Blood–brain barrier and laser technology for drug brain delivery

Here,we discuss an important problem in medicine as development of efctive strategies for brain drug delivery.This problem is related to the blood-brain barrier(BBB),which is a“customs”controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system(CNS).We show three interfaces of anatomical side of BBB and two functional types of BBB一physical and transporter barriers.Although this protective mechanism is essential for health of CNS,it also creates a hindrance to the entry of drugs into the brain.The BBB was discovered over 100 years ago but till now,there is no efective methods for brain drug delivery.There ane more than 70 approaches for overcoming BBB incuding physical,chenical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasi venes,challenge in performing,very costly or lim-itation of drug concentration.Photodynamic therapy(PDT)is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy.Nowadays,the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB.Here,we show the first sucoessful experimental results in this field discussing the adventures and disadv antages of PDT-related BBB disruption as well as altematives to overcome these limitations and possi ble mechanisms with new pathways for brain clearance via gly mphatic and lymphatic systems.

Ultrasound combined blood-brain barrier targeting brain delivery of four-in-one molecular aggregates for the enhancement of anesthetic efficacy and toxicity reduction via propofol-etomidate synergistically inhibition GABA receptor

To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simultaneously.Four-in-one molecular aggregates were prepared to implement this strategy,which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate(GMO)and sur-factant F127 through intermolecular forces.The blood-brain barrier(BBB)targeted lactoferrin(LF)is affixed to their surface,obtaining thefinal molecular aggregates.By employing lactoferrin enrich aggregates to the BBB,followed by ultrasound combine microbubbles to open the BBB,a remarkable 4.5-fold enhancement in brain drug delivery was achieved.The molecular aggregates group maintained sta-ble parameters of heart rate,diastolic blood pressure,and systolic blood pressure.A notable increase of more than twice therapeutic index(TI)value was observed,implying their higher anesthesia efficiency and reduced toxicity.Electroencephalo-gram(EEG)experiments demonstrate a significant elevation in the proportion of θ waves from 28%to 80%for aggregates,accompanied by a nearlyfivefold reduc-tion in the proportion ofθwaves,meaning a significant improvement in synergistic anesthesia effectiveness(interaction index 0.289)with lower drug dosage.Further-more,mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously,resulting in synergistic inhibition of GABA receptors.

The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

The effect of drug loading and multiple administration on the protein corona formation and brain delivery property of PEG-PLA nanoparticles

The presence of protein corona on the surface of nanoparticles modulates their physiological interactions such as cellular association and targeting property.It has been shown that α-mangostin(αM)-loaded poly(ethylene glycol)-poly(l-lactide)(PEG-PLA)nanoparticles(NP-αM)specifically increased low density lipoprotein receptor(LDLR)expression in microglia and improved clearance of amyloid beta(Aβ)after multiple administration.However,how do the nanoparticles cross the blood‒brain barrier and access microglia remain unknown.Here,we studied the brain delivery property of PEG-PLA nanoparticles under different conditions,finding that the nanoparticles exhibited higher brain transport efficiency and microglia uptake efficiency afterαM loading and multiple administration.To reveal the mechanism,we performed proteomic analysis to characterize the composition of protein corona formed under various conditions,finding that both drug loading and multiple dosing affect the composition of protein corona and subsequently influence the cellular uptake of nanoparticles in b.End3 and BV-2 cells.Complement proteins,immunoglobulins,RAB5A and CD36 were found to be enriched in the corona and associated with the process of nanoparticles uptake.Collectively,we bring a mechanistic understanding about the modulator role of protein corona on targeted drug delivery,and provide theoretical basis for engineering brain or microglia-specific targeted delivery system.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Nose-to-brain drug delivery approach：a key to easily accessing the brain for the treatment of Alzheimer＇s disease

Alzheimer＇s disease（AD）：AD,a neurodegenerative disorder and a significant cause of dementia throughout the world mostly affects the older adults but sometimes also seen in young age（early state AD）（Agrawal et al.,2017）.

Liposome based drug delivery as a potential treatment option for Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.

Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain

Indinavir is a protease inhibitor used in the treatment of HIV infection.However,it has limited efficacy in eradicating the virus in the brain due to efflux by P-glycoprotein(P-gp)expressed at the blood–brain barrier(BBB).The objective of this work was to develop an o/w lipid nanoemulsion(LNE)of indinavir using Tween 80 as co-emulsifier to improve its brain specific delivery.LNEs were prepared with different compositions and were characterized for globule size,polydispersity index,zeta potential and in vitro drug release.Five formulations were then evaluated for drug content,entrapment efficiency and stability after which brain uptake studies were carried out using fluorescent labeled LNEs and pharmacokinetic(PK)and tissue distribution studies were conducted after intravenous administration in mice.Brain uptake of indinavir was shown to be improved for a 1%Tween 80 containing formulation(F5)compared to a formulation containing 0.3%cholesterol(F2).In PK studies,the brain level of indinavir subsequent to administration of F5 was significantly(Po0.05)higher than produced by administration of a drug solution(2.44-fold)or a control nanoemulsion(F1)(1.48-fold)or formulation F2(1.6-fold).The increased brain specific accumulation of indinavir from F5 is probably due to enhanced low density lipoprotein-mediated endocytosis and P-gp inhibition by Tween 80 at the BBB.These results suggest Tween 80 containing LNEs could provide a simple but effective means of delivering indinavir to brain.

Non-invasive delivery of levodopa-loaded nanoparticles to the brain via lymphatic vasculature to enhance treatment of Parkinson’s disease

Levodopa(L-DOPA),a precursor of dopamine,is commonly prescribed for the treatment of the Parkinson’s disease(PD).However,oral administration of levodopa results in a high level of homocysteine in the peripheral circulation,thereby elevating the risk of cardiovascular disease,and limiting its clinical application.Here,we report a non-invasive method to deliver levodopa to the brain by delivering L-DOPA-loaded sub-50 nm nanoparticles via brain-lymphatic vasculature.The hydrophilic L-DOPA was successfully encapsulated into nanoparticles of tannic acid(TA)/polyvinyl alcohol(PVA)via hydrogen bonding using the flash nanocomplexation(FNC)process,resulting in a high L-DOPA-loading capacity and uniform size in a scalable manner.Pharmacodynamics analysis in a PD rat model demonstrated that the levels of dopamine and tyrosine hydroxylase,which indicate the dopaminergic neuron functions,were increased by 2-and 4-fold,respectively.Movement disorders and cerebral oxidative stress of the rats were significantly improved.This formulation exhibited a high degree of biocompatibility as evidenced by lack of induced inflammation or other pathological changes in major organs.This antioxidative and drug-delivery platform administered through the brain-lymphatic vasculature shows promise for clinical treatment of the PD.

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors

Worldwide,the incidence of primary brain tumors is on the rise.Unfortunately,noninvasive drug therapy is hampered by poor access of most drugs to the brain due to the insurmountable blood-brain barrier(BBB).Nanotechnology holds great promise for noninvasive therapy of severe brain diseases.Furthermore,recent bioconjugation strategies have enabled the invasion of the BBB via tailored-designed bioconjugates either with targeting moieties or alterations in the physicochemical and/or the pharmacokinetic parameters of central nervous system(CNS)active pharmaceutical ingredients.Multifunctional systems and new entities are being developed to target brain cells and tumor cells to resist the progression of brain tumors.Direct conjugation of an FDA-approved drug with a targeting moiety,diagnostic moiety,or pharmacokinetic-modifying moiety represents another current approach in combating brain tumors and metastases.Finally,genetic engineering,stem cells,and vaccinations are innovative nontraditional approaches described in different patents for the management of brain tumors and metastases.This review summarizes the recent technologies and patent applications in the past five years for the noninvasive treatment of glioblastoma and other brain tumors.Till now,there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases.Intensive research efforts are ongoing to bring novel CNS delivery systems to potential clinical application.

SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

Glial cell line-derived neurotrophic factor(GDNF),a disease-modifying drug for Parkinson’s disease(PD)is in Phase 2 clinical trials(EudraCT number:2011-003866-34),however it is administered by direct intrastriatal delivery via stereotaxy,which is accompanied with intracranial infection,brain tissue damage,and other complications.In addition,because of complex administration routes,clinical trials of GDNF have yielded contrary results,largely due to differences in dose and concentration brought by intracranial device.Herein,a small molecular agonist SC79 was screened to open blood-brain barrier(BBB)and promote GDNF liposomes to get into brain.SC79 reversibly reduces the expression of claudin-5,one of dominant tight junctions of BBB.Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control.Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70%and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%.Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection,improving patients’compliance and providing valuable research ideas for the clinic.