Enhanced Brain Uptake Research Articles

Intranasal bilosomes in thermosensitive hydrogel: advancing desvenlafaxine succinate delivery for depression management

Depression, the second biggest cause of disability worldwide, is widespread. Many antidepressant medications, including Desvenlafaxine Succinate (D.V.S.), function by elevating neurotransmitter levels at the synapse through the inhibition of reabsorption by neurons. However, the effectiveness of these treatments is often limited by their inability to reach the brain using conventional administration methods. Bilosome-stabilized nanovesicles containing bile salts have drawn much interest because of their adaptability and versatility in various applications. This study aimed to address this issue by formulating intranasal bilosomes incorporated into a mucoadhesive in situ gel to deliver D.V.S. directly to the brain for depression treatment. The desvenlafaxine-loaded bilosomes were developed using a thin film hydration method based on the l-optimal design. They were intended to provide a more convenient route of administration for antidepressants, enhancing bioavailability and brain targeting through intranasal delivery. The study assessed the optimized bilosomes for particle size (311.21 ± 0.42 nm), Zeta potential (–37.35 ± 0.43)and encapsulation efficiency (99.53 ± 0.41%) and further evaluated them in ex vivo and in vivo pharmacokinetics studies. Pharmacokinetic data reveal enhanced brain uptake compared to a free drug. A statistically optimized bilosome formulation was determined. The intranasal administration of mucoadhesive in situ gel containing desvenlafaxine succinate-loaded bilosomes facilitated direct nose-to-brain drug delivery, improving brain bioavailability.

[18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) PET imaging repurposed for quantitative estimation of blood-brain barrier permeability in a rat model of Alzheimer's disease

Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS), which can be easily obtained from simple chemical reduction of commercial [18F]2-fluoro-2-deoxy-glucose ([18F]FDG), was investigated as a small-molecule marker of BBB permeability, in a pre-clinical model of AD using in vivo PET imaging. Chemical reduction of [18F]FDG to [18F]FDS was obtained with a 100% conversion yield. Dynamic PET acquisitions were performed in the APP/PS1 rat model of AD (TgF344-AD, n=3) compared with age-matched littermates (WT, n=4). The brain uptake of [18F]FDS was determined in selected brain regions, delineated from a coregistered rat brain template. The brain uptake of [18F]FDS in the brain regions of AD rats versus WT rats was compared using a 2-way ANOVA. The uptake of [18F]FDS was significantly higher in the whole brain of AD rats, as compared with WT rats (P<0.001), suggesting increased BBB permeability. Enhanced brain uptake of [18F]FDS in AD rats was significantly different across brain regions (P<0.001). Minimum difference was observed in the amygdala (+89.0±7.6%, P<0.001) and maximum difference was observed in the midbrain (+177.8±29.2%, P<0.001). [18F]FDS, initially proposed as radio-pharmaceutical to estimate renal filtration using PET imaging, can be repurposed for non-invasive and quantitative determination of BBB permeability in vivo. Making the best with the quantitative properties of PET imaging, it was possible to estimate the extent of enhanced BBB permeability in a rat model of AD.

Intranasal delivery of poly (d-glucosamine) encrusted self-assembled lipidic nanovesicles to enhanced brain uptake of thymoquinone for management of Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is a grade IV primary malignant brain tumour, which is highly infiltrative and exhibits a poor prognosis which results in high mortality. Low solubility and stability are the major hurdles faced while developing drug delivery systems for the treatment of GBM. Therefore, this study focuses on the enhancement of brain uptake of thymoquinone (TH) by formulating poly (d-glucosamine) self-assembled lipidic nanovesicles for intranasal delivery using 3-level and 3-factor central composite design (CCD). The nanovesicles were formulated using thin film hydration technique and were spherical with the particle size of 129.13 ± 2.3 nm and 32.4 ± 2.4 mV of zeta potential. The formulation exhibited high entrapment and drug loading of TH i.e., 95.07 ± 0.8 % and 8.91 ± 0.2 % respectively. The nanovesicles attained a sustained release of TH of 89.62 ± 2.9 % in 48 h with improved drug permeation of 41.89 ± 1.61 % in 12 h from nasal mucosa with enhanced mucoadhesion of 72.98 ± 1.78 %. The in-vitro cellular studies indicated the high anticancer potential of TH by lowering the cell viability to 32.90 ± 0.91 % at 25 μg/mL (IC50;21.10 μg/mL) and high radical scavenging of 69.35 ± 1.91 % (IC50;18.10 μg/mL) and improved cellular uptake of 48.71 ± 0.10ng/100 cells. Greater bioavailability of TH in CNS (∼3 folds that of IV solution) was observed along with a high drug-targeting percentage (98.1 ± 3.90 %) and drug-targeting index (11.67 ± 1.87 %) post-intranasal administration of the formulation. Quantitative uptake of the formulation was estimated using fluorescence imaging, which showed higher uptake in tissues of the brain. The formulation was having very less hemolysis (<8 %). Hence the formulated carriers can be a promising tool for the treatment of GBM.

Enhanced Bioavailability and Higher Uptake of Brain-Targeted Surface Engineered Delivery System of Naringenin developed as a Therapeutic for Autism Spectrum Disorder.

Neuroinflammation resulting from oxidative and nitrosative stress is associated with various neurological disorders and involves the generation of pro-inflammatory cytokines and microglial activation. Dietary phytochemicals are safer and more valuable adjunct neurotherapeutic agents which can be added to the therapeutic regimen. These compounds provide neuroprotection by the modulation of various signaling pathways. Naringenin (NGN) is a phytochemical having low oral bioavailability because of poor solubility, and adding to this limitation is enhanced efflux by P-glycoprotein transporters in neuroinflammatory diseases. Hence, as a solution for these limitations, naringenin encapsulated poly-lactic-co-glycolic acid (PLGA) nanocarriers were developed using the nanoprecipitation technique and coated with 1% glutathione (GSH) and 1% Tween 80 to enhance brain delivery. Coated and uncoated NGN-PLGA nanoparticles (NGN-PLGA-NPs) were spherical, monodispersed, stable, and non-toxic, with a particle size of less than 200 nm. They had negative zeta-potential values, 80% entrapment efficiency, and sustained drug release of 81.8% (uncoated), 80.13%, and 78.43% (coated) in 24 hours. FT-IR, DSC, PXRD, and NMR confirmed the drug encapsulation and coating over nanoparticles. In vivo brain uptake showed greater fluorescence intensity of the coated nanoparticles in the brain than uncoated nanoparticles. In addition, there was a 2.33-fold increase in bioavailability after coating compared to naringenin suspension and enhanced brain uptake. Present studies indicate sustained and targeted brain delivery of naringenin via the ligandcoated delivery system by inhibiting enhanced P-glycoprotein (P-gp) efflux occurring in autism spectrum disorders due to neuroinflammation.

Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates 8-10 featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound 6 in the cAMP GloSensor assays. Radiolabeling of compounds 8 and 9 (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [18F]9 in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [18F]6. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [18F]9. As a selective ligand, [18F]9 has the potential to be developed for translational studies.

Enhanced Brain Uptake and Behaviour Study of Buspirone Loaded in situ Nanoemulsion Gel

Enhanced Brain Uptake and Behaviour Study of Buspirone Loaded in situ Nanoemulsion Gel

Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel.

This paper reports the use of a self‐assembling hydrogel as a delivery vehicle for the Parkinson's disease drug l‐DOPA. Based on a two‐component combination of an l‐glutamine amide derivative and benzaldehyde, this gel has very soft rheological properties and self‐healing characteristics. It is demonstrated that the gel can be formulated to encapsulate l‐DOPA. These drug‐loaded gels are characterized, and rapid release of the drug is obtained from the gel network. This drug‐loaded hydrogel has appropriate rheological characteristics to be amenable for injection. This system is therefore tested as a vehicle for nasal delivery of neurologically‐active drugs—a drug delivery strategy that can potentially avoid first pass liver metabolism and bypass the blood–brain barrier, hence enhancing brain uptake. In vitro tests indicate that the gel has biocompatibility with respect to nasal epithelial cells. Furthermore, animal studies demonstrate that the nasal delivery of a gel loaded with 3H‐labeled l‐DOPA out‐performed a simple intranasal l‐DOPA solution. This is attributed to longer residence times of the gel in the nasal cavity resulting in increased blood and brain concentrations. It is demonstrated that the likely routes of brain penetration of intranasally‐delivered l‐DOPA gel involve the trigeminal and olfactory nerves connecting to other brain regions.

QbD-steered development of mixed nanomicelles of galantamine: Demonstration of enhanced brain uptake, prolonged systemic retention and improved biopharmaceutical attributes

PurposeNumerous oral treatment options have been reported for neurological disorders, especially Alzheimer’s disease (AD). Galantamine (GAL) is one of such drugs duly approved for management of AD. However, it exhibits poor brain penetration, low intestinal permeation and requires frequent dosing in AD treatment. The present studies, accordingly, were undertaken to develop DSPE-PEG 2000-based micelles loaded with GAL for efficient brain uptake, improved and extended pharmacokinetics, along with reduced dosing regimen. MethodsMixed nanomicelles (MNMs) were systematically formulated using QbD approach, and characterized for morphology, entrapment efficiency andin vitrodrug release. ResultsStudies on CaCo-2 and neuronal U-87 cell lines exhibited substantial enhancement in the cellular permeability and uptake of the developed MNMs. Pharmacokinetic studies performed on rats showed significantly improved values of plasma AUC (i.e., 2.28-fold, p < 0.001), ostensibly due to bypassing of hepatic first-pass metabolism and improved intestinal permeability, together with significant rise in MRT (2.08-fold, p < 0.001) and tmax (4.80-fold; p < 0.001) values, indicating immense potential for prolonged drug residence in body.Besides, substantial elevation in brain drug levels, distinctly improved levels of biochemical parameters in brain homogenates and cognitive improvement in β-amyloid-treated rats, testify the superiority in MNMs in therapeutic management of AD. ConclusionsThe preclinical findings of the developed nanocarrier systems successfully demonstrate the notable potential of enhanced drug efficacy, extended duration of action and improved patient compliance.

Physical stability and in vivo brain delivery of polymeric ibuprofen nanoparticles fabricated by flash nanoprecipitation

Ibuprofen (IBP), a common non-steroidal anti-inflammatory drug (NSAID) with a log P of 3.51, has been shown to possess potential benefit in the treatment of Alzheimer’s disease. However, the bioavailability of IBP to the brain is poor, which can be linked to its extensive binding to plasma proteins in the blood. This study aimed to evaluate the nanoparticle production of IBP by flash nanoprecipitation (FNP) technology, and to determine whether the nanoparticles prepared by FNP could enhance the delivery of IBP into the brain. Polymeric IBP nanoparticles were prepared with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) diblock copolymer as stabilizer under optimized conditions using a four-stream multi-inlet vortex mixer (MIVM). The optimized nanoparticles displayed a mean particle size of around 50 nm, polydispersity index of around 0.2, drug loading of up to 30% and physical stability of up to 34 days. In-depth surface characterization using zeta potential measurement, atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) showed that the surfaces of these nanoparticles were covered with the hydrophilic PEG groups from the diblock copolymer. In vivo brain uptake study of the IBP nanoparticles indicated that the particles, when coated with polysorbate 80, displayed an enhanced brain uptake. However, the extent of brain uptake enhancement appeared limited, possibly due to a rapid release of IBP from the nanoparticles into the blood stream following intravenous administration.

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-\u03b2 antibody in a mouse model of Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants – RmAb158, the recombinant murine version of BAN2401, which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients, and the bispecific RmAb158-scFv8D3, which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis.MethodsA single intravenous injection of iodine-125 (125I)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice (tg-ArcSwe). In vivo single-photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks. Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβ and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with Aβ.ResultsDespite faster blood clearance, [125I]RmAb158-scFv8D3 displayed higher brain exposure than [125I]RmAb158 throughout the study. The brain distribution of [125I]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology, while [125I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times. Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for [125I]RmAb158-scFv8D3, whereas [125I]RmAb158 displayed retention and Aβ interactions in lateral ventricles.ConclusionsThe high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging. Moreover, it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle.

Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid-β (Aβ) antibody bapineuzumab (Bapi). TXB2-hFc displayed 20-fold higher brain concentrations compared with a control VNAR-hFc at 18hours post-injection in wt mice. At the same time point, brain concentrations of Bapi-TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain-to-blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi-TXB2 and Bapi was observed for up to 6days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi-TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.

Enhanced nose-to-brain delivery of tranilast using liquid crystal formulations

Intranasal administration is poised as a competent method in delivering drugs to the brain, because the nasal route has a direct link with the central nervous system bypassing the formidable blood-brain barrier. C17-monoglycerol ester (MGE) and glyceryl monooleate (GMO) as liquid crystal (LC)-forming lipids possess desirable formulation characteristics as drug carriers for intranasally administered drugs. This study investigated the effect of LC formulations on the pharmacokinetics of tranilast (TL), a lipophilic model drug, and its distribution in the therapeutic target regions of the brain in rats. The anatomical biodistribution of LC formulations was monitored using micro-computed tomography tandem in vivo imaging systems. MGE and GMO effectively formed LC with suitable particle size, zeta potential, and viscosity supporting the delivery of TL to the brain. MGE and GMO LC formulations enhanced brain uptake by 10- to 12-fold and 2- to 2.4- fold, respectively, compared with TL solution. The olfactory bulb had the highest TL concentration and fluorescent signals among all the brain regions, indicating a direct nose-to-brain delivery pathway of LC formulations. LC-forming lipids, MGE and GMO, are potential biomaterials in formulations intended for intranasal administration.

Niosomes for nose-to-brain delivery of bromocriptine: Formulation development, efficacy evaluation and toxicity profiling

The present study aimed to formulate stable non-ionic surfactant vesicles incorporating Bromocriptine Mesylate (BCM) to enhance brain uptake via the direct nose to brain pathway. The optimized formulation prepared by ethanol injection method exhibited a size of 180 ± 4.5 nm, % encapsulation of 75.8 ± 3.6 and zeta potential of −14.2 ± 1.8 mV. Ex vivo study demonstrated 6.4 times enhancement in permeation across goat nasal mucosa at 24 h as compared to BCM drug suspension. The relative brain bioavailability, drug targeting efficiency and direct transport percentage of intranasal (i.n) niosomes was found to be 1045.51%, 1118.10% and 91.06% respectively, suggesting enhanced CNS targeting via the direct olfactory pathway. Group treated with BCM niosomes i.n revealed a marked attenuation of cataleptic time along with reduced lipid oxidation and restored Glutathione (GSH) levels in the brain. Sub-acute toxicity studies carried out for 28 days revealed no mortality or toxicologically significant changes. The combination of above results proved that BCM niosomes were safe to be administered i.n displaying manifold enhancement in brain distribution and improved pharmacodynamic behavior with 10 times dose reduction. Thus, such a system could be positively exploited as an alternative to oral delivery in the management of Parkinson's Disease (PD).

Inorganic clay nanocomposite system for improved cholinesterase inhibition and brain pharmacokinetics of donepezil

Objective: Brain drug delivery for effective treatment of neurodegenerative disorders is limited due to the selective permeability of blood brain barrier (BBB). During the past few years, development of novel delivery system has attracted considerable attention of formulation scientists to overcome the permeability limitation caused by BBB.Significance: Based on the outcomes of this study and taking into consideration of the unique characteristics of laponite, it can be further explored to deliver many other central nervous system acting drugs.Methods: In the present study, laponite (LAP) nanocomposites were exploited for the improved brain delivery of donepezil (DZ) following encapsulation approach due to their nano-size and positive charge at pH <9.Result: The size of prepared nanocomposites was 53.7 ± 4.0 to 137.7 ± 11.0 nm. The drug was released in a sustained manner till 120 h in phosphate buffer saline (pH 7.4) and acid phthalate buffer (pH 4.0). LAPDZ formulations inhibited acetylcholinesterase approximately by 82%, significantly higher (p < 0.05) than plain DZ (30%). Swiss albino mice exhibited enhanced brain uptake of LAPDZ administered via intravenous route. Promising pharmacokinetic parameters were observed in animals treated with LAPDZ. LAPDZ formulation showed half-life (t1/2), volume of distribution (Vd) and clearance (Cl) as 5.53 ± 0.40 h−1, 0.129 ± 0.02 L, 0.015 ± 0.002 L/h, respectively. While DZ solution showed the same parameters as 1.06 ± 0.12 h−1, 0.168 ± 0.01 L, 0.106 ± 0.013 L/h, respectively. The brain uptake of LAPDZ formulation was improved with quintuplet t1/2.Conclusion: Based on the results of present study, it is proposed that the formulated nanocomposite would result in improved patient compliance with therapeutic effect at lower doses.

Design and Biological Evaluation of Lipoprotein-Based Donepezil Nanocarrier for Enhanced Brain Uptake through Oral Delivery.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory and cognitive impairment. Donepezil is an acetylcholinesterase inhibitor used for the symptomatic treatment of AD. However, high dose of donepezil is prescribed to achieve effective concentration in the brain, which leads to significant side effects, gastrointestinal alterations, and hepatotoxicity. In the present study, ApoE3 conjugated polymeric nanoparticles derived from diblock copolymer methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL) have been used to boost the delivery of donepezil to the brain. mPEG-PCL is an amphiphilic diblock polymer with a tendency to avoid nanoparticle uptake by phagocytic cells in the liver and can significantly reduce the gastric mucosal irritations. Moreover, ApoE3-based nanocarriers showed a promising ability to enhance brain uptake, binding to amyloid beta with high affinity and accelerating its clearance. Donepezil-loaded polymeric nanoparticles were performed by using a nanoprecipitation method and further surface modified with polysorbate 80 and ApoE3 to increase the brain bioavailability and reduce the dose. Optimization of various process parameters were performed using quality by design approach. ApoE3 polymeric nanoparticles were found to be stable in simulated gastric fluids and exhibited a sustained drug release pattern. Cellular uptake studies confirmed better neuronal uptake of the developed formulation, which is further corroborated with pharmacokinetic and biodistribution studies. Orally administered ApoE3 polymeric nanoparticles resulted in significantly higher brain donepezil levels after 24 h (84.97 ± 11.54 ng/mg tissue) as compared to the pure drug (not detected), suggesting a significant role of surface coating. Together, these findings are promising and offer preclinical evidence for better brain availability of donepezil by oral administration.

Enhanced oral bioavailability and brain uptake of Darunavir using lipid nanoemulsion formulation.

The present work aimed to formulate Darunavir loaded lipid nanoemulsion to increase its oral bioavailability and enhance brain uptake. Various batches of lipid nanoemulsion of Darunavir were prepared by high pressure homogenization using soya bean oil, egg lecithin and Tween 80. The optimized batch DNE-3 had globule size of 109.5 nm, zeta potential of -41.1 mV, entrapment efficiency 93% and creaming volume 98%. The batch remained stable at 4 °C for 1 month with an insignificant change in globule size and zeta potential (P > 0.05). In-vivo pharmacokinetics male wistar rats indicated 223% bioavailability of Darunavir relative to drug suspension. Cmax of DNE-3 was twofold higher than suspension form. The organ biodistribution study indicated 2.65 fold higher brain uptake for DNE-3 than that for suspension. The higher bioavailability of Darunavir from nanoemulsion could lessen the dose related side effects. Moreover, high organ distribution results in passive uptake of Darunavir to HIV reservoir organs.

Small-Sized mPEG-PLGA Nanoparticles of Schisantherin A with Sustained Release for Enhanced Brain Uptake and Anti-Parkinsonian Activity.

Schisantherin A (SA) is a promising anti-Parkinsonism natural product. However, its poor water solubility and rapid serum clearance impose significant barriers to delivery of SA to the brain. This work aimed to develop SA in a nanoparticle formulation that extended SA circulation in the bloodstream and consequently an increased brain uptake and thus to be potentially efficacious for the treatment of Parkinson's disease (PD). Spherical SA nanoparticles with a mean particle size of 70 nm were prepared by encapsulating SA into methoxy poly(ethylene glycol)-block-poly(d,l)-lactic-co-glycolic acid (mPEG-PLGA) nanoparticles (SA-NPs) with an encapsulation efficiency of ∼91% and drug loading of ∼28%. The in vitro release of the SA-NPs lasted for 48 h with a sustained-release pattern. Using the Madin-Darby canine kidney (MDCK) cell model, the results showed that first intact nanoparticles carrying hydrophobic dyes were internalized into cells, then the dyes were slowly released within the cells, and last both nanoparticles and free dyes were externalized to the basolateral side of the cell monolayer. Fluorescence resonance energy transfer (FRET) imaging in zebrafish suggested that nanoparticles were gradually dissociated in vivo with time, and nanoparticles maintained intact in the intestine and brain at 2 h post-treatment. When SA-NPs were orally administrated to rats, much higher Cmax and AUC0-t were observed in the plasma than those of the SA suspension. Furthermore, brain delivery of SA was much more effective with SA-NPs than with SA suspension. In addition, the SA-NPs exerted strong neuroprotective effects in zebrafish and cell culture models of PD. The protective effect was partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. In summary, this study provides evidence that small-sized mPEG-PLGA nanoparticles may improve cross-barrier transportation, oral bioavailability, brain uptake, and bioactivity of this Biopharmaceutics Classification System (BCS) Class II compound, SA.

Synthesis and evaluation of copper-64 labeled benzofuran derivatives targeting β-amyloid aggregates

In vivo imaging of β-amyloid (Aβ) aggregates consisting of Aβ(1–40) and Aβ(1–42) peptides by positron emission tomography (PET) contributes to the diagnosis and therapy for Alzheimer’s disease (AD). Because 64Cu (t1/2=12.7h) is a radionuclide for PET with a longer physical half-life than 11C (t1/2=20min) and 18F (t1/2=110min), it is an attractive radionuclide for the development of Aβ imaging probes that are suitable for routine use. In the present study, we designed and synthesized two novel 64Cu labeled benzofuran derivatives and evaluated their utility as PET imaging probes for Aβ aggregates. In an in vitro binding assay, 6 and 8 showed binding affinity for Aβ(1–42) aggregates with a Ki value of 33 and 243nM, respectively. In addition, these probes bound to Aβ plaques deposited in the brain of an AD model mouse in vitro. In a biodistribution experiment using normal mice, these probes showed low brain uptake (0.33% and 0.36% ID/g) at 2min post-injection. Although refinement to enhance brain uptake is needed, [64Cu]6 and [64Cu]8 demonstrated the feasibility of developing novel PET probes for imaging Aβ aggregates.

Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies

The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies forneurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration invivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aβ reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.

Abstract B39: Surfactant coated nanoparticles for brain metastases: A brain uptake perspective

Abstract The global CNS pharmaceutical market is expected to grow significantly, overtaking the cardiovascular therapeutics market in the next 10 years. Although much work has been devoted to finding drugs that can cross the BBB into the brain, no single approach has worked for all drugs. The lack of technology to effectively cross the BBB or the blood-tumor barrier prevents researchers from providing effective therapeutics for most patients with brain disorders. Drug loaded nanoparticles (NPs) can hide the unfavorable drug's physicochemical characteristics, which hinders its ability to cross the BBB. In this study, we investigate the effect of different surfactant coatings, in a single or a blend form, on polymeric NPs loaded with model dyes and drugs on the brain drug uptake. Different NP formulations are conveyed using different cores ((Poly Lactic-co-Glycolic Acid (PLGA) and Chitosan) and coat materials (tweens, poloxamers, thiamine, polyethylene glycol (PEG), propylene glycol (PG) and spans). Chitosan core was formulated via ionic gelation technique. PLGA core was formulated via solvent evaporation technique. Different surfactants with different HLB (Hydrophilic Lipophilic Balance) values were applied as coating materials for the NPs. All NP formulations were characterized with respect to their size; charge, stability, in-vitro drug release to reach the optimal formulation. Female CD-1 mice were used to evaluate the drug brain uptake. Harvesting of the brain takes place within 60 seconds of animal sacrifice. Animals were euthanized, and brain tissue were removed and homogenized. Concentration of Rodamine B (Model dye) in the brain homogenates was analyzed via HPLC. The developed uncoated Chitosan NPs are in the size range of 50-100 nm with small polydispersity Index (PDI) (∼ 0.3) and a reproducible zeta potential of ∼ +19mV. After coating with tween-80 the zeta potential has decreased to -5 mV. The Tween-80 coated NPs were visualized via Transmission Electron Microscope (TEM). The particle size of the coated NP increased over the uncoated one from ∼ 100 nm to (150 - 200 nm). Finally, brain RodamineB concentration was significantly higher in case of tween-80 coated Chitosan and PLGA compared to uncoated NPs. The use of the novel drug carrier systems for drug targeting to brain is a promising alternative to conventional CNS therapy. The currently used polymers in this study are nontoxic, biodegradable, and biocompatible. The surfactant coated NPs for brain drug delivery is a promising technique to enhance brain uptake. The use of the surfactant coat could aid the solubilization of endothelial cell membrane lipids leading to membrane fluidization and enhanced drug permeability at the BBB. Citation Format: Mohamed I. Nounou, Salma Saudi, Ola Elnoweam, Dalia Alian, Amal El-Kamel. Surfactant coated nanoparticles for brain metastases: A brain uptake perspective. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B39.