A Reactive Oxygen Species (ROS)-Responsive Polymer for Safe, Efficient, and Targeted Gene Delivery in Cancer Cells
Stimuli-responsive release: The high levels of reactive oxygen species (ROS) in prostate cancer cells can be exploited to trigger cancer-targeted gene delivery. A ROS-responsive thioketal-based cationic polymer was synthesized and functionalization with a cancer-targeting peptide led to selective and enhanced gene transfection in prostate cancer cells.
[Show abstract] [Hide abstract] ABSTRACT: In order to perform a ratiometric fluorescent sensor to recognize hypochlorite over other reaction oxidation species, a simple phenothiazine probe (QC1) with double dioxaborolane moieties was designed and synthesized. QC1 provided blue emission in aqueous and solid state. Double dioxaborolane and quaternary phosphonium salt was introduced into the molecule to prevent aggregation. The sulphur atom at the centre of phenothiazine was to respond to the hypochlorite at room temperature over other ROS because of its stronger oxidized ability. QC1 gave good linear fitting in the ratiometric mode under both absorption and emission titration experiments. Moreover, QC1 showed lower detection limited that reached 0.95 μM in absorption titration and 0.41 μM in fluorescent titration process.0Comments 0Citations
- "Reactive oxygen species (ROS) plays an indispensable role in a wide variety of biological processes [1e4]. For example, recent studies reported that cancer cells constantly generate high levels of intracellular ROS, due to oncogenic transformation . Among the various ROS, hypochlorous acid (HClO) is a powerful microbicidal agent in the innate immune system for its strong oxidizing property . "
[Show abstract] [Hide abstract] ABSTRACT: Stimuli-triggered drug delivery systems are primarily focused on the applications of the tumor microenvironmental or cellular physiological cues to enhance the release of drugs at the target site. In this study, we applied adenosine-5'-triphosphate (ATP), the primary "energy molecule", as a trigger for enhanced release of preloaded drugs responding to the intracellular ATP concentration that is significantly higher than the extracellular level. A new ATP-responsive anticancer drug delivery strategy utilizing DNA-graphene crosslinked hybrid nanoaggregates as carriers was developed for controlled release of doxorubicin (DOX), which consists of graphene oxide (GO), two single-stranded DNA (ssDNA, denoted as DNA1 and DNA2) and ATP aptamer. The single-stranded DNA1 and DNA2 together with the ATP aptamer serve as the linkers upon hybridization for controlled assembly of the DNA-GO nanoaggregates, which effectively inhibited the release of DOX from the GO nanosheets. In the presence of ATP, the responsive formation of the ATP/ATP aptamer complex causes the dissociation of the aggregates, which promoted the release of DOX in the environment with a high ATP concentration such as cytosol compared with that in the ATP-deficient extracellular fluid. This supports the development of a novel ATP-responsive platform for targeted on-demand delivery of anticancer drugs inside specific cells. Copyright © 2015 Elsevier Ltd. All rights reserved.0Comments 12Citations
- "Stimuli-triggered delivery of anticancer drugs [1e3] is mainly focused on the applications of the tumor microenvironmental or cellular physiological characteristics including higher temperature [4,5], lower pH [6e8], higher redox potential [9e11], enzyme overexpression [12,13] and higher level of reactive oxygen species [14,15] to promote the release of drugs at the target site for cancer treatment. Numerous nanocarriers integrating with the responsive elements, such as liposomes, polymeric nanoparticles, protein/DNA nanostructures and inorganic nanovehicles, have been widely exploited to achieve controlled release of their cargoes within the tumor tissues or cells [16e22]. "
- [Show abstract] [Hide abstract] ABSTRACT: The polymer, OEI-HD, based on beta-propionamide-cross-linked oligoethylenimine and its chemical transferrin conjugate were evaluated for siRNA delivery into murine Neuro2A neuroblastoma cells in vitro and in vivo. An 80% silencing of luciferase expression in neuroblastoma cells, stably transfected with a luciferase gene, was obtained using standard OEI-HD polyplexes or transferrin-conjugated shielded OEI-HD polyplexes. The Ras-related nuclear protein Ran was selected as a therapeutically relevant target protein. Systemic delivery of transferrin-conjugated OEI-HD/RAN siRNA formulations (three intravenous applications at 3 days interval) resulted in >80% reduced Ran protein expression, apoptosis, and a reduced tumor growth in Neuro2A tumors of treated mice. The treatment was not associated with signs of acute toxicity or significant changes in weight, hematology parameters, or liver enzymes (AST, ALT, or AP) of mice. All our results demonstrate that OEI-HD/siRNA formulations can knockdown genes in tumor cells in vitro and in vivo in mice in the absence of unspecific toxicity.0Comments 50Citations