Cholinergic Neuron Targeting Nanosystem Delivering Hybrid Peptide for Combinatorial Mitochondrial Therapy in Alzheimer’s Disease

ACS Nano, Год журнала: 2022, Номер 16(7), С. 11455 - 11472

Опубликована: Июль 15, 2022

Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer’s disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic effects. Therefore, we developed multifunctional hybrid peptide HNSS composed antioxidant SS31 and neuroprotective S14G-Humanin. However, suitable delivery systems with excellent loading capacity effective at-site are still absent. Herein, the nanoparticles made citraconylation-modified poly(ethylene glycol)-poly(trimethylene carbonate) polymer (PEG-PTMC(Cit)) exhibited desirable electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1(FGFR1) overexpression both blood–brain barrier cholinergic neuron, an FGFR1 ligand-FGL was modified nanosystem (FGL-NP(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation brain preferred distribution into diseased region. The acid-sensitive property facilitated lysosomal escape intracellular drug release by charge switching, resulting enrichment directing part. FGL-NP(Cit)/HNSS effectively rescued via PGC-1α STAT3 pathways, inhibited Aβ deposition tau hyperphosphorylation, ameliorated memory defects neuronal damage 3xTg-AD mice. work provides potential platform targeted cationic delivery, harboring utility therapy other neurodegenerative diseases.

Язык: Английский

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Recent Progress of RGD Modified Liposomes as Multistage Rocket Against Cancer

Frontiers in Pharmacology, Год журнала: 2022, Номер 12

Опубликована: Янв. 25, 2022

Cancer is a life-threatening disease, contributing approximately 9.4 million deaths worldwide. To address this challenge, scientific researchers have investigated molecules that could act as speed-breakers for cancer. As an abiotic drug delivery system, liposomes can hold both hydrophilic and lipophilic drugs, which promote controlled release, accumulate in the tumor microenvironment, achieve elongated half-life with enhanced safety profile. further improve impair off-target effect, surface of be modified way easily identified by cancer cells, promotes uptake, facilitates angiogenesis. Integrins are overexpressed on upon activation downstream cell signaling eventually activate specific pathways, promoting growth, proliferation, migration. RGD peptides recognized integrin over expressed cells. Just like multistage rocket, ligand anchored selectively target at site, finally, release desired way. This review highlights role development, so gain more insights into phenomenon initiation survival. Since family, fate has been demonstrated after its binding acceptor’s family. The based targeting various cells also highlighted paper.

Язык: Английский

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Intelligent lesion blood–brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection

Acta Pharmaceutica Sinica B, Год журнала: 2022, Номер 12(4), С. 1987 - 1999

Опубликована: Фев. 10, 2022

The treatment of Alzheimer's disease (AD) is one the most difficult challenges in neurodegenerative diseases due to insufficient blood‒brain barrier (BBB) permeability and unsatisfactory intra-brain distribution drugs. Therefore, we established an ibuprofen FK506 encapsulated drug co-delivery system (Ibu&FK@RNPs), which can target receptor advanced glycation endproducts (RAGE) response high level reactive oxygen species (ROS) AD. RAGE highly specifically expressed on lesion neurovascular unit AD, this property helps improve targeting specificity reduce unselective normal brain. Meanwhile, these two drugs be released astrocytes AD levels ROS. As a result, cognition mice was significantly improved quantity Aβ plaques decreased. Neurotoxicity also alleviated with structural regeneration functional recovery neurons. Besides, neuroinflammation dominated by NF-κB pathway inhibited decreased IL-1β Overall, Ibu&FK@RNPs efficiently successively diseased BBB lesion. Thus it enhances intracephalic accumulation treats anti-neuroinflammation neuroprotection.

Язык: Английский

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Salmonella-mediated blood‒brain barrier penetration, tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Acta Pharmaceutica Sinica B, Год журнала: 2022, Номер 13(2), С. 819 - 833

Опубликована: Сен. 25, 2022

Chemotherapy is an important adjuvant treatment of glioma, while the efficacy far from satisfactory, due not only to biological barriers blood‒brain barrier (BBB) and blood‒tumor (BTB) but also intrinsic resistance glioma cells via multiple survival mechanisms such as up-regulation P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, targeting, chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region modulated microenvironment, including macrophages repolarization neutrophils infiltration. Specifically, migration was employed hitchhiking doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/DOX). By virtue surface pathogen-associated molecular patterns derived native bacteria, OMVs/DOX could be recognized by neutrophils, thus facilitating targeted with significantly enhanced accumulation 18-fold compared classical passive targeting effect. Moreover, P-gp expression on silenced bacteria type III secretion effector sensitize DOX, resulting in complete eradication 100% all treated mice. In addition, were finally cleared anti-bacterial activity DOX minimize potential infection risk, cardiotoxicity avoided, achieving excellent compatibility. This work provides efficient trans-BBB/BTB cell therapy.

Язык: Английский

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Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

Research, Год журнала: 2023, Номер 6

Опубликована: Янв. 1, 2023

Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer’s disease (AD). The intricate pathogenesis causes severe impairment neurons, which, turn, exacerbates Aβ aggregation facilitates AD progression. Herein, multifunctional melanin-like ion chelators neuroinflammation regulators (named PDA@K) were constructed for targeted treatment AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) potent chelating ROS scavenging effects decorated the KLVFF peptide, endowing system capacity enhanced pathological blood–brain barrier (BBB) crossing lesion site accumulation via hitchhiking. vitro vivo experiment revealed that PDA@K had high affinity toward able to hitch a ride on achieve increased BBB crossing. engineered effectively mitigated aggregate alleviated neuroinflammation. modulated inflammatory microenvironment by promoted microglial polarization M2-like phenotype, which restored their functions neuron care plaque removal. After 3-week PDA@K, spatial learning memory deficit as well neurologic changes FAD 4T transgenic mice largely rescued. Transcriptomics analysis further therapeutic mechanism PDA@K. Our study provided an appealing paradigm directly utilizing intrinsic properties nanomaterials therapeutics instead just using them nanocarriers, widen application therapy.

Язык: Английский

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