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Biocompatible and blood-brain barrier permeable carbon dots for inhibition of A? fibrillation and toxicity, and BACE1 activity.

ABSTRACT: Amyloid-? peptide (A?) fibrillation is pathologically associated with Alzheimer's disease (AD), and this has resulted in the development of an A? inhibitor which is essential for the treatment of AD. However, the design of potent agents which can target upstream secretases, inhibit A? toxicity and aggregation, as well as cross the blood-brain barrier remains challenging. In, this research carbon dots for AD treatment were investigated in vitro using experimental and computational methods for the first time. The results presented here demonstrate a novel strategy for the discovery of novel antiamyloidogenic agents for AD treatments.

SUBMITTER: Han X

PROVIDER: S-EPMC5660677 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Biocompatible and blood-brain barrier permeable carbon dots for inhibition of Aβ fibrillation and toxicity, and BACE1 activity.

Han Xu X Jing Zhifeng Z Wu Wei W Zou Bing B Peng Zhili Z Ren Pengyu P Wikramanayake Athula A Lu Zhongmin Z Leblanc Roger M RM

Nanoscale 20170901 35

Amyloid-β peptide (Aβ) fibrillation is pathologically associated with Alzheimer's disease (AD), and this has resulted in the development of an Aβ inhibitor which is essential for the treatment of AD. However, the design of potent agents which can target upstream secretases, inhibit Aβ toxicity and aggregation, as well as cross the blood-brain barrier remains challenging. In, this research carbon dots for AD treatment were investigated in vitro using experimental and computational methods for the ...[more]

PMID: 28850143

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Project description:Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

Dataset Information

Biocompatible and blood-brain barrier permeable carbon dots for inhibition of A? fibrillation and toxicity, and BACE1 activity.

Publications

Biocompatible and blood-brain barrier permeable carbon dots for inhibition of Aβ fibrillation and toxicity, and BACE1 activity.

Similar Datasets

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