Recent progress in mitochondria-targeted drug and drug-free agents for cancer therapy

The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches

Array-Based Protein Sensing Using an Aggregation-Induced Emission (AIE) Light-Up Probe

Protein detection and identification are important for the diagnosis of diseases; however, the development of facile sensing probes still remains challenging. Here, we present an array-based "turn on" protein-sensing platform capable of detecting and identifying proteins using aggregation-induced emission luminogens (AIEgens). The water-soluble AIEgens in which fluorescence was initially turned off showed strong fluorescence in the presence of nanomolar concentrations of proteins via restriction of the intramolecular rotation of the AIEgens. The binding affinities between the AIEgens and proteins were associated with various chemical functional groups on AIEgens, resulting in distinct fluorescent-signal outcomes for each protein. The combined fluorescence outputs provided sufficient information to detect and discriminate proteins of interest by linear discriminant analysis. Furthermore, the array-based sensor enabled classification of different concentrations of specific proteins. These results provide novel insight into the use of the AIEgens as a new type of sensing probe in array-based systems

Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper-Hollow Silica Nanoparticles

Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.ope

Single-cell transcriptome of the mouse retinal pigment epithelium in response to a low-dose of doxorubicin

Single cell transcriptomics pinpoints a cell subpopulation that could be involved in inducing cellular senescence of the retinal pigment epithelium, which in turn may construe retinal degenerative disease. Cellular senescence of the retinal pigment epithelium (RPE) is thought to play an important role in vision-threatening retinal degenerative diseases, such as age-related macular degeneration (AMD). However, the single-cell RNA profiles of control RPE tissue and RPE tissue exhibiting cellular senescence are not well known. We have analyzed the single-cell transcriptomes of control mice and mice with low-dose doxorubicin (Dox)-induced RPE senescence (Dox-RPE). Our results have identified 4 main subpopulations in the control RPE that exhibit heterogeneous biological activities and play roles in ATP synthesis, cell mobility/differentiation, mRNA processing, and catalytic activity. In Dox-RPE mice, cellular senescence mainly occurs in the specific cluster, which has been characterized by catalytic activity in the control RPE. Furthermore, in the Dox-RPE mice, 6 genes that have not previously been associated with senescence also show altered expression in 4 clusters. Our results might serve as a useful reference for the study of control and senescent RPE

Application of self-assembly peptides targeting the mitochondria as a novel treatment for sorafenib-resistant hepatocellular carcinoma cells

Currently, there is no appropriate treatment option for patients with sorafenib-resistant hepatocellular carcinoma (HCC). Meanwhile, pronounced anticancer activities of newly-developed mitochondria-accumulating self-assembly peptides (Mito-FF) have been demonstrated. This study intended to determine the anticancer effects of Mito-FF against sorafenib-resistant Huh7 (Huh7-R) cells. Compared to sorafenib, Mito-FF led to the generation of relatively higher amounts of mitochondrial reactive oxygen species (ROS) as well as the greater reduction in the expression of antioxidant enzymes (P < 0.05). Mito-FF was found to significantly promote cell apoptosis while inhibiting cell proliferation of Huh7-R cells. Mito-FF also reduces the expression of antioxidant enzymes while significantly increasing mitochondrial ROS in Huh7-R cells. The pro-apoptotic effect of Mito-FFs for Huh7-R cells is possibly caused by their up-regulation of mitochondrial ROS, which is caused by the destruction of the mitochondria of HCC cells

Cloaking Nanoparticles with Protein Corona Shield for Targeted Drug Delivery

Nanoscopic delivery vehicles capable of encapsulating drug molecules and releasing them in response to external stimuli are of great interest due to implications in therapeutic applications. Polymeric micellar assemblies are promising scaffolds to overcome many of the problems faced with traditional chemotherapies because of their capacity for non-covalent, hydrophobic guest molecule binding. However, the stability of encapsulation with such self-assembled systems is limited during blood circulation because of a requisite concentration for assembly formation. Thus, deliberate molecular design for stable encapsulation, targeting and triggered release is required. For this purpose, we have developed a facile synthetic method for highly stable, polymeric nanogels or polymer-caged hollow nanoparticles using a simple intra/inter-chain crosslinking reaction. We show a simple method for the preparation of biocompatible nanovehicles that provides the ability to encapsulate hydrophobic or hydrophilic drug molecules. We can control the size of the nano-carriers and release kinetics depending on crosslinking in responsive to stimuli. Nano-carriers showed great stability to encapsulate drug molecules and drugs were only released inside cell. In addition, we can use surface modified nano-carriers for target delivery system. Cancer targeting nanomaterials have been extensively attempted by coating their surfaces with small molecules, peptides, proteins, and antibodies, but the tumor targeting and therapeutic efficacy still exhibits only a modest improvement due to deleterious interactions of nanomaterials with proteins (protein corona formation). We developed mesoporous nanoparticles pre-coated with a recombinant fusion protein featuring HER2-binding affibody molecule and glutathione-S-transferase. Upon stabilized in preferred orientations on nanoparticle, the pre-coated proteins as a corona minimize interactions with serum proteins to prevent the clearance of these particles by macrophages, while ensuring their targeting function in vitroand in vivo. These findings can provide a new insight into intra-mitochondrial assembly for the regulation of cellular functions and a therapeutic approach and new targeting platform for the biomedical community since numerous functional proteins can be installed by the similar fashion

Noncovalent Polymer-Gatekeeper in Mesoporous Silica Nanoparticles as a Targeted Drug Delivery Platform

Nanoscopic delivery vehicles capable of encapsulating drug molecules and releasing them in response to external stimuli are of great interest due to implications in therapeutic applications. Micellar assemblies are promising scaffolds to overcome many of the problems faced with traditional chemotherapies because of their capacity for non-covalent, hydrophobic guest molecule binding. However, the stability of encapsulation with such self-assembled systems is limited during blood circulation because of a requisite concentration for assembly formation and low encapsulation stability. Thus, deliberate molecular design for stable encapsulation, targeting and triggered release is required. For this purpose, we have developed a facile synthetic method for highly stable, polymer-caged hollow nanoparticles using a simple intra/inter-chain crosslinking reaction. We show a simple method for the preparation of biocompatible nanovehicles that provides the ability to encapsulate hydrophobic or hydrophilic drug molecules. We can control the size of the nano-carriers and release kinetics depending on crosslinking in responsive to stimuli. Nano-carriers showed great stability to encapsulate drug molecules and drugs were only released inside cell. In addition, we can use surface modified nano-carriers for target delivery system. Hence, the stimuli responsive nano-carrier formation using self-crosslinking polymers and the corresponding method of surface modification are a promising platform for creating polymer nanogels for a range of biomedical applications, from drug delivery to biosensing