2 research outputs found
Nanoscale detection and real-time monitoring of free radicals in a single living cell under the stimulation of targeting moieties using a nanodiamond quantum sensor
Intracellular radicals play important roles in cell signaling and regulation of growth factors, cytokines, transcription, apoptosis, and immunomodulation, among others. To gain a more comprehensive understanding of their biological functions from a spatio-temporal perspective, there is a great need for nanoscale sensitive tools that allow real-time detection of these reactive species. Currently, intracellular radical probes are based on chemical reactions that could significantly alter radical levels during detection. Due to the excellent biocompatibility and favorable photophysical properties of nitrogen-vacancy (NV–) centers in fluorescent nanodiamonds (fNDs), the fNDs can serve as a powerful and chemically inert nanotool for intracellular radical detection. In this study, a positively charged nanogel (NG) coating was prepared to prevent the precipitation of fNDs and promote cellular internalization. After internalization of nanodiamond-nanogels (fND-NGs), different stimulators, namely somatostatin (SST), triphenylphosphonium (TPP), and trans-activator of transcription (TAT) peptide, which are widely used cell- or organelle-targeting ligands in medicine, drug delivery, and diagnostics, were applied to stimulate the cells. In parallel, the intracellular radical changes under stimulation of SST, TPP, and TAT ligands were monitored by fND-NGs in a home-built optically detected magnetic resonance (ODMR) microscope. Our method allows for detecting intracellular radicals in-situ and monitoring their real-time changes during incubation with the targeting ligands in a single living cell. We believe that our method will provide insights into the generation of radical stress in cells, which could improve our fundamental understanding of the pharmacology and signaling pathways of widely used cell- and organelle-targeting ligands associated with free radicals.</p
Hyaluronic Acid-Shelled Disulfide-Cross-Linked Nanopolymersomes for Ultrahigh-Efficiency Reactive Encapsulation and CD44-Targeted Delivery of Mertansine Toxin
It was and remains
a big challenge for cancer nanomedicines to
achieve high and stable drug loading with fast drug release in the
target cells. Here, we report on novel hyaluronic acid-shelled disulfide-cross-linked
biodegradable polymersomes (HA-XPS) self-assembled from hyaluronic
acid-<i>b</i>-poly(trimethylene carbonate-<i>co</i>-dithiolane trimethylene carbonate) diblock copolymer for ultrahigh-efficiency
reactive encapsulation and CD44-targeted delivery of mertansine (DM1)
toxin, a highly potent warhead for clinically used antibody-drug conjugates.
Remarkably, HA-XPS showed quantitative encapsulation of DM1 even with
a high drug loading content of 16.7 wt %. DM1-loaded HA-XPS (HA-XPS-DM1)
presented a small size of ∼80 nm, low drug leakage under physiological
conditions, and fast glutathione-triggered drug release. MTT assays
revealed that HA-XPS was noncytotoxic while HA-XPS-DM1 was highly
potent to MDA-MB-231 cells with an IC<sub>50</sub> comparable to that
of free DM1. The in vitro and in vivo inhibition experiments indicated
that HA-XPS could actively target MDA-MB-231 cells. Notably, HA-XPS-DM1
while causing little adverse effect could effectively inhibit tumor
growth and significantly prolong survival time in MDA-MB-231 human
breast tumor-bearing mice. HA-XPS-DM1 provides a novel and unique
treatment for CD44-positive cancers