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Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the cerebral accumulation of extracellular amyloid plaques. In a previous study, this histopathological hallmark was used as a target on a dual-functional nanoparticle (TQNP) to deliver biotechnological drugs, such as the H102 peptide, a β-sheet breaker, to AD lesions precisely. This delivery system could reduce the amyloid-β (Aβ) burden in the brains of AD model mice, as well as ameliorated the memory impairment of the mice. Regretfully, the mechanism how nanoparticles penetrated the BBB and subsequently targeted to the plaques is still unclear. In this study, the internalization, subcellular fate and transportation of the nanoparticles on bEnd.3 cells and an in vitro BBB model, demonstrated that TQNP could be taken up through various routes, including caveolae-mediated endocytosis, suggesting that some of TQNP were able to cross the BBB intact. Then, the TQNP were visualized to specifically bind to the Aβ plaques. TQNP targeting to amyloid plaques might lead to enhanced therapeutic efficacy, which was further evaluated in APP/PS1 transgenic mice. The TQNP/H102 obtained better ability in decreasing amyloid plaques, increasing Aβ-degrading enzymes, reducing tau protein phosphorylation, protecting synapses and improving the spatial learning and memory of transgenic mice than nanoparticles modified with a single ligand. And good biocompatibility of TQNP was indicated with subacute toxicity assays. In conclusion, TQNP was a valuable nanodevice for the precise delivery for biotechnological drugs to treat AD. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer's disease (AD) is a common neurodegenerative disorder with few treatments. The limitations imposed by the blood–brain barrier (BBB) and the non-selective distribution of drugs in the brain have hindered the effective treatment of AD and may result in severe side effects on the normal brains. We developed a dual-functional nanoparticle drug delivery system based on a PEGylated poly (lactic acid) (PLA) polymer. Two targeting peptides that were screened by phage display, TGN and QSH, were conjugated to the surface of the nanoparticles. TGN specifically targets ligands at the BBB, while QSH has good affinity with Aβ1-42, which is the main component of amyloid plaque. Tests probing the bEnd.3 cell uptake and in vivo imaging were conducted to determine the best density of TGN on the nanoparticles' surfaces. The optimal amount of QSH was studied using a Thioflavin T (ThT) binding assay and surface plasmon resonance (SPR) experiments. The optimal maleimide/peptide molar ratio was 3 for both TGN and QSH on the surface of the nanoparticles (T3Q3-NP), and these nanoparticles achieved enhanced and precise targeted delivery to amyloid plaque in the brains of AD model mice. A MTT assay also validated the safety of this dual-targeted delivery system; little cytotoxicity was demonstrated with both bEnd.3 and PC 12 cells. In conclusion, the T3Q3-NP might be a valuable targeting system for AD diagnosis and therapy. [Copyright &y& Elsevier]

Within a complex biological sample, the in situ sequential detection of multiple molecules without any interference is greatly desirable. Dual-functional nanoparticles are constructed, with the enzyme-based core-shell structures, for the in situ sequential detection of ATP and H2 O2 within the same biological system., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Alzheimer's disease (AD) is a complex neurodegenerative disease with few effective treatments. The non-targeted distribution of drugs decreases drug efficiency and cause side effects. The cascade targeting strategy has been suggested for precise drug delivery. We developed a dual-functional nanoparticle drug delivery system loaded with β-sheet breaker peptide H102 (TQNP/H102). Two targeting peptides, TGN and QSH, were conjugated to the surface of the nanoparticles for blood-brain barrier transport and Aβ42 targeting, respectively. The prepared nanoparticles were spherical and uniform. The brain distribution study of H102 was conducted with the HPLC-mass spectrometry method to evaluate whether this nano-carrier could achieve increased AD-lesion delivery. The highest uptake of H102 was observed in the hippocampi of the TQNP/H102 group mice 1h after administration, which was 2.62 and 1.86 times the level of non-modified nanoparticles (NP/H102) and TGN modified nanoparticles (TNP/H102), respectively. The neuroprotective effects of H102 preparations were evaluated using Morris water maze experiment, biochemical indexes assay and tissue histology. The spatial learning and memory of the AD model mice in the TQNP/H102 group were significantly improved compared with the AD control group, and were also better than other preparations at the same dosage, even the TNP/H102 group. These results were consistent with the values of biochemical indexes in mouse hippocampi as well as the histological observations. The results demonstrate that TQNP is a promising carrier for peptide or protein drugs, such as H102, for entry into the central nervous system (CNS) and subsequent location of brain AD lesions, thus offering a highly-specific method for AD therapy., (Copyright © 2014 Elsevier B.V. All rights reserved.)