Calixarenes (CAs), representing the third generation of supramolecular hosts and one of the most widely studied macrocyclic scaffolds, offer (almost) unlimited structure and application possibilities ...due to their ease of modification, which allows one to establish a large molecular library as a material basis for diverse biomedical applications. Moreover, CAs and their derivatives engage in various noncovalent interactions for the facile recognition of guests including bioactive molecules and are also important building blocks for the fabrication of supramolecular architectures. In view of their molecular recognition and self‐assembly properties, CAs are extensively applied in biosensing, bioimaging, and drug/gene delivery. Additionally, some CA derivatives exhibit biological activities and can therefore be used as new therapeutic agents. Herein, we summarize the diverse biomedical applications of CAs including in vitro diagnosis (biosensing), in vivo diagnosis (bioimaging), and therapy.
Calixarenes (CAs) represent the third generation of supramolecular hosts and one of the most widely studied macrocyclic scaffolds. They offer almost unlimited structural possibilities due to their ease of modification, providing a tremendous molecular library as a material basis for diverse biomedical applications.
Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor ...retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.
A smart albumin‐based theranostic nanoagent composed of human serum albumin, dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (an HSP90 inhibitor and an effective anticancer drug) is fabricated, which can achieve the synergistic molecular targeting‐mediated mild‐temperature photothermal therapy and chemotherapy of cancer.
Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Several proteins including α-synuclein trigger the activation ...of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD.
There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein.
We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels.
Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.
Excess accumulation of amyloid‐β (Aβ) protein in the brain is the primary pathogenesis of Alzheimer's disease (AD). Inhibition of Aβ fibrillation and disaggregation of Aβ fibrils is an attractive ...therapeutic and preventive strategy for Aβ‐induced AD. Here, near infrared (NIR) light‐responsive nanoparticles (NPs) composed of amphiphilic guanidinocalix5arene (GC5A), 4‐(dodecyloxy)benzamido‐terminated methoxy poly(ethylene glycol), and photothermal conjugated polymer PDPP are fabricated. The NIR light‐responsive NPs can efficiently penetrate the blood‐brain barrier (BBB), inhibit amyloid‐β 42 (Aβ42) fibrillation, and disaggregate fibrils after NIR light irradiation. Through the advantage of containing GC5A, the NPs exhibit extremely strong binding affinity for the Aβ42 protein. Interestingly, upon NIR light irradiation, benefiting from the high photothermal conversion efficiency of PDPP, NPs generate local heat and effectively promote the BBB permeability. Moreover, NPs are multifunctional platforms for the inhibition of Aβ42 fibrillation and disaggregation of fibrils after irradiation with NIR light, distinctly reducing cytotoxicity and eliminating Aβ42 plaques in the hippocampus of AD mice. Hence, NPs provide an interesting strategy for the inhibition and disaggregation of Aβ42 fibrillation and present an excellent therapeutic strategy for amyloidosis.
The near infrared (NIR) light‐responsive nanoparticles (NPs) composed of calixarene (GC5A), and a conjugated polymer (PDPP) exhibit efficient permeability through the blood‐brain barrier and inhibit and disaggregate Aβ42 fibrillation. Upon NIR light irradiation, the NPs generate local heat and efficiently disaggregate Aβ42 fibrils, leading to the cytotoxicity of Aβ42 fibrils reduce, and eliminate Aβ42 plaques in Alzheimer's disease mouse brain.
The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl ...groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O
as a green oxidant. The C-H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2'-deoxy-5-difluoromethyluridine (F
TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.
Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop ...KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.
Pseudo-Nambu-Goldstone dark matter can interact with Standard Model fermion through the Higgs portal, and some models can emerge a cancellation mechanism that helps to escape the stringent ...constraints from direct detection experiments. In this paper we explore new constraints of these cancellation models on parameter space of non-zero momentum transfer, from both the current direct detection experiment and the neutron star temperature via the dark matter reheating mechanism.
An improved equivalent-input-disturbance (EID) approach is devised to enhance the disturbance-rejection performance for a strictly proper plant with a state delay in a modified repetitive-control ...system. A gain factor is introduced to construct an improved EID estimator. This increases the flexibility of system design and enables the adjustment of the dynamical performance of disturbance rejection. Moreover, the commutative condition, which is widely used for the conventional EID estimator, is avoided. Thus, it reduces the conservativeness of design by removing the constraints imposed by the commutative condition. The system is divided into two subsystems, and the separation theorem is applied to simplify the design. For one subsystem, the delay information on both the modified repetitive controller and the plant is used to reduce the conservativeness of stability condition. The resulting linear matrix inequality ('MI) is used to find the gain of the state-feedback controller. Another 'MI is derived to design the gains of the state observer and the improved EID estimator for the other subsystem. A case study on a metal-cutting system validates the superiority of the developed method.
The imbalance of amyloid‐β (Aβ) production and clearance causes aggregation of Aβ1‐42 monomers to form fibrils and amyloid plaques, which is an indispensable process in the pathogenesis of ...Alzheimer's disease (AD), and eventually leads to pathological changes and cognitive impairment. Consequently, Aβ1‐42 is the most important target for the treatment of AD. However, developing a single treatment method that can recognize Aβ1‐42, inhibit Aβ1‐42 fibrillation, eliminate amyloid plaques, improve cognitive impairments, and alleviate AD‐like pathology is challenging. Here, a coassembly composed of cyclodextrin (CD) and calixarene (CA) is designed, and it is used as an anti‐Aβ therapy agent. The CD–CA coassembly is based on the previously reported heteromultivalent recognition strategy and is able to successfully eliminate amyloid plaques and degrade Aβ1‐42 monomers in 5xFAD mice. More importantly, the coassembly improves recognition and spatial cognition deficits, and synaptic plasticity impairment in the 5xFAD mice. In addition, the coassembly ameliorates AD‐like pathology including prevention of neuronal apoptosis and oxidant stress, and alteration of M1/M2 microglial polarization states. This supramolecular approach makes full use of both molecular recognition and self‐assembly of macrocyclic amphiphiles, and is a promising novel strategy for AD treatment.
A heteromultivalent coassembly composed of cyclodextrin and calixarene (CD–CA coassembly) according to the composition of amino acids in Aβ1‐42 effectively recognizes and disaggregates Aβ1‐42 fibrils. Intranasal administration of the CD–CA coassembly eliminates amyloid plaque and neurodegeneration in the brain, and improves cognitive deficits in 5xFAD mice. This supramolecular approach is a promising novel strategy for treatment of Alzheimer's disease (AD).
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