Advances in anti-Alzheimer’s disease nano drug delivery system based on pathogenic mechanism of ferroptosis
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摘要:
铁死亡是一种铁依赖性脂质过氧化和活性氧过度积累诱发的程序性细胞死亡方式，被证明是阿尔茨海默病（Alzheimer’s disease，AD）进展过程中神经元死亡的关键病理机制，形成AD致病“铁死亡假说”。近年，基于铁死亡致病机制的AD治疗研究主要为脑内铁代谢和微环境氧化还原失衡调控，但血脑屏障及脑内复杂病理环境限制了药物脑内转运、分布及治疗效果，对药物递送技术提出了新要求。本综述在阐述细胞铁死亡过程及其调控机制的基础上，探讨了铁过载和氧化还原失衡与神经元丢失及AD进展的相关性，并基于铁过载和氧化还原失衡综述了抗AD纳米药物递送系统研究进展，为AD治疗和新药研发提供新思路。
Abstract:Ferroptosis, a programmed cell death induced by iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species, is a key pathological mechanism of neuronal death during the progression of Alzheimer’s disease (AD), contributing to the formation of “Ferroptosis Hypothesis” for AD pathogenesis. In recent years, there has been extensive research on therapeutic strategies for AD based on the pathogenic mechanism of ferroptosis, focusing primarily on the dysregulation of brain iron metabolism and redox regulation in microenvironment. However, presence of blood-brain barrier and intricate pathological environment within brain impose limitations on intracranial drug transportation, distribution and therapeutic efficacy, thereby necessitating advancements in drug delivery technology. Based on description of ferroptosis process and its regulatory mechanisms, this review explores the association between iron overload and redox imbalance with neuronal loss and AD development, and additionally, summarizes the advancements in nano drug delivery systems targeting iron overload and redox imbalance for potential anti-AD treatments, so as to offer some novel perspectives for AD treatment and drug development.
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Figure 1. Anti-ferroptosis strategies by alleviating iron overload
A: Synthesis of PLGA nanoparticle-chelator conjugate (Nano-N2PY)[5]; B: Schematic diagram of Lactoferrin-galantamine (Lf-Gal) nanoparticle fabrication, and corresponding Gal release upon iron absorption[8]; C: Structure illustration of IgG capped gold nanocage (AuNC-IgG) and photothermal-responsive H2O2-fueled release of guest molecules clioquinol (CQ) from AuNC-IgG[9]; D: Schematic illustration of curcumin-lactoferrin nanoparticles (CUR-LF NPs) preparation, and neuroprotection mechanism of CUR-LF NPs via intranasal administration[10]; E: Fabrication of transferrin-functionalization of nanoparticle[14]; F: Resveratrol (RSV) loaded mesoporous silica nanoparticle with Ac-[cMPRLRGC]c-NH2 peptide modification on surface[15]
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Figure 2. Multiple pathways inhibit ferroptosis by resisting oxidative distress and inhibiting lipid peroxidation, including System Xc-/GSH/GPX4 pathway, FSP1/CoQ10 pathway, GCH/DHFR/BH4 pathway, DHODH/CoQ pathway, and p62/Keap1/Nrf2 pathway (Created with BioRender.com)
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Figure 3. Anti-ferroptosis strategies by regulating lipid peroxidation in neuron
A: Intranasal administration of quercetin, vitamin E, and basil oil for anti-oxidation[17]; B: Preparation of baicalein (Ba) loaded nanoliposome (NLP-Ba) and antioxidation of NLP-Ba neuroprotection[20]; C: Fabrication and intranasal administration of N-acetylcysteine (NAC) and rivastigmine (RIV) co-loaded niosomes[24]; D: Synthesis route of multifunctional double selenium nanosphere (CLNDSe)[29]; E: Formulation and characterization of CoQ10-loaded nano-micelle (Ubisol-Q10)[35]; F: Schematic illustration of micelles co-modified with neural cell adhesion molecule (NCAM) mimetic peptide C3 and triphenylphosphonium (TPP) for targeting the mitochondria of the central neurons, reversing mitochondrial dysfunction[37]
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