Wavelength engineerable porous organic polymer photosensitizers with protonation triggered ROS generation.

Engineering excitation wavelength of photosensitizers (PSs) for enhanced reactive oxygen species (ROS) generation has inspired new windows for opportunities, enabling investigation of previously impracticable biomedical and photocatalytic applications. However, controlling the wavelength corresponding to operating conditions remains challenging while maintaining high ROS generation. To address this challenge, we implement a wavelength-engineerable imidazolium-based porous organic photocatalytic ROS generation system (KUP system) via a cost-effective one-pot reaction. Remarkably, the optimal wavelength for maximum performance can be tuned by modifying the linker, generating ROS despite the absence of metal ions and covalently attached heavy atoms. We demonstrate that protonated polymerization exclusively enables photosensitization and closely interacts with oxygen related to the efficiency of photosensitizing. Furthermore, superior tumor eradication and biocompatibility of the KUP system were confirmed through bioassays. Overall, the results document an unprecedented polymerization method capable of engineering wavelength, providing a potential basis for designing nanoscale photosensitizers in various ROS-utilizing applications.

Mitochondrial targeted AIEgen phototheranostics for bypassing immune barrier via encumbering mitochondria functions.

Photodynamic therapy combined with immunogenic cell death has been proposed to overcome the unsolvable problems of single therapy, such as high levels of tumor recurrence and treatment resistance of tumors. Previous works on this theme have mostly concentrated on endoplasmic reticulum (ER)-stressed damage-associated molecular patterns (DAMPs), ignoring the secretion and function of mitochondria-related DAMPs. Herein, our work reports two intersystem crossing photosensitizers based on well-designed multiarylpyrrole structures and draws valuable attention to mitochondria-related DAMP-TFAM (mitochondrial transcription factor) when cancer cells are under forceful oxidative stress. The tumors vanished, and immunogenic experiments were applied to illuminate the advantages of double treatment. Our discovery of new mitochondria-related DAMPs compensates for the lack of ER-stressed DAMPs and offers an innovative target for immunity therapy.

ROS activated prodrug for ALDH overexpressed cancer stem cells.

Aldehyde dehydrogenase (ALDH), a cancer stem cell biomarker, is related to drug resistance. Co-treatment of anti-cancer drug (CPT) and ALDH inhibitor (DEAB) can overcome the drug resistance of cancer stem cells (CSCs) and finally cure cancers without relapse. We herein introduce a prodrug (DE-CPT) - consisting of 1,3-oxathiolane as an ROS responsive scaffold, and an aldehyde protecting group of DEAB - to deliver the CPT and DEAB upon reaction with ROS. From tests of the sphere-forming ability and CSC marker subpopulation, we found that DE-CPT efficiently decreases the CSCs population and kills the cancer cells.

Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity.

The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.

Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy.

Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.

Fluorescent Diagnostic Probes in Neurodegenerative Diseases.

Neurodegenerative diseases are debilitating disorders that feature progressive and selective loss of function or structure of anatomically or physiologically associated neuronal systems. Both chronic and acute neurodegenerative diseases are associated with high morbidity and mortality along with the death of neurons in different areas of the brain; moreover, there are few or no effective curative therapy options for treating these disorders. There is an urgent need to diagnose neurodegenerative disease as early as possible, and to distinguish between different disorders with overlapping symptoms that will help to decide the best clinical treatment. Recently, in neurodegenerative disease research, fluorescent-probe-mediated biomarker visualization techniques have been gaining increasing attention for the early diagnosis of neurodegenerative diseases. A survey of fluorescent probes for sensing and imaging biomarkers of neurodegenerative diseases is provided. These imaging probes are categorized based on the different potential biomarkers of various neurodegenerative diseases, and their advantages and disadvantages are discussed. Guides to develop new sensing strategies, recognition mechanisms, as well as the ideal features to further improve neurodegenerative disease fluorescence imaging are also explored.

An AIE-Based Probe for Rapid and Ultrasensitive Imaging of Plasma Membranes in Biosystems.

The abnormality of the plasma membrane (PM) is an important biomarker for cell status and many diseases. Hence, visualizing the PM, especially in complex systems, is an emerging field in the life sciences, especially in low-resource settings. Herein, we developed a water-soluble PM-specific probe utilizing electrostatic and hydrophobic interaction strategies with aggregation-induced emission as the signal output. The probe could image the PM with many advanced features (wash-free, ultrafast staining process, excellent PM specificity, and good biocompatibility), which were demonstrated by the PM imaging of neurons. The probe allowed for the first time the imaging of erythrocytes in the complex brain environment through a fluorescence-based method. Moreover, the PM of the epidermal and partial view of the eyeball structure of live zebrafish are also revealed.

A ratiometric fluorescent probe for detecting hypochlorite in the endoplasmic reticulum.

A colorimetric and fluorescent probe ER-ClO was presented in this work to detect cellular hypochlorite with high selectivity and sensitivity. With an organelle targeting unit, ER-ClO was successfully applied in the bio-imaging of exogenous and endogenous hypochlorite in the endoplasmic reticulum in a ratiometric manner.

Comparison of Pure-Tone Average Methods for Estimation of Hearing Loss Caused by Environmental Exposure to Lead and Cadmium: Does the Pure-Tone Average Method Which Uses Low-Frequency Ranges Underestimate the Actual Hearing Loss Caused by Environmental Lead and Cadmium Exposure?

Previous studies have reported that exposure to lead and cadmium can damage the inner ear receptor, which perceives high-frequency sounds. However, few studies have used the pure-tone average (PTA), including high-frequency ranges, for the estimation of hearing loss caused by lead and cadmium exposure. We estimated hearing loss using the PTA test, in low-frequency, speech frequency, and high-frequency ranges and compared the differences in the results using 3 PTA calculation methods. We analyzed the data of 2,387 participants, between the ages of 19 and 85 years, that were obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) of 2010-2012. A dose-response relationship between hearing loss and heavy metal exposure was observed in the high-frequency method after adjustment for confounding factors. When using the high-frequency PTA, it was found that doubling of the levels of lead and cadmium in the blood was associated with a 1.88- (95% CI 1.11-3.17) and 1.89-fold (95% CI 1.02-3.50) increase in the OR for hearing loss. In the case of the low-frequency and speech frequency PTA, however, there were no significant relationships between hearing loss and the concentrations of lead and cadmium in the blood. The outcomes of the present study suggest that the estimation of hearing loss caused by environmental exposure to lead and cadmium is affected by the frequencies used in the PTA calculation.