Redox Potential-Sensitive <i>N</i>‑Acetyl Cysteine-Prodrug Nanoparticles Inhibit the Activation of Microglia and Improve Neuronal Survival

One hallmark of neuroinflammation is the activation of microglia, which triggers the production and release of reactive oxygen species (ROS), nitrate, nitrite, and cytokines. <i>N</i>-Acetyl cysteine (NAC) is a free radical scavenger that is involved in the intracellular and extracellular detoxification of reactive oxygen species in the brain. However, the clinical application of NAC is limited by its low bioavailability and short half-life. Herein, NAC was conjugated to a polymer through a disulfide bond to form a NAC-prodrug nanoparticle (NAC-NP). Dynamic light scattering found that the NAC-NP has a size of around 50 nm. In vitro studies revealed that the release of NAC from NAC-NP is responsive to its environmental redox potential. For mimicking neuroinflammation in vitro, microglial cells were stimulated by a lipopolysaccharide (LPS), and the effect of NAC-NP on activated microglia was investigated. The study found that the morphology as well as the expression of microgliosis marker Iba-1 of the cells treated with NAC-NPs and LPS were close to those of control cells, indicating that NAC-NPs can inhibit the activation of microglia stimulated by LPS. Compared with free NAC, the production of ROS, NO₃-, NO₂-, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β from the LPS-stimulated microglia was considerably decreased when the cells were pretreated with NAC-NPs. Furthermore, LPS-induced microglial phagocytocis of neurons was inhibited in the presence of NAC-NPs. These results indicated that NAC-NPs are more effective than free NAC for reversing the effect of LPS on microglia and subsequently protecting neurons

pH and Redox Dual Responsive Nanoparticle for Nuclear Targeted Drug Delivery

To mimic the clinic dosing pattern, initially administering high loading dose and then low maintenance dose, we designed a novel poly­(2-(pyridin-2-yldisulfanyl)­ethyl acrylate) (PDS) based nanoparticle delivery system. Side chain functional PDS was synthesized by free radical polymerization. Polyethylene glycol and cyclo­(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide was conjugated to PDS through thiol–disulfide exchange reaction to achieve RPDSG polymer. RPDSG/DOX, RPDSG nanoparticle loaded with doxorubicin, was fabricated by cosolvent dialysis method. The size of the nanoparticles was 50.13 ± 0.5 nm in PBS. The RPDSG/DOX nanoparticle is stable in physiological condition while quickly releasing doxorubicin with the trigger of acidic pH and redox potential. Furthermore, it shows a two-phase release kinetics, providing both loading dose and maintenance dose for cancer therapy. The conjugation of RGD peptide enhanced the cellular uptake and nuclear localization of the RPDSG/DOX nanoparticles. RPDSG/DOX exhibits IC₅₀ close to that of free doxorubicin for HCT-116 colon cancer cells. Due to the synergetic effect of RGD targeting effect and its two-phase release kinetics, RPDSG/DOX nanoparticles display significantly higher anticancer efficacy than that of free DOX at concentrations higher than 5 μM. These results suggest that RPDSG/DOX could be a promising nanotherapeutic for tumor-targeted chemotherapy

Redox Potential Ultrasensitive Nanoparticle for the Targeted Delivery of Camptothecin to HER2-Positive Cancer Cells

Ideal “smart” nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer–drug conjugate of poly­[2-(pyridin-2-yldisulfanyl)]-<i>graft</i>-poly­(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An <i>in vitro</i> drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2-positive cancer cells while not affecting HER2-negative cells