Peptoid Nanosheet-Based Sensing System for the Diagnosis and Surveillance of Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by progressive cognitive decline. Early diagnosis and dynamic monitoring are essential to the treatment and care of AD but challenging. Here we develop a noninvasive, blood-based AD detection method based on surface plasmonic resonance imaging (SPRi) technique. The functionalized sensing SPRi chips were constructed with self-assembled loop-displaying peptoid nanosheets to improve the detection sensitivity of plasma amyloid ß42 (Aß42). We analyze the plasma from 30 clinically diagnosed AD patients, 29 amnestic cognitive impairment (aMCI) patients, and 30 control individuals and demonstrate that this sensing system can significantly distinguish the three groups with high sensitivity and specificity. In the follow-up studies of the aMCI patients, we find that decrease in the binding signals in the patients correlates with the disease progression into AD whereas the almost unchanged signals correlate with stable disease remaining at aMCI status. These results show the capability of the peptoid-nanosheet-based SRPi sensing system for the early diagnosis and dynamic monitoring of AD.

Persistent Regulation of Tumor Hypoxia Microenvironment via a Bioinspired Pt-Based Oxygen Nanogenerator for Multimodal Imaging-Guided Synergistic Phototherapy.

Multifunctional nanoplatforms for imaging-guided synergistic antitumor treatment are highly desirable in biomedical applications. However, anticancer treatment is largely affected by the pre-existing hypoxic tumor microenvironment (TME), which not only causes the resistance of the tumors to photodynamic therapy (PDT), but also promotes tumorigenesis and tumor progression. Here, a continuous O2 self-enriched nanoplatform is constructed for multimodal imaging-guided synergistic phototherapy based on octahedral gold nanoshells (GNSs), which are constructed by a more facile and straightforward one-step method using platinum (Pt) nanozyme-decorated metal-organic frameworks (MOF) as the inner template. The Pt-decorated MOF@GNSs (PtMGs) are further functionalized with human serum albumin-chelated gadolinium (HSA-Gd, HGd) and loaded with indocyanine green (ICG) (ICG-PtMGs@HGd) to achieve a synergistic PDT/PTT effect and fluorescence (FL)/multispectral optoacoustic tomography (MSOT)/X-ray computed tomography (CT)/magnetic resonance (MR) imaging. The Pt-decorated nanoplatform endows remarkable catalase-like behavior and facilitates the continuous decomposition of the endogenous H2O2 into O2 to enhance the PDT effect under hypoxic TME. HSA modification enhances the biocompatibility and tumor-targeting ability of the nanocomposites. This TME-responsive and O2 self-supplement nanoparticle holds great potential as a multifunctional theranostic nanoplatform for the multimodal imaging-guided synergistic phototherapy of solid tumors.

Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease by the Plasma and Serum Amyloid-beta 42 Assay through Highly Sensitive Peptoid Nanosheet Sensor.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with a continuous pathophysiological process starting from the preclinical and mild cognitive impairment (MCI) phases to the dementia phase. Early diagnosis is prerequisite for the early intervention of AD but meanwhile challenging. Amyloid-beta 1-42 (Aß42) plays a crucial part in AD pathology. Positron-emission tomography (PET) imaging of Aß42 in the brain and the measurement of Aß42 in the cerebrospinal fluid (CSF) have been adopted for the auxiliary diagnosis of AD, but their widespread clinical application has been limited due to the radiation and the high-cost of PET and the invasive lumbar puncture for collecting CSF. Noninvasive and cost-effective blood-based assay is desirable for the early diagnosis of AD. Here, a label-free assay for the quantification of blood Aß42 was developed using the high-throughput surface plasmon resonance imaging method with the aid of an antibody-mimetic peptoid nanosheet equipping Aß42-recognizing loops. We demonstrated that this nanosheet-based sensor system could distinguish the plasma and sera from normal individuals and patients suffering AD and amnestic MCI with high sensitivity and specificity, preceding the diagnostic performance of the Aß42-recognizing molecule and the antibody specific to Aß42. This work provides a label-free, cost-effective, highly sensitive, and high-throughput blood-based assay for early detection of AD.

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas.

Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a "one-bead one-compound" (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both in vitro and in vivo, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.

Detection of Parkinson's Disease through the Peptoid Recognizing α-Synuclein in Serum.

Parkinson's disease (PD) is a severe neurodegenerative disease and there is great need for developing a biochemical detection method to precisely diagnose it. Alpha-synuclein (α-syn) participates in the main pathology of PD and serves as an important biomarker of PD. Here, we identified peptoid ASBP-7 that had high affinity and specificity to α-syn by screening a peptoid library using the high-throughput surface plasmon resonance imaging method. We confirmed that ASBP-7 could significantly distinguish PD sera from the normal ones through identifying α-syn in the serum. We also demonstrated the high sensitivity of this system in detecting PD serum. This work provides a method for the blood-based, label-free, high-throughput analysis of PD serum, and holds great potential for the early diagnosis and dynamic monitoring of PD.

In Situ Observation of Amyloid Nucleation and Fibrillation by FastScan Atomic Force Microscopy.

Amyloidogenic proteins are key components in various amyloid diseases. The aggregation process and the local structural changes of the toxic species from toxic oligomers to protofibrils and subsequently to mature fibrils are crucial for understanding the molecular mechanism of the amyloidgenic process and also for developing a treatment strategy. Exploration on amyloid aggregation dynamics in situ under real liquid condition is feasible for reflection of the whole process with biological correlations. Herein we report the in situ dynamic study and structure exploration of Amylin1-37 aggregation by FastScan atomic force microscopy. Amylin1-37 nucleation process was observed in which smaller oligomers or monomers were assimilated by the surrounding big oligomers. Amylin1-37 protofibril aggregation was positively correlated with monomer concentration, whereas no direct relationship was observed between fibril elongation and monomer concentration. Growing end and passivated end were found during Amylin1-37 fibrillation. In the assembly process, the growing end kept its structure, and its stiffness was lower than the aggregate body, whereas the passivated end might experience rearrangements of ß-structures, which eventually enabled fibril growth from this end. This work is beneficial to the insights of amyloid fibrillation and may shed light on the development of drugs targeting the specific phase of amyloid aggregation.

Emerging Nanotechnologies for Liquid Biopsy: The Detection of Circulating Tumor Cells and Extracellular Vesicles.

Liquid biopsy enables noninvasive and dynamic analysis of molecular or cellular biomarkers, and therefore holds great potential for the diagnosis, prognosis, monitoring of disease progress and treatment efficacy, understanding of disease mechanisms, and identification of therapeutic targets for drug development. In this review, the recent progress in nanomaterials, nanostructures, nanodevices, and nanosensors for liquid biopsy is summarized, with a focus on the detection and molecular characterization of circulating tumor cells (CTCs) and extracellular vesicles (EVs). The developments and advances of nanomaterials and nanostructures in enhancing the sensitivity, specificity, and purity for the detection of CTCs and EVs are discussed. Sensing techniques for signal transduction and amplification as well as visualization strategies are also discussed. New technologies for the reversible release of the isolated CTCs and EVs and for single-CTC/EV analysis are summarized. Emerging microfluidic platforms for the integral on-chip isolation, detection, and molecular analysis are also included. The opportunities, challenges, and prospects of these innovative materials and technologies, especially with regard to their feasibility in clinical applications, are discussed. The applications of nanotechnology-based liquid biopsy will bring new insight into the clinical practice in monitoring and treatment of tumor and other significant diseases.