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The binding affinity of anti-Aβ1-42 MAb-decorated nanoliposomes to Aβ1-42 peptides in vitro and to amyloid deposits in post-mortem tissue

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... The latter is connected by a type I β-turn centered on G25 and S26 to a less regular second α-helix that spans residues K28 to G38 13 . This structural motif has also been found in Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) 14 . However, as the water content of this mixture is increased to approximately 80% to 90%, the Aβ(1-42) peptide sharply changes from a predominantly helical to a β-sheet structure. ...
... Moreover, the solved NMR structure showed that this conformational change is accompanied by the loss of the β-turn and part of the C-terminal α-helix, while the N-terminal helicity is maintained as the environment goes from apolar to essentially polar, with MD simulations revealing the formation of a possible antiparallel β-sheet comprising residues V18 to E22 and G37 to I41 15 . In these conditions, the structure of Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) also undergoes a significant decrease in C-terminal helicity, but maintains its β-turn structure between residues G25 and N27 14 . ...
... The STAB-MAb characterized in this study is a murine anti-Aβ monoclonal antibody that was developed with a therapeutic purpose. In a previously published study, this antibody has demonstrated picomolar affinities for both monomers (K D = 80 pM) and fibrils (K D = 130 pM) of Aβ(1-42) using SPR assays 27 . Immunohistochemistry and immunofluorescence staining further showed high binding affinities of STAB-MAb for diffuse, focal, and vascular amyloid deposits in mice and human samples. ...
Article
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Alzheimer´s Disease (AD) is one of the most common neurodegenerative disorders worldwide. Excess of β-amyloid (Aβ), a peptide with a high propensity to misfold and self-aggregate, is believed to be the major contributor to the observed neuronal degeneration and cognitive decline in AD. Here, we characterize the epitope of a novel anti-Aβ monoclonal antibody, the STAB-MAb, which has previously demonstrated picomolar affinities for both monomers (KD = 80 pM) and fibrils (KD = 130 pM) of Aβ(1–42) and has shown therapeutic efficacy in preclinical mouse models of AD. Our findings reveal a widespread epitope that embraces several key Aβ residues that have been previously described as important in the Aβ fibrillation process. Of note, STAB-MAb exhibits a stronger affinity for the N-terminus of Aβ and stabilizes an α-helix conformation in the central to N-terminal region of the peptide, in addition to disrupting a characteristic salt-bridge of a hairpin structure present in fibrils. The NMR derived epitope supports the observed results from ThT-monitored fluorescence and electron microscopy experiments, in which STAB-MAb was shown to inhibit the formation of aggregates and promote disruption of preformed fibrils. In combination with the published in vitro and in vivo assays, our study highlights STABMAb as a rare and versatile antibody with analytical, diagnostic and therapeutic efficacy.
... Here we have addressed the peripheral-sink hypothesis [19,21,26,27] by a multivalency approach involving conjugation of a recently in-house developed anti-Aβ monolclonal antibody [29,30] (referred to as STAB-MAb) to PEGylated liposomes. We limited our studies to stealth liposomes, since they are stable and offer the necessary attributes for detailed pharmaceutical characterization, reproducibility, up scaling and manufacturing processing. ...
... We first assessed the binding affinity of STAB-MAb for Aβ peptides and performed epitope mapping [29,30]. Accordingly, we used three different synthetic human Aβ peptides (1-40, 1-42 and 1-43) as well as different peptide fragments from the human sequence of Aβ 1-42 . ...
... Accordingly, we used three different synthetic human Aβ peptides (1-40, 1-42 and 1-43) as well as different peptide fragments from the human sequence of Aβ 1-42 . We further performed a comparison study between STAB-MAb and 6E10 MAb, a well-known commercially available anti-Aβ monoclonal antibody [20,22,29]. ...
... In a different approach, anti-A␤ mAb-conjugated liposomes, with mean diameters between 124 and 134 nm, were stable when incubated with serum proteins and were able to bind to A␤ monomers and fibrils in vitro [174]. Moreover, A␤-mAb-liposomes were found to bind amyloid deposits in post-mortem AD brain samples, suggesting their potential application in the diagnosis and therapy of AD. ...
... Anti-A␤ mAb in vitro Binding of A␤ monomers and fibrils in vitro; binding of amyloid deposits in post-mortem AD brain samples [174] Cardiolipin-rich liposomes conjugated with WGA NGF and curcumin in vitro Transport of NGF and curcumin across human BBB model in vitro; protection of SK-N-MC cells against A␤42 fibrils-induced apoptosis [175] Phospholipid-based gelatin NLC bFGF rats (intranasal) Enhanced concentrations in olfactory bulb and striatum; no damage of nasal mucosa; improved functional recovery and protected against chemically-induced neurodegeneration [181] Polymer-based nanoparticles Tetronic micelles conjugated with heparin bFGF in vitro Sustained release for 2 months without initial burst effect [185] PEG-b-PCL polymersomes conjugated with OX26 model peptide NC-1900 mice (i.v.) Improved scopolamine-induced learning and memory impairments [187] Polymersomes conjugated with hNgfEE hNgfEE (NGF mimetic peptide) ...
Article
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-? peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies.
... Similarly, Aβ 1-15 peptides encapsulated in PLGA NPs enhanced serum Abs responses; Balb/c mice immunized with Aβ 1-15 -loaded PLGA NPs had high circulating anti-Aβ Abs comparable to the response induced by the potent Freund's adjuvant [48]. Compared with active immunotherapy, anti-Aβ monoclonal Ab (Aβ-mAb)-decorated liposomes had higher affinities for Aβ monomers and fibrils [49], and Aβ-mAb nanoliposomes dramatically reduced circulating and brain levels of Aβ 1-40 and Aβ 1-42 in APP/PS1 mice. In addition, the ratio of phosphorylated to total Tau and the levels of glial fibrillary acidic protein and reactive glia decreased after Aβ-mAb nanoliposome treatment [50]. ...
... Agents with high affinity for Aβ are crucial for the development of potential novel therapeutics and diagnostics. Numerous molecules have been studied for improving Aβ affinity when decorating NPs, including PA or cardiolipin (22-60 nM) [65], curcumin (1-5 nM) [66], Aβ-mAb-decorated PACA NPs (700 pM for monomers and 300 pM for fibrils) [67] and Aβ-mAb-attached nanoliposomes (500 pM for fibrils) [49,68]. Additionally, Brambilla's group demonstrated that PEGylated NPs exhibited a high affinity for both soluble and serum Aβ monomers and soluble oligomers and possessed a drastically increased blood half-life [68]. ...
Article
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Alzheimer's disease, Parkinson's disease and stroke are the most common CNS diseases, all characterized by progressive cellular dysfunction and death in specific areas of the nervous system. Therapeutic development for these diseases has lagged behind other disease areas due to difficulties in early diagnosis, long disease courses and drug delivery challenges, not least due to the blood-brain barrier. Over recent decades, nanotechnology has been explored as a potential tool for the diagnosis, treatment and monitoring of CNS diseases. In this review, we describe the application of nanotechnology to common CNS diseases, highlighting disease pathogenesis and the underlying mechanisms and promising functional outcomes that make nanomaterials ideal candidates for early diagnosis and therapy. Moreover, we discuss the limitations of nanotechnology, and possible solutions.
... Antimouse CD71 IgG2a (clone RI7217) anti-transferin monoclonal antibody (Mab), mentioned as RI in this article, was from Biolegend. The monoclonal antibody against Aβ1-42 (Aβ-Mab), was produced by Stab Vida (Portugal), as previously described [11,18]. ...
... The lipid compositions of all the nanoliposomes (NLs) used for hemocompatibility tests are presented in Table 1 and their physicochemical properties are shown in Table 2. The formation of all the types of NLs was done without encountering any problems, since the applied procedures have been optimized before [13][14][15][16][17][18], especially for the liposomes that incorporate the curcumin derivatives in their lipid membrane and/or are decorated on their surface with two or more ligands. The incorporation of the lipid-curcumin derivatives was performed (as explained above), by mixing the appropriate amount of presynthesized lipid derivatives, before the formation of the thin-lipid film [13][14][15][16]. ...
Article
Targeted liposomes with different combinations of five ligands (for brain/amyloid targeting) were evaluated for hemocompatibility. Results reveal that all liposomes studied, caused minimum hemolysis; targeted liposomes slightly reduced blood coagulation time, but not significantly more than control liposomes; and compliment factors SC5b9 and iC3b increased when compared with the buffer, by most targeted liposomes. However, the specific amounts of both factors were similar with those induced by control liposomes. Thus, the targeted liposomes are unanticipated to cause hypersensitivity problems. Good correlations between vesicle size and produced factor amounts were observed. In conclusion, the current targeted liposomes are not expected to cause serious blood toxicity, if used in vivo.
... Nanoparticulate systems functionalized with Ab-specific ligands are considered promising vehicles for imaging probes and as therapeutic agents for neurodegenerative diseases such as AD 192 . The NLs can be used as carriers of peptides that inhibit the protein aggregation of AD. ...
Article
Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood-brain barrier (BBB). In order to solve these problems, nanoparticulate systems with dimensions of 1–1000 nm able to incorporate small and macromolecules with therapeutic value, to protect and deliver them directly to the brain, have recently been developed, but their use for targeting polyQ disease-mediated protein misfolding and aggregation remains scarce. This review provides an update of the polyQ protein aggregation process and the development of therapeutic strategies for halting it. The main features that a nanoparticulate system should possess in order to enhance brain delivery are discussed, as well as the different types of materials utilized to produce them. The final part of this review focuses on the potential application of nanoparticulate system strategies to improve the specific and efficient delivery of therapeutic agents to the brain for the treatment of polyQ diseases.
... The development of nanotechnology has provided useful strategies for Aβ-targeting therapy. Nanocarriers such as anti-Aβ 1−42 mAb-decorated nanoliposomes, 5 curcumin-decorated nanoliposomes, 6 curcumin-conjugated magnetic nanoparticles, 7 and phosphatidic acid and cardiolipin-based lipid nanocarrier 8,9 have been developed and showed high affinity to Aβ and their aggregates. However, most of these nanocarriers lack permeability across the blood−brain barrier (BBB), which locates at the level of the cerebral microvasculature, is critical for maintaining the homeostasis of the central nervous system (CNS), but represents a major obstacle to the brain drug delivery. ...
Article
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Amyloid beta (Aβ) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer’s disease (AD). Therefore, the development of nanocarriers that possess both blood–brain barrier permeability and Aβ-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aβ oligomers and fibrils and accelerate Aβ cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aβ aggregates. Following the loading of α-M, the Aβ-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aβ1–42 was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.
... ζ-potential was determined by using an interferometic Doppler velocimetry with the same instrument equipped with ZetaPALS device. Liposomes stability was determined following the size and PDI in physiological buffer by DLS for 7 days, and by measuring the calcein release from liposomes in physiological buffer and in mouse plasma following the procedure already described [18]. ...
Article
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Aim: To investigate if and how the ability of liposomes, previously designed for Alzheimer's therapy, to reach the brain changes in aging/pathological conditions with respect to the healthy state. Methods: Biodistribution and pharmacokinetics of liposomes in young or aged healthy mice and in an Alzheimer's mouse model were measured by radiochemical techniques. The expression of brain receptors and structural proteins was evaluated by Western blot. Results: At equal blood levels, the amount and integrity of liposomes in the brain were dramatically lower in Alzheimer's or aged mice, with respect to young animals. These differences are likely attributable to molecular alterations in the brain vasculature. Conclusion: Brain alterations in pathology or aging should be considered in the design of drug delivery systems for brain targeting.
... In an in vitro study, Canovi et al. (2011) showed that nano-liposomes decorated with an anti-Aβ monoclonal antibody (Aβ-MAb) have a strong potential as vector for targeting Aβ 1−42 peptides in vitro and plaque deposits in postmortem AD tissue. In addition to antibody-based targeting agents, several types of amyloid-specific cell receptor ligands are employed for targeted delivery of drug carriers across BBB. ...
Article
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Alzheimer disease (AD) is characterized by cognitive inability manifested through the accumulation of β-amyloid, formation of hyper phosphorylated neurofibrillary tangles (NFT’s) and malfunctioned cholinergic system. The degeneration integrity of neuronal network can appear long after the onset of disease. Nanotechnology based interventions has opened an exciting area via theranostics of AD in terms of tailored nanomedicine, which are able to target and deliver drugs across the blood brain barrier (BBB). The exciting interface of medicinal plants and nanotechnology is an emerging feat in medicine, which has delivered promising results in the treatment of AD. In order to assess the potential applications of the medicinal plants, their derived components and various nanomedicinal approaches, a review of literature was deemed as necessary. In the present review, numerous phytochemicals and various feats in nanomedicine for the treatment of AD has been discussed mechanistically for the first time. Furthermore, recent trends in nanotechnology like green synthesis of metal nanoparticles with reference to the treatment of AD have been elaborated. Foreseeing the recent progress, we hope that the interface of medicinal plants and nanotechnology will result in highly effective theranostic strategies for the treatment of AD in near future.
... Thus can be the utilized as promising carrier for the diagnosis and AD treatment. 176 Mourtas et al. developed curcumin-phospholipid conjugate liposomes for AD treatment. The in-vitro results revealed higher affinity of liposomes to Aβ fibrils with much lower affinity to Aβ monomers. ...
Article
Therapeutics and biotherapeutics-based fabrication of nanoparticles has fascinated scientists since the past two decades and exciting challenges have been surmounted. Particular interest has been paid to the exploitation of functionalized nanocarriers in the treatment of Alzheimer's disease (AD) using nasal route. Development of various material-based nanocarriers is a common approach to obtain advanced drug delivery systems possessing the ability to follow intranasal (IN) route for brain targeting, which would ultimately ameliorate the effect of AD. This review highlights the various pathological theories for AD along with their controversies. This work intends to provide a thorough, up-to-date, and holistic discussion on various pathways for nose-to-brain delivery and different formulation factors impacting on nasal absorption. The various material properties and their engineered nanocarriers as a smart delivery system, including synergistic effect of therapeutic/biotherapeutic agent in IN delivery as well as in AD therapy have been discussed. This review also emphasizes toxicity, especially neurotoxicity concerns pertaining to drug delivery systems.
... In an another study it has been observed that these NLs have greater affinity towards Aβ and diminished the toxicity of these peptides in ex-vivo condition [61]. Canovi et al. developed NL formulation with anti-Aβ mAb, indicating higher affinity for Aβ in ex-vivo as well as in vivo studies [62]. In addition to these, Mourtas et al. developed another formulation of NL with curcumin derivative, which displayed high affinity towards Aβ and inhibited Aβ aggregation in an in vitro model [63,64]. ...
Article
Conventional drug delivery systems are inadequate in providing essential cyto-architecture restoration and connection patterns because of restrictions posed by the restrictive blood-brain barrier. Nanotechnological approaches involve various nano-sized carrier systems and other devices, which stimulate the action of therapeutic agents on molecular level and revolutionized the treatment and diagnosis of neurodegenerative disorders with minimal side effects. Over the conventional approaches, nanotechnological approaches have various promising strategies to cross blood brain barrier and increase the bioavailability of therapeutics in brain. This review article emphasizes the current and future utility of nano drug delivery systems for the treatment of various neurodegenerative disorders.
... Examples of surface decorated nanoliposomes proposed for AD diagnosis/therapy include phosphatidic acid (PA) and cardiolipin (CL) nanoliposomes which were able to target aggregated forms of Aβ1-42 with high binding affinity (KD: 22-60 nM) [18]. Additionally, nanoliposomes decorated with curcumin derivatives demonstrated high affinity for Aβ1-42 fibrils (KD: 1-5 nM) and sufficient integrity/stability for in vivo applications [19], while anti-Aβ monoclonal antibody (Aβ-MAb) decorated nanoliposomes demonstrated high affinity towards Aβ monomers and fibrils (with KD values between 0.5 and 2 nM) [20]. Also, nanoliposomes which were decorated with tetracycline derivatives [21] and non-planar curcumin derivatives [19,22,23] were efficient in delaying the aggregation of Aβ peptide monomers. ...
Article
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Amyloid β (Aβ) species are considered as potential targets for the development of diagnostics/therapeutics towards Alzheimer’s disease (AD). Nanoliposomes which are decorated with molecules having high affinity for Aβ species may be considered as potential carriers for AD theragnostics. Herein, benzothiazolyl (BTH) decorated nanoliposomes were prepared for the first time, after synthesis of a lipidic BTH derivative (lipid-BTH). The synthetic pathway included acylation of bis(2-aminophenyl) disulfide with palmitic acid or palmitoyl chloride and subsequent reduction of the oxidized dithiol derivative. The liberated thiols were able to cyclize to the corresponding benzothiazolyl derivatives only after acidification of the reaction mixture. Each step of the procedure was monitored by HPLC analysis in order to identify all the important parameters for the formation of the BTH-group. Finally, the optimal methodology was identified, and was applied for the synthesis of the lipid-BTH derivative. BTH-decorated nanoliposomes were then prepared and characterized for physicochemical properties (size distribution, surface charge, physical stability, and membrane integrity during incubation in presence of buffer and plasma proteins). Pegylated BTH-nanoliposomes were demonstrated to have high integrity in the presence of proteins (in comparison to non-peglated ones) justifying their further exploitation as potential theragnostic systems for AD.
... The high affinity of these liposomes in vitro to Aβ oligomers, but not to monomers, suggests that they may be useful for the targeted delivery of diagnostic and therapeutic compounds in animal models of AD and clinical trials (Gobbi et al., 2010). Canovi et al. (2011) prepared PEGylated nanoliposomes functionalized with anti-Aβ monoclonal antibodies. The results showed significant binding of the liposomes to Aβ monomers and fibrils in vitro, with a twofold higher affinity for the fibrils. ...
Article
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Alzheimer’s disease as a progressive and fatal neurodegenerative disease represents a huge unmet need for treatment. The low efficacy of current treatment methods is not only due to low drug potency, but also to the presence of various obstacles in the delivery routes. One of the main barriers is the blood-brain barrier. The increasing prevalence of Alzheimer’s disease and the low efficacy of current therapies have increased the amount of research on unraveling of disease pathways and development of treatment strategies. One of the interesting areas for the latter subject are biomaterials and their applications. This interest originates from the fact that biomaterials are very useful for the delivery of therapeutic agents such as drugs, proteins and/or cells, in order to treat diseases and regenerate tissues. Recently, manufacturing of nano-sized delivery systems has increased the efficacy and delivery potential of biomaterials. In this article, we review the latest developments with regard to the use of biomaterials for the treatment of Alzheimer’s disease, including nanoparticles and liposomes for delivery of therapeutic compounds as well as scaffolds for cell delivery strategies.
... Amyloid β (Aβ) complex aggregates are considered as possible targets for therapy and for diagnosis of Alzheimer disease (AD), and nanoparticles link with Aβ-specific ligands are find promising vehicles for imaging probes and therapeutic agents. In this, we characterized the binding properties of nanoliposomes decorated with an anti-Aβ monoclonal antibody (Aβ-MAb) (Canovi et al., 2011). ...
Article
Full-text available
Objective: Aim of this review is to summarized various causes alzheimer's disease (AD) among the elderly, In India affecting more than 4 million people and worldwide at least 50 million people are living with dementia, making the disease a global health crisis that must be addressed.Anexcess of senile plaques (β-amyloid protein) and neuro�brillary tangles (tau protein) specify iden�fy in Alzheimer disease. Unfortunately, targeted drug delivery to Alzheimer's, is complicated by limited mechanisms imposed at the blood–brain barrier (BBB). Method: Various reports were taken from research paper published in journals, data from various books and other online available literature.A summary ofvarious drug deliveries through NP is provided along with their advantage and disadvantage. Conclusion: This review gives description of lipdic nanoparticles for management of Alzheimer's diseases with appropriate surface modi�cations that can deliver drugs for therapeutic applications inADdisorders. Nasal delivery of nanoparticles can be used for directly delivery of drug into brain bypass blood brain.
... The effectiveness of this method was supported by a postmortem study of AD brains, treated with DSPC-Chol liposome NPs, functionalized with an Aβ monoclonal antibody (Aβ-MAb(to attach to the Aβ fibrils. 93 Clearing already-formed senile plaques from the brain is the third method. Employing gold (Au) NPs and reconstituted high density lipoprotein NPs enhanced the BBB permeability and finally increased target efficacy to re-dissolve and destroy aggregates. ...
Article
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which leads to progressive dysfunction of cognition, memory and learning in elderly people. Common therapeutic agents are not only inadequate to suppress the progression of AD pathogenesis but also produce deleterious side effects; hence development of alternative therapies is required to specifically suppress complications of AD. The current review provides a commentary on conventional as well as novel therapeutic approaches with an emphasis on stem cell and nanobased therapies for improvement and management of AD pathogenesis. According to our overview of the current literature, AD is a multi-factorial disorder with various pathogenic trajectories hence a multifunctional strategy to create effective neuroprotective agents is required to treat this disorder.
... High affinity for Aβ peptide [63] AD mouse. Transcranial FU has also been used as a strategy to establish whether anti-Aβ antibodies delivered to the brain employing MRI-guided FU were able to reduce Aβ plaque pathology. ...
Article
Introduction: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. Areas covered: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. Expert Opinion: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.
... Studying these NL in vitro, researchers found that they were highly sensitive to Aβ and had its protective effect (Bereczki et al., 2011). The findings of Mourtas et al. (2011) and Canovi et al. (2011) show that NL coated with an anti-A monoclonal antibody, which has strong affinity for Aβ either in vitro or ex vivo on post-mortem AD brain tissues, may suppress Aβ aggregation in vitro and in vivo (Taylor et al., 2011). The capacity of fullerenes C60 to prevent Aβ fibrillization is being studied in a similar fashion (Podolski et al., 2007). ...
Article
Full-text available
Alzheimer's disease (AD) is a kind of dementia that creates serious challenges for sufferers' memory, thinking, and behavior. It commonly targeting the aging population and decay the brain cells, despite attempts have been performed to enhance AD diagnostic and therapeutic techniques. Hence, AD remains incurable owing to its complex and multifactorial consequences and still there is lack of appropriate diagnostics/therapeutics option for this severe brain disorder. Therefore, nanotechnology is currently bringing new tools and insights to improve the previous knowledge of AD and ultimately may provide a novel treatment option and a ray of hope to AD patients. Here in this review, we highlighted the nanotechnologies-based findings for AD, in both diagnostic and therapeutic aspects and explained how advances in the field of nanotechnology/nanomedicine could enhance patient prognosis and quality of life. It is highly expected these emerging technologies could bring a research-based revolution in the field of neurodegenerative disorders and may assist their clinical experiments and develop an efficacious drug for AD also. The main aim of review is to showcase readers the recent advances in nanotechnology-based approaches for treatment and diagnosing of AD.
... Amyloid β (Aβ) complex aggregates are considered as possible targets for therapy and for diagnosis of Alzheimer disease (AD), and nanoparticles link with Aβ-specific ligands are find promising vehicles for imaging probes and therapeutic agents. In this, we characterized the binding properties of nanoliposomes decorated with an anti-Aβ monoclonal antibody (Aβ-MAb) (Canovi et al., 2011). ...
Article
The objective of present work was to enquire the potential use of embelin-loaded nanolipid carriers for brain targeting. The average particle size and polydispersity index (PDI) of optimized formulation (F19) were found to be 152619.7nm and 0.14360.023, respectively. Nanolipid carrier (NLC) was also significantly attenuated pentylenetetrazole (PTZ)-induced biochemical parameters in comparison to plain embelin that results in an increase in the level of malondialdehyde (MDA), nitrite, and reduction in the level of glutathione. From the results, it was concluded that embelin-NLCs developed as a beneficial carrier to achieve sustained release and brain targeting through nasal route.
... Dissociation constants of receptor-antibody complexes (K d ) and rate constants of their formation and dissociation (k on and k off, respectively) had extreme values, with K d = 0.1-5.0 nM, k on = (10 4 to 10 6 ) M −1 s −1 and k off = (10 −6 to 10 −3 ) s −1 [81][82][83][84][85][86], corresponding to residence times of hours and even days, which were unfavorable for drug delivery. In contrast, peptides with moderate receptor binding affinities of K d = 0.1-5.0 ...
Article
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Research has increasingly focused on the delivery of high, often excessive amounts of drugs, neglecting negative aspects of the carrier’s physical preconditions and biocompatibility. Among them, little attention has been paid to “small but beautiful” design of vehicle and multiple cargo to achieve effortless targeted delivery into deep tissue. The design of small biopolymers for deep tissue targeted delivery of multiple imaging agents and therapeutics (mini-nano carriers) emphasizes linear flexible polymer platforms with a hydrodynamic diameter of 4 nm to 10 nm, geometrically favoring dynamic juxtaposition of ligands to host receptors, and economic drug content. Platforms of biodegradable, non-toxic poly(β-l-malic acid) of this size carrying multiple chemically bound, optionally nature-derived or synthetic affinity peptides and drugs for a variety of purposes are described in this review with specific examples. The size, shape, and multiple attachments to membrane sites accelerate vascular escape and fast blood clearance, as well as the increase in medical treatment and contrasts for tissue imaging. High affinity antibodies routinely considered for targeting, such as the brain through the blood–brain barrier (BBB), are replaced by moderate affinity binding peptides (vectors), which penetrate at high influxes not achievable by antibodies.
... Additionally, several experiments indicated that PEG-coated liposomes were used to operate on monoclonal anti-A antibodies. Apart from liposomes binding to A deposition in postmortem Alzheimer's disease brain samples, significant liposome binding to A monomers has been observed in vitro (Canovi et al. 2011;Karthivashan et al. 2018). Natural compounds such as curcumin and quercetin have anti-inflammatory, antioxidant, and anticancer effects. ...
Chapter
Alzheimer’s disease (AD) is a degenerative brain disease that is the leading cause of dementia among the human population. AD is characterized by accumulating amyloid plaques which are insoluble deposits of a 4 kDa peptide of ~40–42 amino acids in length, known as amyloid-β (Aβ). The imbalance between Aβ generation and clearance in the brain leads to the progression of AD. AD pathology is characterized by the deposition of oligomeric and fibrillar forms of amyloid-β (Aβ) in the neuropil and cerebral vessel walls. Neurofibrillary tangles are composed mainly of hyperphosphorylated tau and neurodegeneration. Polyphenols are the most abundant antioxidants in the diet. More than 8000 naturally occurring polyphenols exist. Numerous studies have indicated that high consumption of fruits and vegetables rich in flavonoids and other polyphenols reduces the risk/incidence of age-related neurodegenerative disorders, highlighting the importance of these polyphenols as neuroprotective agents. Due to polyphenols’ ability to influence and modulate multiple targets in the cascade of the pathogenesis of neurodegenerative diseases, they are considered a candidate with a promising result against neurodegeneration, halting the progression of the disease. There is now substantial evidence indicating that oxidative damage to the brain is an early AD pathogenesis event. Oxidative stress and damage to brain macromolecules are vital processes in neurodegenerative diseases. The antioxidant properties of many polyphenols are purported to provide neuroprotection. There are pieces of evidence that some of the polyphenols can easily cross the blood-brain barrier (BBB). This chapter will provide deeper insights into various polyphenols that play a pivotal role in AD and shed light on the roles of these in the context of AD therapeutics.
... Additionally, several experiments indicated that PEG-coated liposomes were used to operate on monoclonal anti-A antibodies. Apart from liposomes binding to A deposition in postmortem Alzheimer's disease brain samples, significant liposome binding to A monomers has been observed in vitro (Canovi et al. 2011;Karthivashan et al. 2018). Natural compounds such as curcumin and quercetin have anti-inflammatory, antioxidant, and anticancer effects. ...
Chapter
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Neurodegenerative diseases are becoming more common in the people of old age. Numerous complications have occurred in the treatment of neurodegenerative diseases, some of which are multi-systemic in nature. Since the structure, efflux pumps, and expression of the blood-brain barrier’s (BBB) metabolism are limited, traditional drug delivery systems are ineffective for treating neurodegenerative disorders. Nanotechnology has the potential to significantly improve neurodegenerative disease treatment by bioengineered systems that interact with biological systems on a molecular level. This chapter discusses the applications of nanoparticles in the treatment of Alzheimer’s disease.
... Additionally, several experiments indicated that PEG-coated liposomes were used to operate on monoclonal anti-A antibodies. Apart from liposomes binding to A deposition in postmortem Alzheimer's disease brain samples, significant liposome binding to A monomers has been observed in vitro (Canovi et al. 2011;Karthivashan et al. 2018). Natural compounds such as curcumin and quercetin have anti-inflammatory, antioxidant, and anticancer effects. ...
... Additionally, several experiments indicated that PEG-coated liposomes were used to operate on monoclonal anti-A antibodies. Apart from liposomes binding to A deposition in postmortem Alzheimer's disease brain samples, significant liposome binding to A monomers has been observed in vitro (Canovi et al. 2011;Karthivashan et al. 2018). Natural compounds such as curcumin and quercetin have anti-inflammatory, antioxidant, and anticancer effects. ...
Chapter
Psychotic illness is a major health burden at the present world. Common psychotic disorders like autism spectrum disorders and schizophrenia frequently share clinical manifestations caused by brain dysfunction. However, there is a clear distinction between early- and late-onset psychotic illnesses. Despite appreciable advancement in identifying the genetic risk factors for most psychiatric illnesses, it is still unknown how these genetic variants interact with epigenetic risk factors and environmental factors that predispose risk for these clinically distinct disorders. In this chapter, we tried to trace the clinical features of psychotic illnesses and the relationship between these disorders with genetic insight. Furthermore, we reviewed the common therapeutic targets for these conditions. From the discussion, it is clear that psychotic illnesses share a genetic overlap and the therapeutic target of these abnormalities relies on the same pipeline. Therefore, prospects will be to develop more specific therapies for treating psychotic illnesses.
... Additionally, several experiments indicated that PEG-coated liposomes were used to operate on monoclonal anti-A antibodies. Apart from liposomes binding to A deposition in postmortem Alzheimer's disease brain samples, significant liposome binding to A monomers has been observed in vitro (Canovi et al. 2011;Karthivashan et al. 2018). Natural compounds such as curcumin and quercetin have anti-inflammatory, antioxidant, and anticancer effects. ...
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This book talks about the multidimensional biological etiology of Alzheimer’s disease and autism spectrum disorder which leads to distinctive ways of perception, thinking and learning in affected individuals. It provides a deeper emphasis on the need for early diagnosis, continuous assessment of patients and the proper educational methods and environment required towards enabling people affected with these disorders capable of evolving and learning. This book explores alternative solutions for autism spectrum disorder based on the theory of brain plasticity, the relationship between the gut microbiota and the central nervous system along with genetic factors and toxic metal exposures which are responsible for the oxidative damage resulting in a decreased ability of the patients to use objects or response to auditory stimuli. It also identifies and provides the latest research towards dealing with memory loss, which is the first sign of cognitive impairment followed by behavioral disturbances. These symptoms are associated with a rigorous neuronal decline and the appearance of two brain lesions, senile plaques and neurofibrillary tangles, which are mainly composed of Aβ and hyper phosphorylated tau protein respectively. This book also provides the latest research towards reducing autism disorder severity such as targeting the disease with symptomatic treatments such as cholinesterase inhibitors, NMDA receptor antagonist, β-secretase and γ-secretase inhibitors, α-secretase stimulators, tau inhibitors, immunotherapy, nutraceuticals, and nano drugs. This book will not only be a good resource for professors and lecturers teaching in the area of neuroscience, medicine, biochemistry, neuroinformatics, and nanotechnology, etc. but also for professionals working in the field of occupational therapy and geriatric clinics and rehabilitation.
... Considerable research has focused on polyester-based drug delivery systems that degrade in the presence of physiological esterases (for example PLGA) [28,45,47,68,[103][104][105][106][107][108][109]. In addition, various types of NP such as gold, silica, hydrogels, liposome, etc. have been currently explored for CNS drug delivery applications [40,58,80,81,101,108,[110][111][112][113][114][115][116][117][118]. By delivering the drugs to the sites where they are needed, these nanoparticles can greatly increase their therapeutic effects by directly depositing a much higher dose of medication specifically to diseased areas without saturating the entire body with drugs. ...
Article
Full-text available
Drug delivery to central nervous system (CNS) diseases is very challenging since the presence of the innate blood–brain barrier (BBB) and the blood-cerebrospinal fluid barrier that impede drug delivery. Among new strategies to overcome these limitations and successfully deliver drugs to the CNS, nanotechnology-based drug delivery platform, offers potential therapeutic approach for the treatment of some common neurological disorders like Alzheimer’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease. This review aimed to highlight advances in research on the development of nano-based therapeutics for their implications in therapy of CNS disorders. The challenges during clinical translation of nanomedicine from bench to bed side is also discussed.
... Moreover, Taylor et al. demonstrated that curcumin-modified liposome synthesized using click chemistry was the most effective in the inhibition of Aβ aggregation [178]. Canovi et al. decorated NLs with an anti-Aβ monoclonal antibody (Aβ-MAb) to achieve a high affinity toward Aβ monomers and fibrils [179]. Moreover, the multifunctional conjugation of NLs containing PA, CL, curcumin with apolipoprotein E or the anti-transferrin receptor antibody can facilitate the crossing of the BBB and enhance the uptake in the brain capillary cells without the sacrifice of Aβ targeting [180][181][182]. ...
Article
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The aberrant aggregation of amyloid-β (Aβ) peptides in the brain has been recognized as the major hallmark of Alzheimer’s disease (AD). Thus, the inhibition and dissociation of Aβ aggregation are believed to be effective therapeutic strategiesforthe prevention and treatment of AD. When integrated with traditional agents and biomolecules, nanomaterials can overcome their intrinsic shortcomings and boost their efficiency via synergistic effects. This article provides an overview of recent efforts to utilize nanomaterials with superior properties to propose effective platforms for AD treatment. The underlying mechanismsthat are involved in modulating Aβ aggregation are discussed. The summary of nanomaterials-based modulation of Aβ aggregation may help researchers to understand the critical roles in therapeutic agents and provide new insight into the exploration of more promising anti-amyloid agents and tactics in AD theranostics.
... However, the study was done ex vivo in post-mortem tissue. Aβ-monoclonal antibody (MAb) liposomes were found to bind amyloid deposits and enhance amyloid clearance (Canovi et al., 2011). Immunemodulating nano-strategies to deliver anti-inflammatory drugs to inflammatory sites may also have therapeutic potential in AD. ...
Chapter
Critical advances have recently been made in the field of immunotherapy, contributing to an improved understanding of how to harness and balance the power of immune responses in the treatment of diseases such as cancer, cardiovascular disease, infectious diseases, and autoimmune diseases. Combining nanomedicine with immunotherapy provides the opportunity for customization, rational design, and targeting to minimize side effects and maximize efficacy. This review highlights current developments in the design and utilization of nano-based immunotherapy systems, including how rationally-designed nanosystems can target and modify immune cells to modulate immune responses in a therapeutic manner. We discuss the following topics: targeted immuno-engineered nanoformulations, commercial formulations, clinical applicability, challenges associated with current approaches, and future directions.
... Liposomes consisting of 1,2-distearoyl-sn-glycero-3phosphocholine (DSPC):Cholesterol at 2:1 molar ratio, were prepared by the thin film hydration method, as previously described. 27 The thin film was hydrated above the transition temperature with 10 mM PBS and the liposomes size was decreased by extrusion, using first 400 nm and subsequently 200 nm polycarbonate membranes. For lipid coating of chitosan particles, 50ul of liposome dispersion (500 μg lipid) were added dropwise to 2 ml of chitosan-pDNA NP dispersion (C-NP), under stirring conditions for 30 min at 60°C. ...
Article
Respiratory Syncytial Virus (RSV) has been a major health concern globally for decades, yet no effective prophylactic or treatment regimen is available. The key viral proteins responsible for RSV pathology include the fusion protein (F), the immunomodulatory non-structural-protein 1 (NS1) and the Phosphoprotein (P) involved in viral replication. Herein, we developed a novel shell-core multifunctional nanosystem with dual payload: a plasmid construct encoding for shRNAs against NS1 and P, and an anti-fusion peptide (HR2D). Anti-ICAM1 antibody conjugated on the nanoparticle (NP) surface is used to target RSV infected cells. Our data show the potential of this nanosystem as a prophylactic and/or a therapeutic regimen against RSV infection. Furthermore, therapy of RSV infected mice with this nanosystem, in addition to reducing viral load, modulated expression of Th2 and allergy-associated cytokines such as IL4, IL-13 and IL-17 indicating a direct role of this nanosystem in the mechanisms involved in the immunoregulation of disease pathogenesis.
... 21,22 Curcuminoid-decorated liposomes demonstrated high affinity (K D : 1−5 nM) for Aβ42 fibrils, 23 similar to the affinity (K D : 0.5−2 nM) of liposomes that were functionalized with a monoclonal antibody against Aβ. 24 Phosphatidic acid (PA) and cardiolipin (CL) 25 are two other substances that were used for the surface modification of liposomes. However, they exhibited only moderate binding affinity for aggregated forms of Aβ42 (K D : 22−60 nM). ...
Article
The potential of 2-benzothiazolyl-decorated liposomes as theragnostic systems for Alzheimer’s disease was evaluated in vitro, using PEGylated liposomes that were decorated with two types of 2-benzothiazoles: (i) the unsubstituted 2-benzothiazole (BTH) and (ii) the 2-(4-aminophenyl)benzothiazole (AP-BTH). The lipid derivatives of both BTH-lipid and AP-BTH-lipid were synthesized, for insertion in liposome membranes. Liposomes (LIP) containing three different concentrations of benzothiazoles (5, 10, and 20%) were formulated, and their stability, integrity in the presence of serum proteins, and their ability to inhibit β-amyloid (1–42) (Αβ42) peptide aggregation (by circular dichroism (CD) and thioflavin T (ThT) assay), were evaluated. Additionally, the interaction of some LIP with an in vitro model of the blood–brain barrier (BBB) was studied. All liposome types ranged between 92 and 105 nm, with the exception of the 20% AP-BTH-LIP that were larger (180 nm). The 5 and 10% AP-BTH-LIP were stable when stored at 4 °C for 40 days and demonstrated high integrity in the presence of serum proteins for 7 days at 37 °C. Interestingly, CD experiments revealed that the AP-BTH-LIP substantially interacted with Αβ42 peptides and inhibited fibril formation, as verified by ThT assay, in contrast with the BTH-LIP, which had no effect. The 5 and 10% AP-BTH-LIP were the most effective in inhibiting Αβ42 fibril formation. Surprisingly, the AP-BTH-LIP, especially the 5% ones, demonstrated high interaction with brain endothelial cells and high capability to be transported across the BBB model. Taken together, the current results reveal that the 5% AP-BTH-LIP are of high interest as novel targeted theragnostic systems against AD, justifying further in vitro and in vivo exploitation.
... Another study that was held by Canovi et al. developed nanoliposomes that showed very high binding potential for amyloid in both invitro and ex vivo AD post-mortem samples (Canovi et al., 2011). Nanoliposomes encapsulated with curcumin were also developed that showed high binding and inhibiting potential against amyloid under invitro evaluation and one more investigation was performed based on the ability of fullerenes C60 to inhibit the fibrillization of amyloid (Mourtas et al., 2011). ...
Article
Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia. To overcome the limitations of diagnosis and treatment nanotechnology research is bringing more needed and optimum clinical results. The use of nanocarriers for delivering bio-actives to treat neurodegenerative diseases has shown many benefits over common therapies such as the possibility of loading various payloads, controllable delivery, and amenability to surface modification with target ligands that can promote the crossing of the blood-brain barrier (BBB) for efficient distribution of bioactive into the brain. This review spotlights the applications of nanocarriers such as magnetic nanoparticles, carbon nanotubes, quantum dots, polymeric nanocapsules, multifunctional nanoliposomes, and nanoemulsions in the treatment of neurodegenerative diseases. The production of biosensors for the identification of Alzheimer's disease biomarkers has made considerable progress due to advances in nanoscience. The special properties of nanomaterials (such as graphene, carbon nanotubes, silver, gold, magnetic nanoparticles, polymers, and quantum dots) can improve the optical and electrochemical behavior of transducers. Therefore, electrochemical and optical biosensors with better sensitivity, selectivity, and prolonged stability desired. After all, the methods that focused on the identification of multiple analytes should be strengthened to reduce misdiagnosis.
Chapter
Beta-amyloid (Aβ) is a well-known pathological marker for Alzheimer's disease. Cell surface glycans such as sialic acid are known to play important roles in facilitating the aggregation of Aβ and the formation of amyloid plaques. Mimicking this process, researchers have synthesized a variety of sialic acid-coated nanoparticles for Aβ studies. Immobilizing sialic acid onto nanoparticles greatly enhanced the avidities with Aβ through the polyvalency effect. These glyconanoparticles could enable Aβ detection and protect the cells from Aβ-induced cytotoxicities. With further development, glyconanoparticles can become a useful tool to facilitate Aβ research.
Article
NAD project (large cooperative; 19 partners, funded by the E.C., FP72007-2013, G.A. n° 212043) is aiming to the therapy and diagnosis, even combined, of Alzheimer Disease, by creating different multiple-functionalized nanoparticles, able to bind, detect and remove p-amyloid peptide (Aβ) from the brain and from the blood. The results obtained so far show the ability of liposomes functionalized to bind Abeta, to cross the blood-brain barrier either in vitro and in vivo and to reduce the Aβ burden from the brain of transgenic animal models of the disease, thus opening new vistas for the possible therapy of Alzheimer Disease in humans.
Article
Aggregation of Amyloid-β peptide (Aβ) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ. PINPs also bound to Aβ with high affinity (Kd = 13.2–50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aβ, crossed an in vitro blood–brain-barrier model (hCMEC/D3 cell monolayer), entered the brains of C57/BL6 mice, and protected against memory loss in APPSWE transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD.
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Le cancer pancréatique représente la cinquième cause de décès par cancer dans les pays occidentaux. Son mauvais pronostic (survie à 5 ans inférieure à 3,5 % des cas) est dû à l’absence de facteurs de risques spécifiques interdisant une prévention efficace, et à un diagnostic tardif qui révèle un cancer agressif chez environ 90% des patients. Actuellement, le seul traitement curatif de ce cancer est la chirurgie, mais celle-ci ne peut être envisagée que dans 10 à 15 % des cas. L’adressage de molécules thérapeutiques vers l’organe, le tissu ou la cellule malade constitue aujourd’hui un défi majeur pour le traitement des maladies humaines notamment infectieuses, cancéreuses ou d’origine génétique. C’est pour ces raisons que le développement de nanotechnologies, en tant que vecteurs de médicaments, a pris un essor considérable au cours des dernières années. Dans ce contexte, le concept de squalènisation repose sur le couplage chimique entre le squalène (SQ), un lipide naturel précurseur de la synthèse du cholestérol, et des principes actifs (notamment des molécules anticancéreuses). Les bioconjugués ainsi formés sont alors capables de s’auto-assembler en solution aqueuse pour former des nanoparticules stables de diamètres compris entre 100 et 300 nm. L’exemple de référence dans ce domaine est la nanoparticule de gemcitabine-squalène (SQdFdC) qui a donné lieu à des résultats spectaculaires in vitro sur des lignées de cellules cancéreuses humaines In vivo, les nanoparticules de gemcitabine-squalène se sont avérées beaucoup plus efficaces que la gemcitabine libre sur des tumeurs solides greffées par voie sous-cutanée ainsi que sur des modèles murins de leucémies agressives métastatiques.Au vu de ces résultats encourageants, le projet de thèse a été développé autour de deux axes de recherche. (I) Dans un premier temps, les nanoparticules de gemcitabine-squalène ont été fonctionnalisées par un peptide capable de reconnaître et de cibler spécifiquement les cellules cancéreuses pancréatiques. (II) Le deuxième axe de recherche a visé l’encapsulation d’un second principe actif au sein des nanoparticules de gemcitabine-squalène afin de développer le concept de nanoparticule « multi-thérapeutique ».
Chapter
http://www.appleacademicpress.com/nutraceuticals-and-dietary-supplements-applications-in-health-improvemepnt-and-disease-management-/9781771888738 https://www.taylorfrancis.com/books/e/9780367821517
Article
Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140–148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain / liver + spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1 mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4 mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05 mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies.
Article
Several million people in the world are affected by dementia, especially by Alzheimer's disease (AD), a frequently encountering neurodegenerative disorder in the brain, and it is predicted to double by every 20 years. The growing population of aging leads to an increase in the number of individuals at the risk of AD. Up to now, the epidemiological other than age and familial factors of AD remain elusive, although amyloid β peptide (extracellular neuritic plaque) and tau protein (intracellular neurofibrillary tangle) are regarded as the two major pathological features. In addition, a few critical issues emerge at the moment and are required to be ascertained. Is there any scheme for resolving the exact mechanism of AD? Are there any vaccines and drugs to completely reverse the AD progress? Is there any possibility for the early stage detection of AD? And, is there a permanent cure for AD? These questions are haunting researchers to identify the best pharmaceuticals and accurate pathways for AD-related evolution. This paper discusses about the etymology, pathology, therapeutic strategy and technology on recent advancement, facilitating scientists and medical practitioners to discover the physiological causes and therapeutic targets to improve AD treatment.
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Nanoparticles, especially liposomes, have gained prominence in the field of drug delivery for the treatment of human diseases, particularly cancer; they provide several advantages, including controlled drug release, protection of the drug against degradation, improved pharmacokinetics, long circulation, and passive targeting to tumors and inflammatory sites due to the enhanced permeability and retention effect. The functionalization of liposomes with monoclonal antibodies or antibody fragments to generate immunoliposomes has emerged as a promising strategy for targeted delivery to and uptake by cells overexpressing the antigens to these antibodies, with a consequent reduction in side effects. In this review, we address functionalization strategies for the non-covalent and covalent attachment of monoclonal antibodies and their fragments to liposomal surfaces. The main reaction occurs between the sulfhydryl groups of thiolated antibodies and maleimide-containing liposomes. Furthermore, we explore the main targeting possibilities with these ligands for the treatment of a variety of pathologies, including HER2- and EGFR-positive cancers, inflammatory and cardiovascular diseases, infectious diseases, and autoimmune and neurodegenerative diseases, which have not previously been reviewed together. Overall, many studies have shown selective delivery of immunoliposomes to target cells, with promising in vivo results, particularly for cancer treatment. Although clinical trials have been conducted, immunoliposomes have not yet received clinical approval. However, immunoliposomes are promising formulations that are expected to become available for therapeutic use after clinical trials prove their safety and efficacy, and after scaling issues are resolved.
Article
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Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is “drug repositioning” or “drug repurposing”. In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.
Article
Alzheimer’s disease is an irreversible neurodegenerative disorder affecting approximately 6 million Americans, 90% of which are over the age of 65. The hallmarks of the disease are represented by amyloid plaques and neurofibrillary tangles. While the neuronal characteristics of Alzheimer’s disease are well known, current treatments only provide temporary relief of the disease symptoms. Many of the approved therapeutic agents for the management of cognitive impairments associated with the disease are based on neurotransmitter or enzyme modulation. However, development of new treatment strategies is limited due to failures associated with poor drug solubility, low bioavailability, and the inability to overcome obstacles present along the drug delivery route. In addition, treatment technologies must overcome the challenges presented by the blood-brain barrier. This complex and highly regulated barrier surveys the biochemical, physicochemical, and structural features of nearby molecules at the periphery, only permitting passage of select molecules into the brain. To increase drug efficacy to the brain, many nanotechnology-based platforms have been developed. These methods for assisted drug delivery employ sophisticated design strategies and offer serveral advantages over traditional methods. For example, nanoparticles are generally low-cost technologies, which can be used for non-invasive administrations, and formulations are highly tunable to increase drug loading, targeting, and release efficacy. These nanoscale systems can facilitate passage of drugs through the blood-brain barrier, thus improving the bioavailability, pharmacokinetics, and pharmacodynamics of therapeutic agents. Examples of such nanocarriers which are discussed herein include polymeric nanoparticles, dendrimers, and lipid-based nanoparticles.
Article
Traditional drug delivery approaches remained ineffective in offering better treatment to various neurodegenerative disorders (NDs). In this context, diverse types of nanocarriers have shown their great potential to cross blood-brain barrier (BBB) and have emerged as a prominent carrier system in the drug delivery. Moreover, nanotechnology-based methods usually involve numerous nano-sized carrier platforms, which potentiate the effect of the therapeutic agents in the therapy of NDs especially in diagnosis and drug delivery with negligible side effects. In addition, nanotechnology-based techniques have offered several strategies to cross BBB to intensify the bioavailability of drug moieties in the brain. In last few years, diverse kinds of nanoparticles (NPs) have been developed by incorporating various biocompatible components (e.g., polysaccharide-based NPs, polymeric NPs, selenium NPs, AuNPs, protein-based NPs, gadolinium NPs, etc.), that showed great therapeutic benefits against NDs. Eventually, this review provides deep insights to explore recent applications of some innovative nanocarriers enclosing active molecules for the efficient treatment of NDs.
Chapter
Nanoparticles have appeared as valuable outcomes of nanotechnology because of their unique physicochemical characteristics based on variable shape, size, and surface properties. Among transition metal oxide‐based nanoparticles, titanium dioxide (TiO2) nanoparticles have demonstrated significant potential owing to their fascinating properties and utilization in water treatment, fabrication of energy devices, soil remediation, paint and paper productions, and as additives in food and cosmetic products. In nanobiotechnology and nanomedicine, the admirable photocatalytic ability, biocompatibility, and low toxicity of TiO2 nanoparticles have been exploited for genetic and tissue engineering, manufacturing healthcare products, bioimaging, and the treatment of certain diseases such as cancer. In this chapter, we highlighted from basic to advance properties of TiO2 nanoparticles that are responsible for their usage in numerous applications as a potential candidate. The various facile techniques for the preparation of TiO2 nanoparticles are discussed in detail, which help to understand the modification strategies of these nanoparticles for practical applications. Finally, we also provided introductions to the applications of TiO2 nanoparticles in various fields including nanomedicine and nanobiotechnology.
Chapter
Neurodegenerative diseases (NDs) have been a major threat to human especially for elders. Despite a rapid increase in the severity and prevalence of the disease, early diagnosis of NDs is still challenging due to the low accuracy or high cost of neuropsychological tests and neuroimaging. With the good biocompatibility and excellent photocatalytic performance, nano‐titanium dioxide (TiO2) has been widely used, i.e. as a biomaterial for the detection of ND's biomarkers and a drug delivery for the treatment of disease, for the early diagnosis and therapy of ND. In this chapter, we introduce the major challenge of NDs and the application of TiO2 for NDs' diagnostics and therapy in an early stage.
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The accumulation of extracellular amyloid-beta (Aβ), denoted as senile plaques, and intracellular neurofibrillary tangles (formed by hyperphosphorylated Tau protein) in the brain are two major neuropathological hallmarks of Alzheimer’s disease (AD). The current and most accepted hypothesis proposes that the oligomerization of Aβ peptides triggers the polymerization and accumulation of amyloid, which leads to the senile plaques. Several strategies have been reported to target Aβ oligomerization/polymerization. Since it is thought that Aβ levels in the brain and peripheral blood maintain equilibrium, it has been hypothesized that enhancing peripheral clearance (by shifting this equilibrium towards the blood) might reduce Aβ levels in the brain, known as the sink effect. This process has been reported to be effective, showing a reduction in Aβ burden in the brain as a consequence of the peripheral reduction of Aβ levels. Nanoparticles (NPs) may have difficulty crossing the blood-brain barrier (BBB), initially due to their size. It is not clear whether particles in the range of 50–100 nm should be able to cross the BBB without being specifically modified for it. Despite the size limitation of crossing the BBB, several NP derivatives may be proposed as therapeutic tools. The purpose of this review is to summarize some therapeutic approaches based on nanoliposomes using two complementary examples: First, unilamellar nanoliposomes containing Aβ generic ligands, such as sphingolipids, gangliosides or curcumin, or some sphingolipid bound to the binding domain of ApoE; and second, nanoliposomes containing monoclonal antibodies against Aβ. Following similar rationale NPs of poly(lactide-co-glycolide)-poly (ethylene glycol) conjugated with curcumin-derivate (PLGA-PEG-B6/Cur) were reported to improve the spatial learning and memory capability of APP/PS1 mice, compared with native curcumin treatment. Also, some new nanostructures such as exosomes have been proposed as a putative therapeutic and prevention strategies of AD. Although the unquestionable interest of this issue is beyond the scope of this review article. The potential mechanisms and significance of nanoliposome therapies for AD, which are still are in clinical trials, will be discussed.
Chapter
The central nervous system (CNS) is one of the most important systems in the human body, and thus, CNS disorders are causing a significant threat to human health. Researchers from around the world are making impressive efforts to come up with therapeutics and solutions to treat neurodegenerative disorders. However, the issue of brain targeting remains an unsolved challenge due to the blood-brain barrier (BBB) existence. Due to the many unique properties of engineered nanomaterials, their use could make it possible to overcome difficulties in the diagnosis and treatment of neurodegenerative disorders, provide promising neuroprotective strategies, and stimulate neuronal differentiation and nerve generation as a therapeutic approach. In contrast, despite the rapid development of the nanomaterials industry and the spread of its applications in the biomedical field, there is lacking evidence regarding their possible adverse health effects, and very little is known about their toxicity. Numerous in vivo and in vitro studies have emerged, providing evidence of neurotoxic effects of various types of nanoparticles (NPs), and therefore the advantages of nanomaterials should be weighed against their potential effects. In this chapter, we focused on the applications of nanomaterials in neurological disorders, neuronal differentiation, neuroprotection, and neurotoxicity.
Article
Plaques containing β-amyloid (AP42) peptides are one of the hallmarks of Alzheimer's disease (AD) and the reduction of Aβ is considered a primary therapeutic target (Mehta PD, Curr Alzh Res 2007). Studies in mouse models of AD have indicated that lowering Aβ42 levels in the brain can minimize the neurodegeneration (Boche D, Curr Opin Neurol 2005). Recently many strategies have been employed to reduce Aβ42 brain levels and one of them is based on the 'sink effect' hypothesis, that is the peripheral administration of Aβ42 binding agents able to reduce Aβ42 brain amount by sequestering it in the plasma. This study for the first time investigates the potential effect of dually-decorated liposomes on the Aβ exchange across an in vitro model of the blood-brain barrier (BBB). The results obtained show that liposomes significantly enhance the cellular uptake from the bottom side (corresponding in vivo to brain compartment), and the passage to the apical side (corresponding in vivo to blood compartment) of Aβ42 across the BBB compared to Aβ42 alone.
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We have characterized amyloid β peptide (Aβ. concentration, Aβ deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD. patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Aβ deposition, Aβ-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Aβ, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Aβ clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Aβ40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Aβ42. Aβ40 is known to be elevated in cerebrovascular amyloid deposits, and Aβ40 (but not Aβ42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Aβ, particularly soluble Aβ40. Previous experiments attempting to relate Aβ deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.
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Plaques containing -amyloid (A) peptides are one of the pathological features of Alzheimer's disease, and the reduction of A is considered a primary therapeutic target. Amyloid clearance by anti-A antibodies has been reported after immunization, and recent data have shown that the antibodies may act as a peripheral sink for A, thus altering the periphery/brain dynamics. Here we show that peripheral treatment with an agent that has high affinity for A (gelsolin or GM1) but that is unrelated to an antibody or immune modulator reduced the level of A in the brain, most likely because of a peripherally acting effect. We propose that in general, compounds that sequester plasma A could reduce or prevent brain amyloidosis, which would enable the development of new therapeutic agents that are not limited by the need to penetrate the brain or evoke an immune response.
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Anti-amyloid-beta immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-beta active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques (i.e. beyond 50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-beta immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-beta immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's disease.
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Shown to lower amyloid deposits and improve cognition in APP transgenic mouse models, immunotherapy appears to be a promising approach for the treatment of Alzheimer's disease (AD). Due to limitations in available animal models, however, it has been unclear whether targeting amyloid is sufficient to reduce the other pathological hallmarks of AD-namely, accumulation of pathological, nonmutated tau and neuronal loss. We have now developed two transgenic mouse models (APPSw/NOS2(-/-) and APPSwDI/NOS2(-/-)) that more closely model AD. These mice show amyloid pathology, hyperphosphorylated and aggregated normal mouse tau, significant neuron loss, and cognitive deficits. A beta(1-42) or KLH vaccinations were started in these animals at 12 months, when disease progression and cognitive decline are well underway, and continued for 4 months. Vaccinated APPSwDI/NOS2(-/-) mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain A beta and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2(-/-) vaccinated mice, brain A beta was reduced by 65-85% and hyperphosphorylated tau by 50-60%. Furthermore, neurons were completely protected, and memory deficits were fully reversed. Microhemorrhage was observed in all vaccinated APPSw/NOS2(-/-) mice and remains a significant adverse event associated with immunotherapy. Nevertheless, by providing evidence that reducing amyloid pathology also reduces nonmutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD.
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The neurotoxic beta-amyloid peptide (Abeta), formed in anomalous amounts in Alzheimer's disease (AD), is released as monomer and then undergoes aggregation forming oligomers, fibrils and plaques in diseased brains. Abeta aggregates are considered as possible targets for therapy and/or diagnosis of AD. Since nanoparticles (NPs) are promising vehicles for imaging probes and therapeutic agents, we realized and characterized two types of NPs (liposomes and solid lipid nanoparticles, 145 and 76 nm average size, respectively) functionalized to target Abeta(1-42) with high affinity. Preliminary immunostaining studies identified anionic phospholipids [phosphatidic acid (PA) and cardiolipin (CL)] as suitable Abeta(1-42) ligands. PA/CL-functionalized, but not plain, NPs interacted with Abeta(1-42) aggregates as indicated by ultracentrifugation experiments, in which binding reaction occurred in solution, and by Surface Plasmon Resonance (SPR) experiments, in which NPs flowed onto immobilized Abeta(1-42). All these experiments were carried out in buffered saline. SPR studies indicated that, when exposed on NPs surface, PA/CL display very high affinity for Abeta(1-42) fibrils (22-60 nm), likely because of the occurrence of multivalent interactions which markedly decrease the dissociation of PA/CL NPs from Abeta. Noteworthy, PA/CL NPs did not bind to bovine serum albumin. The PA/CL NPs described in this work are endowed with the highest affinity for Abeta so far reported. These characteristics make our NPs a very promising vector for the targeted delivery of potential new diagnostic and therapeutic molecules to be tested in appropriate animal models.
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Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide - a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis - are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.
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Nanoparticles bearing surface-conjugated targeting ligands are increasingly being explored for a variety of biomedical applications. The multivalent conjugation of targeting ligands on the surface of nanoparticles is presumed to enhance binding to the desired target. However, given the complexities inherent in the interactions of nanoparticle surfaces with proteins, and the structural diversity of nanoparticle scaffolds and targeting ligands, our understanding of how conjugation of targeting ligands affects nanoparticle binding remains incomplete. Here, we use surface plasmon resonance (SPR) to directly and quantitatively study the affinity and binding kinetics of nanoparticles that display small molecules conjugated to their surface. We studied the interaction between a single protein target and a structurally related series of targeting ligands whose intrinsic affinity varies over a 4500-fold range and performed SPR at protein densities that reflect endogenous receptor densities. We report that even weak small molecule targeting ligands can significantly enhance target-specific avidity (by up to 4 orders of magnitude) through multivalent interactions and also observe a much broader range of kinetic effects than has been previously reported. Quantitative measurement of how the affinity and kinetics of nanoparticle binding vary as a function of different surface conjugations is a rapid, generalizable approach to nanoparticle characterization that can inform the design of nanoparticles for biomedical applications.
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The intense and uncontrollable self-assembling nature of amyloid beta peptide (Abeta) 1-42 is known to cause difficulties in preparing monomeric Abeta1-42; this results in irreproducible or discrepant study outcomes. Herein, we report novel features of a pH click peptide of Abeta1-42 that was designed to overcome these problems. The click peptide is a water-soluble precursor peptide of Abeta1-42 with an O-acyl isopeptide structure between the Gly25-Ser26 sequence. The click peptide adopts and retains a monomeric, random coil state under acidic conditions. Upon change to neutral pH (pH click), the click peptide converts to Abeta1-42 promptly (t(1/2) approximately 10 s) and quantitatively through an O-to-N intramolecular acyl migration. As a result of this quick and irreversible conversion, monomer Abeta1-42 with a random coil structure is produced in situ. Moreover, the oligomerization, amyloid fibril formation and conformational changes of the produced Abeta1-42 can be observed over time. This click peptide strategy should provide a reliable experimental system to investigate the pathological role of Abeta1-42 in Alzheimer's disease.
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To design a smart nano-vehicle (SNV) capable of permeating the blood-brain barrier (BBB) to target cerebrovascular amyloid formed in both Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA). SNV consists of a chitosan polymeric core prepared through ionic gelation with tripolyphosphate. A polyamine modified F(ab') portion of IgG4.1, an anti-amyloid antibody, was coated as a biosensor on the SNV surface. A similar polymeric core coated with bovine serum albumin (BSA) served as a control nano-vehicle (CNV). The BBB uptake of (125)I-SNVs and (125)I-CNVs was evaluated in mice. The uptake and transcytosis of SNVs and CNVs across bovine brain microvascular endothelial cells (BBMECs) was evaluated using flow cytometry and confocal microscopy. Plasma clearance of (125)I-SNVs was nine times higher than that of the (125)I-CNVs. However, the uptake of (125)I-SNVs in various brain regions was about 8 to 11 times higher than that of (125)I-CNVs. The uptake of FITC-BSA loaded SNVs in BBMECs was twice the uptake of FITC-BSA loaded CNVs. Confocal micrographs demonstrated the uptake and transcytosis of Alexa Fluor 647 labeled SNVs, but not CNVs, across the BBMEC monolayer. SNVs are capable of carrying a payload of model protein across the BBB to target cerebral amyloid.
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Ovine prolactin was biotinylated with N-hydroxysuccinimidobiotin. Biotinylation was proportional to the molar ratio of reactants. Gel electrophoresis of the biotinylated derivative revealed little or no change in migration, but isoelectric focusing showed an acidic shift when compared to oPRL. Biotinylated ovine prolactin (B-oPRL) was detected by anti-oPRL antiserum and avidin-fluorescein-isothiocyanate (FITC) on protein blots. Competitive binding assays using 125I-B-oPRL and 125I-oPRL revealed: (a) similar dissociation constants and ID50 values for binding to anti-oPRL antibodies; (b) similar dissociation constants and maximum binding values for binding to liver membrane preparations; and (c) similar dissociation curves for displacement by several pituitary hormones. In contrast, binding of biotinylated oPRL to Nb2 node cells was reduced by approximately 70% and its bioreactivity was only 10% of that of oPRL. Our results indicate that biotinylation of oPRL does not alter its binding characteristics as measured by radioimmunoassay and radioreceptor assay using hepatic lactogenic receptors, but decreases its binding and bioreactivity when measured in Nb2 lymphoma cells. Assuming that N-hydroxysuccinimidobiotin interacts with reactive free amino groups of oPRL, our results suggest that these groups are essential for binding and bioreactivity of the molecule in the Nb2 lymphoma cell system.
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A novel non-covalent method of attaching antibodies to liposomes which exploits the high affinity of streptavidin for biotin, is described. The two-step coupling protocol involves the initial attachment of streptavidin to liposomes containing biotin PE, followed by the coupling of biotinated antibodies to streptavidin-liposomes. The association of streptavidin with liposomes containing biotinated PE is rapid (less than 5 min), resulting in a maximum association of 40 molecules of streptavidin per 100 nm vesicle. In the presence of equimolar cholesterol, the amount of streptavidin bound is twice that observed when biotin PE/egg PC liposomes are used. Irrespective of the mole ratio of biotin to antibody (e.g. for 1-6 biotins per antibody), or the molar ratio of antibody to streptavidin in the second incubation step, equimolar amounts of antibody bind to streptavidin. It is shown that anti-rat-erythrocyte IgG or F(ab')2 complexed to liposomes via the streptavidin linker bind specifically to rat erythrocytes but not to human erythrocytes. This coupling protocol can be readily extended to other biotinated antibodies.
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Phospholipids may be measured colorimetrically (as dipalmitoyl lecithin) without conventional acid digestion and color development procedures by forming a complex with ammonium ferrothiocyanate.
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Amyloid (A beta) deposition was investigated in cases of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch type, due to mutations in the amyloid precursor protein (APP) gene using the end-specific monoclonal antibodies BA27 and BC05 that recognize A beta 40 or A beta 42(43), respectively. In cases of APP717 mutation the predominant A beta species within plaques terminate at A beta 42(43) with relatively little A beta 40 being present. The total amount of A beta deposited as A beta 42(43) is significantly greater than in sporadic Alzheimer's disease, consistent with the suggestion that this mutation might influence the processing of APP so as to produce more of the highly aggregatable form, A beta 1-42. In cases of APP670/671 mutation the major peptide in plaques is also A beta 42(43), although the proportion of plaques containing A beta 40, and the total A beta load is similar to that in sporadic Alzheimer's disease. As in sporadic Alzheimer's disease, the vascular amyloid in APP670/671 and APP717 and in cases of hereditary cerebral hemorrhage with amyloidosis, Dutch type is predominantly A beta 40 in this latter disorder, however, parenchymal deposits are exclusively A beta 42(43). Although the various APP mutations may influence the type, quantity, and location of A beta deposited, the predominant, and possibly the initial, species deposited in the brain parenchyma is A beta 42(43).
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The effect of bile salts (sodium cholate and sodium taurocholate), and pancreatic lipases on the structural integrity of SUV liposomes of different lipid compositions was studied. Liposomal membrane integrity was judged by bile salt or pancreatin-induced release of vesicle encapsulated 5,6-carboxyfluorescein, and vesicle size distribution before and after incubations. Bile salt concentration was 10 mM, while a saturated solution of pancreatin (mixed with equal volume of liposomes) was utilized. Results agree with earlier studies, demonstrating the instability of liposomes composed of lipids with low transition temperatures (PC and DMPC) in presence of cholates. Addition of cholesterol (1:1 lipid:chol molar ratio) does not substantially increase the encapsulated molecule retention. Nevertheless, liposomes composed of lipids with high transition temperatures (DPPC, DSPC and SM), retain significantly higher amounts of encapsulated material, under all conditions studied. Furthermore, the vesicles formed by mixing cholesterol with these lipids will possibly be sufficiently stable in the gastrointestinal tract for long periods of time. Sizing results reveal that in most cases release of encapsulated molecules is mainly caused by their leakage through holes formed on the lipid bilayer. However, in stearylamine containing DPPC and DSPC vesicles, the cholate-induced drastic decrease in vesicle size suggests total liposome disruption as the possible mechanism of encapsulated material immediate release.
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Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.