Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease

Muntimadugu, Eameema; Dhommati, Raju; Jain, Anjali; Challa, Venu Gopala Swami; Shaheen, Mohamed A.; Khan, Wahid

doi:10.1016/j.ejps.2016.05.012

Cited by 201 publications

(68 citation statements)

References 48 publications

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“…5 This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat 29 was associated with worsening of activities in daily leaving and increased rates of infections and skin cancer, avagacestat 41 was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration. 42 Serious safety concerns for γ-secretase inhibitors remove γ-secretase from the role of appropriate target for the treatment of AD 43 until in depth studies on this key enzyme could help to therapeutically target γ-secretase in a safe way. 44 No γ-secretase modulators are currently studied in phase 1-3 clinical trials.…”

Section: Current Landscape In Treatment Research For Admentioning

confidence: 99%

Current and Future Treatments in Alzheimer Disease: An Update

Yiannopoulou

Papageorgiou

2020

J Cent Nerv Syst Dis

591

378

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Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

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Section: Current Landscape In Treatment Research For Admentioning

confidence: 99%

Current and Future Treatments in Alzheimer Disease: An Update

Yiannopoulou

Papageorgiou

2020

J Cent Nerv Syst Dis

591

378

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“…It is likely that the attachment of TMC-modified NPs in the mouse nasal cavity resulted in sustained absorption. 39,45 The Kel of HupA Lf-TMC NPs in plasma and the brain was minimal, reflecting good pharmacokinetic properties. Such evidence strongly suggests that Lf-TMC NPs may be a promising nanocarrier for delivery of HupA from the nose to brain for AD treatment.…”

Section: Biodistribution Studymentioning

confidence: 99%

“…8 In contrast, PLGA NPs are not as readily adsorbed by nasal mucosa, leading to breathing or nasal mucociliary clearance into the lungs. 45 No fluorescence was detected in the heart, liver, spleen, or kidneys. Although in vivo imaging of NPs in mice is only qualitative, this result further highlighted that intranasal administration of TMCand Lf-co-modified NPs increased drug-targeted delivery from the nose to brain.…”

mentioning

confidence: 99%

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Meng¹,

Wang²,

Hua³

et al. 2018

IJN

244

101

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Background Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer’s disease (AD). Purpose To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf)-conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment. Methods HupA Lf-TMC NPs were prepared using the emulsion–solvent evaporation method and optimized using the Box–Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography–tandem mass spectrometry. Results Optimized HupA Lf-TMC NPs had a particle size of 153.2±13.7 nm, polydispersity index of 0.229±0.078, zeta potential of +35.6±5.2 mV, drug entrapment efficiency of 73.8%±5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%±1.8%, which was significantly higher than that onto PLGA NPs (32.1%±2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively. Conclusion Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier.

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“…9,10 Furthermore, nose-to-brain drug delivery has been performed because of its advantages, including reduced drug delivery to nontarget sites, avoidance of hepatic first-pass metabolism, and convenience, for drugs such as rasagiline, alginate, tarenflurbil, and piperine. [11][12][13][14] Therefore, nose-to-brain drug delivery was used in the present study to improve the brainspecific targeting of rotigotine.…”

Section: Introductionmentioning

confidence: 99%

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

Yan¹,

Xu²,

Bi³

et al. 2018

IJN

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Introduction Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson’s disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference ( P <0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD. Conclusion Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.

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Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease

Cited by 201 publications

References 48 publications

Current and Future Treatments in Alzheimer Disease: An Update

Current and Future Treatments in Alzheimer Disease: An Update

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

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Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer's disease

Cited by 201 publications

References 48 publications

Current and Future Treatments in Alzheimer Disease: An Update

Current and Future Treatments in Alzheimer Disease: An Update

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer&rsquo;s disease

Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects

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Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease