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A Novel Targeted and High?Efficiency Nanosystem for Combinational Therapy for Alzheimer's Disease

ABSTRACT: Abstract Alzheimer's disease (AD) remains the most prevalent neurodegenerative disease, and no effective treatment is available yet. Metal?ion?triggered aggregates of amyloid?beta (A?) peptide and acetylcholine imbalance are reported to be possible factors in AD pathogenesis. Thus, a combination therapy that can not only inhibit and reduce A? aggregation but also simultaneously regulate acetylcholine imbalance that can serve as a potential treatment for AD is needed. Here, clioquinol (metal?ion chelating agent) and donepezil (acetylcholinesterase (AChE) inhibitor) co?encapsulated human serum albumin (HSA) nanoparticles (dcHGT NPs) are designed, which are modified with transcriptional activator protein (TAT) and monosialotetrahexosylganglioside (GM1). The GM1 lipid and TAT peptide endow this drug delivery nanosystem with high brain entry efficiency and long?term retention capabilities through intranasal administration. It is found that dcHGT NPs can significantly inhibit and eliminate A? aggregation, relieve acetylcholine?related inflammation in microglial cells, and protect primary neurons from A? oligomer?induced neurotoxicity in vitro. The alleviation of A??related inflammation and AChE?inhibited effect further synergistically adjust acetylcholine imbalance. It is further demonstrated that dcHGT NPs reduce A? deposition, ameliorate neuron morphological changes, rescue memory deficits, and greatly improve acetylcholine regulation ability in vivo. This multifunctional synergetic nanosystem can be a new candidate to achieve highly efficient combination therapy for AD. This study demonstrates that clioquinol and donepezil co?encapsulated human serum albumin nanoparticles (dcHGT NPs) mitigate AD dysfunction to modulate A??related inflammation and neuronal damage. The alleviation of A??related inflammation and AChE inhibited effect further synergistic ally adjust acetylcholine imbalance, which inhibits the subsequent pathological cascades. dcHGT NPs could be a promising high?efficiency targeting nanoplatform for the combination therapy of AD.

SUBMITTER: Yang H

PROVIDER: S-EPMC7539195 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:BackgroundTargeted delivery of anticancer chemotherapeutics such as mitoxantrone (MTX) can significantly intensify their cytotoxic effects selectively in solid tumors such as breast cancer. In the current study, folic acid (FA)-armed and MTX-conjugated magnetic nanoparticles (MNPs) were engineered for targeted eradication of folate receptor (FR)-positive cancerous cells. Polyethylene glycol (PEG), FA and MTX were covalently conjugated onto the MNPs to engineer the PEGylated FA-MTX-MNPs. The internalization studies were performed using fluorescein isothiocyanate (FITC)-labeled FA-decorated MNPs (FA-FITC-MNPs) in both FR-positive MCF-7 cells and FR-negative A549 cells by means of fluorescence microscopy and flow cytometry. The cellular and molecular impacts of FA-MTX-MNPs were examined using trypan blue cell viability and FITC-labeled annexin V apoptosis assays and 4',6-diamidino-2-phenylindole (DAPI) staining, DNA ladder and quantitative polymerase chain reaction (qPCR) assays.ResultsThe FR-positive MCF-7 cells showed significant internalization of the FA-FITC-MNPs, but not the FR-negative A549 cells. The FR-positive cells treated with the PEGylated FA-MTX-MNPs exhibited the IC50 values of 3 ?g/mL and 1.7 ?g/mL, 24 h and 48 h post-treatment, respectively. DAPI staining and DNA ladder assays revealed significant condensation of nucleus and fragmentation of genomic DNA in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs as compared to the FR-negative A549 cells. The FITC-labeled annexin V assay confirmed emergence of late apoptosis (>80%) in the FR-positive MCF-7 cells treated with the PEGylated FA-MTX-MNPs, but not in the FR-negative A549 cells. The qPCR analysis confirmed profound cytotoxic impacts via alterations of apoptosis-related genes induced by MTX-FA-MNPs in MCF-7 cells, but not in the A549 cells.ConclusionOur findings evince that the engineered PEGylated FA-MTX-MNPs can be specifically taken up by the FR-positive malignant cells and effectively demolish them through up-regulation of Bcl-2-associated X protein (Bax) and Caspase 9 and down-regulation of AKt. Hence, the engineered nanosystem is proposed for simultaneous targeted imaging and therapy of various cancers overexpressing FRs.

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A Novel Targeted and High?Efficiency Nanosystem for Combinational Therapy for Alzheimer's Disease

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