A Novel Method Based on GAN Using a Segmentation Module for Oligodendroglioma Pathological Image Generation.

Digital pathology analysis using deep learning has been the subject of several studies. As with other medical data, pathological data are not easily obtained. Because deep learning-based image analysis requires large amounts of data, augmentation techniques are used to increase the size of pathological datasets. This study proposes a novel method for synthesizing brain tumor pathology data using a generative model. For image synthesis, we used embedding features extracted from a segmentation module in a general generative model. We also introduce a simple solution for training a segmentation model in an environment in which the masked label of the training dataset is not supplied. As a result of this experiment, the proposed method did not make great progress in quantitative metrics but showed improved results in the confusion rate of more than 70 subjects and the quality of the visual output.

CD44-Mediated Methotrexate Delivery by Hyaluronan-Coated Nanoparticles Composed of a Branched Cell-Penetrating Peptide.

Branched polymers as drug delivery carriers have been widely attempted due to their outstanding drug loading capability and complex stability like branched polyethyleneimine (B-PEI). However, branched polymers without biodegradability may cause toxicity as they can accumulate in the body. Herein, we report branched modified nona-arginine (B-mR9) composed of redox-cleavable disulfide bonds to form stable complexes with methotrexate (MTX) as an anticancer agent, which is further coated with hyaluronic acid (HA). The HA-coated nanoparticles provide targetability for the CD44 cell surface receptor. The B-mR9-MTX/HA can effectively aid in intracellular MTX delivery to CD44 overexpressing cancer cells being degradable by the reducing environments of the cancer cells. The B-mR9-MTX/HA exhibits not only a glutathione-triggered degradability but also an outstanding CD44-mediated MTX delivery efficacy. In addition, its superior tumor inhibition capability was confirmed through an in vivo study. The results suggest that the HA-coated B-mR9 nanoparticle can be used as a drug delivery platform.

A Helical Polypeptide-Based Potassium Ionophore Induces Endoplasmic Reticulum Stress-Mediated Apoptosis by Perturbing Ion Homeostasis.

Perturbation of potassium homeostasis can affect various cell functions and lead to the onset of programmed cell death. Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death are unclear and the bioapplicability is limited. In this study, helical polypeptide-based potassium ionophores are developed to induce endoplasmic reticulum (ER) stress-mediated apoptosis. The polypeptide-based potassium ionophores disturb ion homeostasis and then induce prolonged ER stress in the cells. The ER stress results in oxidative environments that accelerate the activation of mitochondria-dependent apoptosis. Moreover, ER stress-mediated apoptosis is triggered in a tumor-bearing mouse model that suppresses tumor proliferation. This study provides the first evidence showing that helical polypeptide-based potassium ionophores trigger ER stress-mediated apoptosis by perturbation of potassium homeostasis.

Author Correction: Evaluation of cell penetrating peptide coated Mn:ZnS nanoparticles for paclitaxel delivery to cancer cells.

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Curcumin as a Novel Nanocarrier System for Doxorubicin Delivery to MDR Cancer Cells: In Vitro and In Vivo Evaluation.

Curcumin (CRC) has been widely used as a therapeutic agent for various drug delivery applications. In this work, we focused on the applicability of CRC as a nanodrug delivery agent for doxorubicin hydrochloride (DOX) (commercially known as Adriamycin) coated with poly(ethylene glycol) (PEG) as an effective therapeutic strategy against multidrug-resistant cancer cells. The developed PEG-coated CRC/DOX nanoparticles (NPs) (PEG-CRC/DOX NPs) were well localized within the resistant cancer cells inducing apoptosis confirmed by flow cytometry and DNA fragmentation assays. The PEG-CRC/DOX NPs suppressed the major efflux proteins in DOX-resistant cancer cells. The in vivo biodistribution studies on HCT-8/DOX-resistant tumor xenograft showed improved bioavailability of the PEG-CRC/DOX NPs, and thereby suppressed tumor growth significantly compared to the other samples. This study clearly shows that curcumin nanoparticles could deliver DOX efficiently into the multidrug-resistant cancer cells to have potential therapeutic benefits.

Evaluation of cell penetrating peptide coated Mn:ZnS nanoparticles for paclitaxel delivery to cancer cells.

This work aimed at formulating paclitaxel (PTX) loaded cell penetrating peptide (CPP) coated Mn doped ZnS nanoparticles (Mn:ZnS NPs) for improved anti-cancer efficacy in vitro and in vivo. The developed PTX loaded Mn:ZnS NPs with different CPPs (PEN, pVEC and R9) showed enhanced anti-cancer effect compared to bare PTX, which has been validated by MTT assay followed by apoptosis assay and DNA fragmentation analysis. The in vivo bio-distribution and anti-cancer efficacy was studied on breast cancer xenograft model showing maximum tumor localization and enhanced therapeutic efficacy with R9 coated Mn:ZnS NPs (R9:Mn:ZnS NPs) and was confirmed by H/E staining. Thus, R9:Mn:ZnS NPs could be an ideal theranostic nano-carrier for PTX with enhanced  the rapeutic efficacy toward cancer cells, where penetration and sustainability of therapeutics are essential.

Protease-activatable cell-penetrating peptide possessing ROS-triggered phase transition for enhanced cancer therapy.

Reactive oxygen species (ROS)- or protease-responsive materials have been utilized as carriers in cancer therapies because ROS and specific proteases are overproduced in cancer cells. Methionine-based polypeptides containing a thioether group are promising candidates due to their ROS-responsiveness which provides a phase transition. Herein, we developed protease-activatable cell-penetrating peptide containing a ROS-responsive methionine, a cell permeable lysine chain, and a matrix metalloproteinase (MMP)-cleavable linker. We designed a poly(l-methionine-block-l-lysine)-PLGLAG-PEG (MLMP) and doxorubicin (DOX) was loaded into the micelle core. The MLMP exhibited MMP-sensitive cleavage and ROS-induced DOX release. Moreover, we confirmed efficient DOX delivery into cancer cells and induction of the apoptotic capability in vitro. In a bio-distribution study, IR-780 dye encapsulated MLMP showed superior tumor targetability with long retention. Furthermore, MLMP (DOX) exhibited outstanding tumor inhibition capability with non-toxicity compared to free DOX, indicating that dual stimuli-MLMP has great potential as an anticancer drug delivery platform.

Conformation-switchable helical polypeptide eliciting selective pro-apoptotic activity for cancer therapy.

Artificial cationic helical peptides possess an enhanced cell-penetrating property. However, their cell-penetrability is not converted by cellular environmental changes resulting in nonspecific uptake. In this study, pH-sensitive anion-donating groups were added to a helical polypeptide to simultaneously achieve tumor targeting and pro-apoptotic activity. The mitochondria-destabilizing helical polypeptide undergoing pH-dependent conformational transitions selectively targeted cancer cells consequently disrupting mitochondrial membranes and subsequently inducing apoptosis. This work presents a promising peptide therapeutic system for cancer therapy.

pH-controllable cell-penetrating polypeptide that exhibits cancer targeting.

Helical peptides were naturally-occurring ordered conformations that mediated various biological functions essential for biotechnology. However, it was difficult for natural helical polypeptides to be applied in biomedical fields due to low bioavailability. To avoid these problems, synthetic alpha-helical polypeptides have recently been introduced by further modifying pendants in the side chain. In spite of an attractive biomimetic helical motif, these systems could not be tailored for targeted delivery mainly due to nonspecific binding events. To address these issues, we created a conformation-transformable polypeptide capable of eliciting a pH-activated cell-penetrating property solely at the cancer region. The developed novel polypeptide showed that the bare helical conformation had a function at physiological conditions while the pH-induced helical motif provided an active cell-penetrating characteristic at a tumor extracellular matrix pH. The unusual conformation-transformable system can elicit bioactive properties exclusively at mild acidic pH. STATEMENT OF SIGNIFICANCE: We developed pH-controllable cell-penetrating polypeptides (PCCPs) undergoing pH-induced conformational transitions. Unlike natural cell-penetrating peptides, PCCPs was capable of penetrating the plasma membranes dominantly at tumor pH, driven by pH-controlled helicity. The conformation of PCCPs at neutral pH showed low helical propensity because of dominant electrostatic attractions within the side chains. However, the helicity of PCCPs was considerably augmented by the balance of electrostatic interactions, thereby inducing selective cellular penetration. Three polypeptides undergoing different conformational transitions were prepared to verify the selective cellular uptake influenced by their structures. The PCCP undergoing low-to-high helical conformation provided the tumor specificity and enhanced uptake efficiency. pH-induced conformation-transformable polypeptide might provide a novel platform for stimuli-triggered targeting systems.

Bioreducible branched poly(modified nona-arginine) cell-penetrating peptide as a novel gene delivery platform.

Cell-penetrating peptides (CPPs) have been widely used to deliver nucleic acid molecules. Generally, CPPs consisting of short amino acid sequences have a linear structure, resulting in a weak complexation and low transfection efficacy. To overcome these drawbacks, a novel type of CPP is required to enhance the delivery efficacy while maintaining its safe use at the same time. Herein, we report that a bioreducible branched poly-CPP structure capable of responding to reducing conditions attained both outstanding delivery effectiveness and selective gene release in carcinoma cells. Branched structures provide unusually strong electrostatic attraction between DNA and siRNA molecules, thereby improving the transfection capability through a tightly condensed form. We designed a modified type of nona-arginine (mR9) and synthesized a branched-mR9 (B-mR9) using disulfide bonds. A novel B-mR9/pDNA polyplex exhibited redox-cleavability and high transfection efficacy compared to conventional CPPs, with higher cell viability as well. B-mR9/VEGF siRNA polyplex exhibited significant serum stability and high gene-silencing effects in vitro. Furthermore, the B-mR9 polyplex showed outstanding tumor accumulation and inhibition ability in vivo. The results suggest that the bioreducible branched poly CPP has great potential as a gene delivery platform.