Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Bloode-brain barrier(BBB)strictly controls matter exchange between blood and brain,and severely limits brain penetration of systemically administered drugs,resulting in ineffective drug therapy of brain diseases.However,during the onset and progression of brain diseases,BBB alterations evolve inevitably.In this review,we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer’s disease,Parkinson’s disease,epilepsy,stroke,traumatic brain injury and brain tumor.The advances on optimization of small molecules for BBB crossing and non-systemic administration routes(e.g.,intranasal treatment)for BBB bypassing are not included in this review.

Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer

Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the present work,gastrodin,the main bioactive ingredient of the traditional Chinese drug“Tianma”(Rhizoma Gastrodiae)was used as a model drug to explore reasonable application of borneol.Sustained-release solid dispersions(SRSDs)for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder.The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy,differential scanning calorimetry,and powder X-ray diffractometry.The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form.Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model.Subsequently,gastric mucosa irritation and the brain targeting of the SRSDs were evaluated.Compared with the free mixture of gastrodin and borneol,brain targeting of SRSDs was slightly weaker(brain targeting index:1.83 vs.2.09),but stomach irritation obviously reduced.Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.

Oral delivery of polyester nanoparticles for brain-targeting: Challenges and opportunities

Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance;and(4) restriction by the BBB. Then the key factors influencing brain-targeting efficiency of orally administered polyester nanoparticles are also discussed, such as size, shape and surface properties. Finally, recent brain-targeting delivery strategies using oral polyester nanoparticles as carriers and their effects on brain drugs transport are reviewed, and the delivery ‘as a whole’ strategy of polyester nanoparticles will provide new insight for oral brain-targeting delivery. And by combination of multiple strategies, both the stability and permeability of polyester nanoparticles can be greatly improved for oral brain drug delivery.

Extracellular vesicle–based drug delivery system boosts phytochemicals’therapeutic effect for neurodegenerative diseases

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.

Potential Alzheimer’s disease therapeutic nano-platform: Discovery of amyloid-beta plaque disaggregating agent and brain-targeted delivery system using porous silicon nanoparticles

There has been a lot of basic and clinical research on Alzheimer’s disease(AD)over the last 100 years,but its mechanisms and treatments have not been fully clarified.Despite some controversies,the amyloid-beta hypothesis is one of the most widely accepted causes of AD.In this study,we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles(pSiNPs)as a therapeutic nano-platform to overcome AD.We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library.As a result of the in vitro assay of amyloid plaques and library screening,we confirmed that 6-amino-2-naphthalenesulfonic acid(ANA)showed the highest efficacy for plaque disaggregation as a hit compound.To confirm the targeted delivery of ANA to the AD brain,a nano-platform was created using porous silicon nanoparticles(pSiNPs)with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol(PEG)surface functionalization.The resulting nano-formulation,named Biotin-CaCl2-ANA-pSiNPs(BCAP),delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain.This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.

Intranasal administration nanosystems for brain-targeted drug delivery

The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,Parkinson’s disease(PD),and Alzheimer’s disease(AD).With the advantage of bypassing the BBB and avoiding systemic distribution,intranasal administration has emerged as an alternative method of delivering drugs to the brain.Drug delivery directly to the brain using intranasal nanosystems represents a new paradigm for neurological disease treatment because of its advantages in improving drug solubility and stability in vivo,enabling targeted drug delivery and controlled release,and reducing non-specific toxicity.And it has shown efficacy in animal models and clinical applications.Herein,this review describes the mechanisms of intranasal delivery of brain-targeted drugs,the properties of nanosystems for intranasal administration(e.g.,liposomes,nanoemulsions,and micelles),and strategies for intranasal drug delivery to enhance brain-targeted drug delivery.Recent applications of nanosystems in intranasal drug delivery and disease treatment have been comprehensively reviewed.Although encouraging results have been reported,significant challenges still need to be overcome to translate these nanosystems into clinics.Therefore,the future prospects of intranasal drug delivery nanosystems are discussed in depth,expecting to provide useful insights and guidance for effective neurological disease treatment.

Emerging transporter-targeted nanoparticulate drug delivery systems

Transporter-targeted nanoparticulate drug delivery systems(nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed,focusing on the specific transporter-based targeting strategies. Recent developments in transportermediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.

Studies on tissue distribution of scutellarin and methyl polyethylene glycol (mPEG)-scutellarin prodrug in mice

This study was to determine tissue distribution and pharmacokinetics of mPEG-scutellarin prodrug(7e),a chemical entity previously shown to have a beneficial effect in cerebral ischemia/reperfusion(I/R)injury.After injecting scutellarin or prodrug 7e,the concentrations of scutellarin and 7e in tissues were determined and the pharmacokinetic parameters were calculated.The results showed that the distribution of scutellarin in tissues was enhanced by PEGylation.The distribution of 7e in brain was approximately 2.1-fold higher than that of scutellarin,indicating that PEGylation increased the brain penetration of scutellarin.We conclude that 7e could exert more effective protection on cerebral I/R injury in mice.This study also provided a simple and convenient strategy to identify novel drugs with potential protective function for I/R injury in mice.

Synergistic effects of IL-3 release and Mn^(2+)-doped Prussian blue nanoparticles camouflaged with MES23.5 cell membranes on Alzheimer’s disease therapy

Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder with prolonged latency during the prodromal stage.However,current clinical approaches to pharmacological interventions for AD remain challenge.An effective treatment strategy is to eliminate protein aggregates and prevent their regeneration.In this study,interleukin(IL)-3-loaded porous manganese(Mn^(2+))-doped Prussian blue(PB)nanoparticles(NPs)were coated with dopaminergic MEs23.5 neuronal cell membranes(PBMn-IL3@CM)and then used to combat AD progression.The PBMn-IL3@CM NPs possessed a high targeting efficiency,being able to traverse the blood-brain barrier and specifically affect the brain to reduce oxidative stress.The Mn2-doped PB NPs effectively scavenged reactive oxygen radicals produced by microglia,inducing the pro-inflammatory M1 microglia.In addition,the released IL-3 activated microglia,causing the polarization of the M1 phenotype to the anti-inflammatory M2 phenotype in vitro and in vivo.The transition reduced phosphorylated tau accumulation,mediated neurotoxicity,and eliminated tau aggregates,which reversed cognitive impairment in AD mice.The PBMn-IL3@CM NPs showed excellent biocompatibility without significant adverse effects;consequently,they represent a promising AD treatment.