Tau‑targeting multifunctional nanocomposite based on tannic acid-metal for near-infrared fluorescence/magnetic resonance bimodal imaging-guided combinational therapy in Alzheimer's disease

“It is known that oxidative stress can induce apoptosis by activating the pro-apoptotic BCL2-associated X (Bax) and the downstream caspase-3 protein (Figure 4A) [48].”

“The etiology of AD includes the aggregation of amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) caused by hyperphosphorylated tau protein [1, 2].”

“To further confirm the antioxidative properties of IR780-Mn@TA-TPL NPs, a free radical scavenging experiment was performed using the classic α,α -diphenyl- β -picrylhydrazyl (DPPH) assay [39].”

“In the pathogenic milieu of AD, tau protein undergoes aberrant phosphorylation and then initiates a cascade of self-replicating protein aggregation that forms neurotoxic NFTs, resulting in neuronal injury and synaptic dysfunction [7].”

“Although significant efforts have been directed towards Aβ -centric interventions over the past few decades, the weak association between Aβ levels and cognitive decline highlights the urgent need to explore alternative therapeutic approaches [3-6].”

“Excess ROS generation can lead to mitochondrial dysfunction resulting in lower ΔΨm [45, 46].”

“DSPE-PEG-based nanocarriers are distinguished by their low critical micelle concentration (CMC), stable drug-loading capacity, and functional groups that are amenable to target-specific modification [27].”

“Consistent with previous studies, the expression of Bax and caspase 3 was increased in OA-induced cells (Figure 4B-D) [11].”

“Concurrently, during the asymptomatic prodromal phase of AD, there is a marked increase in reactive oxygen species (ROS) within the hippocampal and cortical regions, implicating oxidative stress may serve as a precursory event in AD pathogenesis [8-10].”

“The zeta potential of IR780-Mn@TA-TPL NPs was determined to be -16.5 mV, indicative of their suitability for in vivo applications (Figure 1C) [38].”

“…copolymer polyethylene glycol distearoylphosphatidylethanolamine (DSPE-PEG) is frequently employed in nanomedicine engineering due to its good biocompatibility and biodegradability, and it has been approved by the U.S. food and drug administration (FDA) for use in the medical field [26].”

“The etiology of AD includes the aggregation of amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) caused by hyperphosphorylated tau protein [1, 2].”

“Additionally, the catechol moieties within TA facilitate strong chelating interaction with metal ions for magnetic resonance imaging (MRI) that could achieve non-invasive imaging of brain tissues in AD with a high spatial resolution [18, 21].”

“Therefore, we introduced the Y-maze behavior test to explore spatial learning and memory in AD rats by recording the frequency and duration they spent in the new arm [52, 53].”

“To further tailor the nanocomposite for targeted AD therapy, we functionalized the NPs with a fusion peptide TPL ( l -TGNYKALHPHNGGGGGHLNILSTL WKYR) [33] that comprises a blood brain barrier (BBB)-penetrating peptide TGN and a neuron binding peptide Tet1 through a four-glycine linker, yielding…”

“The architecture of the nanocomposite utilizes the self-assembly of DSPE-PEG polymer molecules into nanomicelles with hydrophobic cavities that encapsulate IR780, a near-infrared (NIR) fluorescent dye that can be used for in vivo imaging due to its high photostability and minimal phototoxicity [32].”

“Natural polyphenolic antioxidants are increasingly recognized for their potential in AD therapy, attributable to their widespread availability, good biocompatibility and potent antioxidative properties [12].”

“Tannic acid (TA), a polyphenol comprised of a glucose core esterified with ten gallic acid units, stands out for its multifaceted therapeutic possibilities in AD [13-16].”

“Several works have employed Mn-enhanced MRI in preclinical animal models of neurodegenerative diseases through locally injected MnCl 2 to enhance of the contrast in the brain [23, 24].”

“…OA (300 ng in 1.5 µL of saline) or saline (0.9% NaCl for medical use, 1.5 µL) was stereotaxically microinjected into the right dorsal hippocampus (AP -3.8 mm, ML -2.5 mm, and DV -3.2 mm, according to the Rat Brain Paxinos Atlas) to establish the AD model and sham groups, respectively [11, 51].”

“Mouse brain microvascular endothelial (bEnd.3) cells were cultured on the upper layer for 7 days to form a monolayer layer of endothelial barrier (Figure S14B), and PC12 cells were seeded in the basolateral side [42].”

“In addition, tau pathogenesis in AD involves two key serine/threonine-specific protein kinases, protein kinase B (AKT) and its downstream kinase glycogen synthase kinase 3β (GSK3β) [49].”

“Thereafter, we induced an AD cell model by subjecting PC12 cells to 50 nM okadaic acid (OA) for 12 h, which provoked excessive neuronal ROS production, along with abnormal tau protein hyperphosphorylation and aggregation [43].”

“The dense hydroxyl groups of TA confer a robust capacity to neutralize deleterious ROS such as hydroxyl radical (•OH), hydrogen peroxide (H 2 O 2 ), and superoxide anions (O 2 •− ) [17, 18].”

“…structure of TA enables it to recognize the R3 peptide region of tau protein by forming hydrogen bond-mediated hairpin-like configurations, which is postulated to impede pathological conformational transitions and consequently mitigate the aggregation of neurotoxic tau filaments [19, 20].”

“Yet, TA suffers from the inherent limitations such as poor physiological stability and rapid degradation, which prevent it from reaching efficacious concentrations within the cerebral milieu and thereby limit its therapeutic potential [25].”

“The former aids in swiftly and effectively monitoring NPs accumulation at the lesion site via in vivo NIR FL imaging, thereby facilitating the investigation of dosage regimens to optimize the therapeutic efficacy of NPs [35, 36].”

“Mitochondrial superoxide constitutes the primary ROS species contributing to neuronal oxidative stress and subsequent cell death [44].”

“Several works have employed Mn-enhanced MRI in preclinical animal models of neurodegenerative diseases through locally injected MnCl 2 to enhance of the contrast in the brain [23, 24].”

“Tannic acid (TA), a polyphenol comprised of a glucose core esterified with ten gallic acid units, stands out for its multifaceted therapeutic possibilities in AD [13-16].”

“The screening was based on the thioflavin S (ThS) fluorescence assay where the emission of ThS was strongly increased upon binding to β -sheet structures present in tau aggregates [11, 40].”

“Moreover, Fourier-Transform Infrared (FT-IR) spectrum revealed that the strength of the phenolic hydroxyl group of TA at 3334 cm -1 was significantly weakened upon the formation of NPs (Figure 1B and S3), which hinted at intermolecular hydrogen bonding between TA and the PEG segments [29, 30].”

“In our study, we address this challenge by aligning TA at the nanoparticle interface through hydrogen bonding with PEG [29-31], thus devising an alternative encapsulation strategy for the preparation of TA-based nanotherapeutics.”

“Additionally, the catechol moieties within TA facilitate strong chelating interaction with metal ions for magnetic resonance imaging (MRI) that could achieve non-invasive imaging of brain tissues in AD with a high spatial resolution [18, 21].”

“Therefore, we introduced the Y-maze behavior test to explore spatial learning and memory in AD rats by recording the frequency and duration they spent in the new arm [52, 53].”

“We established an in vivo AD model by intracerebral administration of OA into rats to induce oxidative stress damage and tau hyperphosphorylation within the hippocampus (Figure 5A) [11, 50, 51].”

“Although significant efforts have been directed towards Aβ -centric interventions over the past few decades, the weak association between Aβ levels and cognitive decline highlights the urgent need to explore alternative therapeutic approaches [3-6].”

“However, the hydrophilic nature of TA poses a challenge for encapsulation within DSPE-PEG nanocarriers using standard nanoprecipitation techniques [28].”

“…structure of TA enables it to recognize the R3 peptide region of tau protein by forming hydrogen bond-mediated hairpin-like configurations, which is postulated to impede pathological conformational transitions and consequently mitigate the aggregation of neurotoxic tau filaments [19, 20].”

“Among MRI contrast agents, manganese (Mn) exhibits strong paramagnetism and significantly shortens the T1 relaxation time, making it an excellent candidate for MRI applications [22].”

“Concurrently, during the asymptomatic prodromal phase of AD, there is a marked increase in reactive oxygen species (ROS) within the hippocampal and cortical regions, implicating oxidative stress may serve as a precursory event in AD pathogenesis [8-10].”

“The former aids in swiftly and effectively monitoring NPs accumulation at the lesion site via in vivo NIR FL imaging, thereby facilitating the investigation of dosage regimens to optimize the therapeutic efficacy of NPs [35, 36].”

“Excess ROS generation can lead to mitochondrial dysfunction resulting in lower ΔΨm [45, 46].”

“Moreover, Fourier-Transform Infrared (FT-IR) spectrum revealed that the strength of the phenolic hydroxyl group of TA at 3334 cm -1 was significantly weakened upon the formation of NPs (Figure 1B and S3), which hinted at intermolecular hydrogen bonding between TA and the PEG segments [29, 30].”

“…in the formation of IR780-Mn@TA NPs. X-ray photoelectron spectroscopy (XPS) analysis of O 1s spectra suggested the formation of O-Mn with a binding energy located at 530.26 eV, indicating the presence of coordination between Mn and the hydroxyl groups of TA in IR780-Mn@TA NPs (Figure S4) [37].”

“This includes engineering small, lipophilic nanoparticles or applying external stimuli like focused ultrasound or light [229].”

“[120].”

“Under physiological conditions, Tau stabilizes neuronal microtubules; however, hyperphosphorylation reduces its binding affinity, leading to microtubule destabilization, formation of neurofibrillary tangles, and ultimately impaired axonal transport, synaptic loss, and neurode-generation [139–141].”

“A significant portion of the studies use MRI with contrast agents based on gadolinium [70,71], SPIONs [58,63,73,83], or manganese ions [72], reflecting the researchers’ desire to create platforms potentially applicable in clinical practice.”

“In addition, imaging-oriented theranostic approaches have been explored to monitor Tau pathology progression and therapeutic response [ 19 ].”

“91 Ultrasound-responsive carriers exploit inertial cavitation (microbubbles) for transient BBB opening or piezoelectric materials (eg, MoS 2 @Bi 2 S 3 ) for non-thermal ROS generation and antioxidant catalysis.”

“Overcoming the BBB remains a major bottleneck for CNS drug delivery, and receptor-mediated transcytosis (RMT) has been validated as one of the most practical and effective pathways to address this challenge [32,33].”