Extending dual-targeting upper-limit in liposomal delivery of lithospermic acid B for Alzheimer's mitochondrial revitalization.
J Control Release
; 367: 604-619, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38295997
ABSTRACT
Mitochondrial dysfunction is a pivotal event in Alzheimer's disease (AD) pathogenesis. Lithospermic acid B (LA) has shown promise in safeguarding mitochondria, yet the underlying mechanism remains elusive. Here, we present evidence that LA rejuvenated AD-related mitochondrial pool by co-activating mitophagy and mitochondria biogenesis via PINK1/LC3B/P62 and PGC-1α/Nrf2. To advance in vivo application, hydrophilic LA was encapsulated in liposome (MT-LIP@LA) composed of D-mannosamine-cholesterol/DSPE-PEG2000-Tet1/lecithin (molar ratio, 30.310) for cascaded brain-neuron targeting. MT-LIP demonstrated 4.3-fold enhanced brain accumulation (2.57%dose/g-brain) than LIP (0.60%dose/g-brain) and precisely targeted neurons at AD lesion sites. Mechanism studies unraveled factors contributing to the preeminent brain targeting ability of MT-LIP (1) high-density modified mannose efficiently binds to glucose transporter 1 (GLUT1) on blood-brain barrier (BBB); (2) prone to trafficking towards caveolin-Golgi pathway during transcytosis. This augmented therapeutic platform efficiently restored mitochondrial health, prevented neurodegeneration, and ameliorated memory deficits in 3 × Tg-AD transgenic mice. Our studies revealed the underlying pharmacological mechanism of LA and provided a concise but efficient platform for neuronal mitochondria quality control in vivo.
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Base de datos:
MEDLINE
Asunto principal:
Benzofuranos
/
Depsidos
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Enfermedad de Alzheimer
Idioma:
En
Revista:
J Control Release
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article