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Dual targeting nanoparticles for epilepsy therapy.

ABSTRACT: For epilepsy therapy, one-third of the patients worldwide are resistant to antiepileptic drugs mainly due to the existence of the blood-brain barrier (BBB) that prevents the drugs from reaching the epileptic lesions. Here, we design a double targeting nanoparticle carrying lamotrigine (LTG) to cross the BBB and further concentrate at the neurons. We prepare the nanoparticles on a microfluidic chip by encapsulating LTG in poly(lactic-co-glycolic acid) (PLGA) to form a core (PL) and capping the core with a shell of lipids conjugated with the D-T7 peptide (targeting the BBB) and Tet1 peptide (targeting the neuron) to form D-T7/Tet1-lipids@PL nanoparticles (NPs). In vitro and in vivo experiments show that D-T7/Tet1-lipids@PL NPs have excellent neuron targeting, antiepileptic, and protecting effects. Our approach provides a new strategy for improving the therapeutic efficacy of existing antiepileptic drugs.

SUBMITTER: Hou Q

PROVIDER: S-EPMC9645397 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Dual targeting nanoparticles for epilepsy therapy.

Hou Qinghong Q Wang Lulu L Xiao Feng F Wang Le L Liu Xiaoyan X Zhu Lina L Lu Yi Y Zheng Wenfu W Jiang Xingyu X

Chemical science 20221019 43

For epilepsy therapy, one-third of the patients worldwide are resistant to antiepileptic drugs mainly due to the existence of the blood-brain barrier (BBB) that prevents the drugs from reaching the epileptic lesions. Here, we design a double targeting nanoparticle carrying lamotrigine (LTG) to cross the BBB and further concentrate at the neurons. We prepare the nanoparticles on a microfluidic chip by encapsulating LTG in poly(lactic-<i>co</i>-glycolic acid) (PLGA) to form a core (PL) and capping ...[more]

PMID: 36519053

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Project description:ObjectiveThe ability to regulate B cell development has long been recognized to have therapeutic potential in a variety of autoimmune diseases. However, despite the presence of a classic autoantibody in primary biliary cholangitis (PBC), B cell depleting therapy and indeed therapy with other biologic agents has been disappointing. Unsuccessful treatment using Rituximab is associated with elevation of B-cell activating factor (BAFF) level. Indeed, therapies for PBC remain directed at modulating bile salt biology, rather than targeting effector pathways. With these data in mind, we proposed that targeting two major stages of B cell development, namely long-lived memory B cells and short-lived peripheral autoreactive plasma cells would have therapeutic potential.MethodsTo address this thesis, we administrated anti-BAFF and anti-CD20 monoclonal antibody to ARE-Del mice, a well-characterized murine model of human PBC. We evaluated and compared the therapeutic efficacy of the two agents individually and the combination of anti-BAFF and anti-CD20 in female mice with well-established disease.ResultsOur data demonstrate that there was an increased level of B cell depletion that resulted in a significantly more effective clinical and serologic response using the combination of agents as compared with the use of the individual agents. The combination of anti-BAFF and anti-CD20 treatment was more effective in reducing serum levels of antimitochondrial antibody (AMA), total IgM and IgG compared to mice treated with the 2 individual agents. Combination treatment efficiently depleted B cells in the peripheral blood, peritoneal cavity and spleen. Importantly, we identified a unique IgM+ FCRL5+ B cell subset which was sensitive to dual B-cell targeting therapy and depletion of this unique population was associated with reduced portal infiltration and bile duct damage. Taken together, our data indicate that dual B cell targeting therapy with anti-BAFF and anti-CD20 not only led to the efficient depletion of B cells both in the peripheral blood and tissues, but also led to significant clinical improvement. These findings highlight the potential application of combination of anti-BAFF and anti-CD20 in treating patients with PBC. However, additional studies in other animal models of PBC should be undertaken before considering human trials in those PBC patients who have incomplete responses to conventional therapy.

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Dual targeting nanoparticles for epilepsy therapy.

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Dual targeting nanoparticles for epilepsy therapy.

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