Lysine-Polydopamine Nanocrystals Loaded with the Codrug Abemaciclib-Flurbiprofen for Oral Treatment of Cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with chemotherapeutic agents for the treatment of colorectal cancer (CRC) are a promising therapeutic strategy. NSAIDs can effectively boost the antitumor efficacy of chemotherapeutic agents by inhibiting the synthesis of COX-2. However, hazardous side effects and barriers to oral drug absorption are the main challenges for combination therapy with chemotherapeutics and NSAIDs. To address these issues, a safe and effective lysine-polydopamine@abemaciclib-flurbiprofen (Flu) codrug nanocrystal (Lys-PDA@AF NCs) was designed. Abemaciclib (Abe), a novel and effective inhibitor of the CDK4/6 enzyme, and Flu were joined to prepare Abemaciclib-Flu codrug (AF) by amide bonds, and then the AF was made into nanocrystals. Lysine-modified polydopamine was selected as a shell to encapsulate nanocrystals to enhance intestinal adhesion and penetration and lengthen the duration time of drugs in vivo. Nuclear magnetic resonance, Fourier transform infrared, Massspectrometry, X-ray photoelectron spectroscopy, Transmission electron microscopy, and drug loading were used to evaluate the physicochemical characteristics of the nanocrystals. In our study, Abe and Flu were released to exert their synergistic effect when the amide bond of AF was broken and the amide bond was sensitive to cathepsin B which is overexpressed in most tumor tissues, thus increasing the selectivity of the drug to the tumor. The results showed that Lys-PDA@AF NCs had higher cytotoxicity for CRC cell with an IC50 of 4.86 µg/mL. Additionally, pharmacokinetics showed that Abe and Flu had similar absorption rates in the Lys-PDA@AF NCs group, improving the safety of combination therapy. Meanwhile, in vivo experiments showed that Lys-PDA@AF NCs had excellent antitumor effects and safety. Overall, it was anticipated that the created Lys-PDA@AF NCs would be a potential method for treating cancer.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis.

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

ROS/pH dual-sensitive emodin-chlorambucil co-loaded micelles enhance anti-tumor effect through combining oxidative damage and chemotherapy.

The high level of reactive oxygen species (ROS) at the tumor site has been widely used in the tumor targeted delivery. However, the ROS stimulus-responsive vector itself is also a ROS consumer, and the consumption of endogenous ROS may not be sufficient to maintain sustained drug release. In this study, we designed and synthesized ROS/pH dual-sensitive polymer micelles for the co-delivery of emodin (EMD) and chlorambucil (CLB). The release of quinone methides (QM) can consume glutathione (GSH), on the one hand, it can enhance the chemotoxicity of phenylbutyrate nitrogen mustard, on the other hand, emodin can induce oxidative damage of tumor cells and maintain the sustained targeted release of drugs.

A Single Session of Aerobic Exercise Mediates Plasticity-Related Phosphorylation in both the Rat Motor Cortex and Hippocampus.

A single session of aerobic exercise may offer one means to "prime" motor regions to be more receptive to the acquisition of a motor skill; however, the mechanisms whereby this priming may occur are not clear. One possible explanation may be related to the post-translational modification of plasticity-related receptors and their associated intracellular signaling molecules, given that these proteins are integral to the development of synaptic plasticity. In particular, phosphorylation governs the biophysical properties (e.g., Ca2+ conductance) and the migratory patterns (i.e., trafficking) of plasticity-related receptors by altering the relative density of specific receptor subunits at synapses. We hypothesized that a single session of exercise would alter the subunit phosphorylation of plasticity-related receptors (AMPA receptors, NMDA receptors) and signaling molecules (PKA, CaMKII) in a manner that would serve to prime motor cortex. Young, male Sprague-Dawley rats (n = 24) were assigned to either exercise (Moderate, Exhaustion), or non-exercising (Sedentary) groups. Immediately following a single session of treadmill exercise, whole tissue homogenates were prepared from both the motor cortex and hippocampus. We observed a robust (1.2-2.0× greater than sedentary) increase in tyrosine phosphorylation of AMPA (GluA1,2) and NMDA (GluN2A,B) receptor subunits, and a clear indication that exercise preferentially affects pPKA over pCaMKII. The changes were found, specifically, following moderate, but not maximal, acute aerobic exercise in both motor cortex and hippocampus. Given the requirement for these proteins during the early phases of plasticity induction, the possibility exists that exercise-induced priming may occur by altering the phosphorylation of plasticity-related proteins.