomes. 234 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com milk-derived exosomes (Exo-Anthos), and Exo-Anthos owing to their short biological half-life, rapid metabo- significantly enhanced the drug’s oral bioavailability and lism, and clearance. Based on previous studies, the oral [102] its bioactivity . bioavailability of resveratrol, curcumin, and C3G was [110–112] Unlike exogenous loading methods, endogenous less than 1% . Their low bioavailability prevents drug-loading methods do not cause EV denaturation drug accumulation at the concentrations necessary for because natural compounds are sorted into EVs based successful therapy in target tissues. Fourth, the concen- on their natural cell mechanism. However, endogenous trations of phytochemicals and their metabolites did not loading methods have a much lower drug-loading effi- reach the concentrations expected to achieve in vivo bio- ciency than exogenous loading methods. Therefore, logical effects. A previous study demonstrated that C3G loading strategies must be optimized to ensure effective levels in the brain of rats intravenously administered a [113] utilization of exosomes as drug delivery systems. bolus of 668 nmol C3G were only nM . Numerous studies in vitro and in vivo have demonstrated that the concentration accumulated in the target tissue should Applications of phytochemical-loaded EVs for ND reach a μM magnitude to interact with molecular targets therapy and influence the related pathways. New strategies are required because the success of Phytochemicals have huge potential as preventive or an ND therapy depends greatly on the higher solubil- therapeutic agents; however, their clinical application has ity, absorption, bioavailability, and accumulated con- several limitations. First, the solubility of phytochemicals centration of phytochemicals in the brain. Considering is essential for absorption and eliciting biologically effi- the superiority of EVs as natural drug-loading tools that cient blood levels. The absorption of phytochemicals is [103] offer various advantages, harnessing their beneficial lower in powder form than in soluble form . Following properties to overcome the limitations of phytochemicals oral administration of a 500 mg tablet, the plasma level is a promising prospect. In this section, we review the of resveratrol is of nM magnitude, and the plasma level [104] most recent studies on the applications of phytochemi- of its metabolites can reach μM magnitude . However, cal-loaded EVs in ND therapy (Table 3). resveratrol plasma levels in beverages (red wine) can [105] reach higher concentrations within several hours . [106] [107] Approximately 75% or 60% to 66% of the dose is Curcumin absorbed following the oral administration of resveratrol or curcumin, respectively, but these absorptions are insuf- Curcumin is a hydrophobic molecule with a logP value of ficient as therapeutic agents. Second, the administration approximately 3.0, and a molecular weight of 368.38 Da. methods affect the concentration accumulation of phy- It has a simple structure with two phenolic functional [120] tochemicals in brain tissue. Oral delivery of curcumin is groups connected by a conjugated b-diketone system . less effective because of its low solubility in water, poor Only molecules with high lipophilicity and low molec- absorption, and rapid biotransformation, resulting in ular weight can cross the BBB. Unfortunately, non-spe- [108] lower systemic bioavailability . Notably, tail vein injec- cific absorption and poor bioavailability of curcumin in [114] tion, or more precisely, intracerebral injection through the brain were inevitable. Wang et al. proposed that [109] a cannula, prevents brain tumor formation in mice . exosomes derived from curcumin-primed macrophage Third, most phytochemicals exhibit low bioavailability RAW264.7 cells (Exo-Cur) should be harvested using Table 3 Phytochemical-loaded extracellular vesicles for neurodegenerative disease therapy Phytochemicals EV source Models Administration Outcomes Reference [114] Curcumin RAW264.7 cells Okadaic acid–induced AD rats Peritoneal injection BBB penetration of drug increase; Tau Wang et al. 2019 phosphorylation inhibited; learning and memory ability improved [115] Resveratrol Microglia Spinal cord injury rat model Intraperitoneal The neuronal survival rate and Fan et al. 2020 injection autophagy rate increased; the locomotor function improved [116] Silibinin RAW264.7 cells Injected daily into mice Huo 2021 Aβ -induced AD mouse Aβ aggregation reduced; astrocyte via the tail vein model inflammation-mediated neuronal damage alleviated; cognitive deficits ameliorated [117] Curcumin MSCs from mice 1-Methyl-4-phenyl-1,2,3,6- Nasal administration α-Synuclein aggregates reduced, Peng et al. 2022 bone marrow tetrahydropyridine–induced the neuron function recovered, PD mice neuroinflammation alleviated; the movement and coordination ability of mice improved [118] Quercetin Plasma exosomes Okadaic acid–induced AD rats Intravenous injection Tau protein aggregation inhibited Qi et al. 2020 [119] Berberine M2-type primary Spinal cord injury rat model Tail vein injection Anti-inflammatory and anti-apoptotic Gao et al. 2021 macrophages effect enhanced; the motor function of mice improved AD: Alzheimer disease; BBB: Blood-brain barrier; MSCs: Mesenchymal stem cells; PD: Parkinson disease. 235 Zhu et al. • Volume 2 • Number 4 • 2022 www.ahmedjournal.com an endogenous drug-loading method. The encapsula- The bioavailability of Que improved as the area under tion efficiency and loading capacity of curcumin in exo- the plasma concentration–time curve from zero time somes were 84.8% and 15.1%, respectively. Therefore, to infinity (AUC ) of Que in exosome-que (Exo-Que) 0–t exosomes improved the solubility and bioavailability of increased to 7.5-fold when compared to free Que. Exo- curcumin and targeted brain tissues with highly effec- Que significantly improved the brain-targeting and bio- tive BBB-crossing via receptor-mediated transcytosis. availability of Que. Exo-Que inhibited cyclin-dependent Moreover, Exo-Cur inhibited tau phosphorylation by kinase 5-mediated tau phosphorylation and reduced the activating the AKT/glycogen synthase kinase-3β pathway formation of insoluble neurofibrillary tangles, improving [114] [118] and the recovery of neuronal function in AD therapy . cognitive function in AD mice . Exogenous drug-loading methods have also been used to successfully load curcumin into many types of cell-de- Ber rived exosomes, such as curcumin-loaded embryonic Ber was directly mixed with exosomes derived from stem cell exosomes (MESC-Exo-Cur). Administration M2-type primary macrophages in mice using an of MESC-Exo-Cur via the nasal route in ischemia-in- [121] exogenous drug-loading method. The Ber content in jured mice improved the neurological score . Peng et [117] exosome-Ber (Exo-Ber) was 17.13 ± 1.64% after ultrason- al. developed another complex strategy in which they ication. Exo-Ber was slowly released in vitro. At 48 h, the embedded curcumin micelles into functionalized MSC- cumulative release reached 71.44 ± 2.86%. The AUC derived exosomes to create a self-oriented nanocarrier, 0–inf of Exo-Ber was three times higher than that of the free PR-EXO/PP@Cur. The loading capacity of curcumin in Ber. Exo-Ber can be efficiently targeted to deliver drugs the nanocarrier was 75.53%. It can resist the clearance to the injured spinal cord owing to the natural advantage of the nasal mucosa across multiple membrane barriers of exosomes across the BBB. Exo-Ber had anti-inflamma- and accurately identify target neuronal cells after intra- tory and anti-apoptotic effects by inducing macrophage nasal administration. Curcumin accumulation at the or microglial polarization from the M1 phenotype to the action site effectively reduces α-syn aggregates, promotes M2 phenotype. Moreover, Exo-Ber treatment significantly neuron function recovery, alleviates neuroinflammation, [119] improved motor function in SCI mice . and improves movement and coordination ability in PD [117] model mice . Conclusions and perspectives Silibinin NDs are characterized by nervous system damage, mainly caused by misfolded protein aggregation, inflam- Silibinin, a flavonoid compound, has poor delivery across mation, oxidative stress, mitochondrial dysfunction, and the BBB, with a logP value of 0.86 and a molecular genetic mutations in the brain. BBB significantly limits weight of 482.44 Da. In addition, the low bioavailability the therapeutic efficacy of clinically approved drugs. of silibinin contributes to its poor clinical efficacy in NDs. [116] EVs are likely to solve this problem because they can Huo et al. isolated exosome-silibinin (Exo-Slb) by pass through the BBB and deliver drugs to the brain. co-incubating silibinin with RAW264.7 cells, an endog- Phytochemicals have proven to be preventive and thera- enous drug-loading method. The encapsulation effi- peutic compounds for NDs. However, several unresolved ciency and loading capacity of silibinin in exosomes were issues, such as instability, solubility, low bioavailabil- 41.8% and 21.2%, respectively. Exo-Slb can improve ity, inability to cross the BBB, and lack of selectivity the brain-targeting ability of silibinin. After entering the for brain lesion sites, limit the use of phytochemicals brain, Exo-Slb selectively interacts with Aβ monomers to to treat brain disease. Nano-sized EVs have a tendency reduce aggregation. Simultaneously, Exo-Slb is internal- to cross the BBB, attach to cellular membranes through ized in astrocytes to inhibit their activation and alleviate receptor–ligand interactions, release functional cargos, astrocyte inflammation-mediated neuronal damage, thus [116] and avoid the endosomal pathway and lysosomal degra- ameliorating cognitive deficits in AD mice . dation. In particular, exosomes are used to encapsulate phytochemicals to enhance their accumulation in the Resveratrol brain. Exosome products, such as ExoPr0, derived from [122] cyclophosphamide neural stem cells are approaching Resveratrol-primed exosomes (Exo-Res) secreted by pri- clinical trials for the treatment of NDs. In this review, mary microglia from rats were collected using an endog- we elucidated the emerging applications of phytochem- enous drug-loading method, which solved the problems ical-loaded EVs in ND treatment. A brief description of associated with drug solubility and bioavailability of the encapsulation strategies, mechanisms of action, and resveratrol. Additionally, Exo-Res displayed greater therapeutic outcomes in AD, PD, and other brain disor- enhancement of neuronal survival and increased autoph- ders was provided. agy rates, while reducing apoptosis levels than free res- [115] Notwithstanding, several challenges still exist before veratrol in spinal cord injury (SCI) model rats . phytochemical-loaded EVs can be used in clinical applications, including low reproducibility, limited Que drug-loading capacity, and safety concerns. First, the Que was encapsulated in blood plasma-derived exo- source of EVs is critical, and standardization of sep- somes using an exogenous drug-loading method. Que aration techniques suitable for mass production and had an encapsulation efficiency and drug-loading capac- high purification is required. Stem cells are an excel- ity of 30.00 ± 8.30% and 17.30 ± 6.34%, respectively. lent choice for the production of EVs. 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Acupunct Herb Med 2022;2(4):242–252. doi: 2013;95:1233–1238. 10.1097/HM9.0000000000000039
Journal
Acupuncture & Herbal Medicine – Wolters Kluwer Health
Published: Dec 26, 2022