Poor cell uptake of drugs is one of the major challenges for anticancer therapy. Moreover, the inability to release adequate drug at tumor sites and inherent multidrug resistance (MDR) may further limit the therapeutic effect. Herein, a delivery nanosystem with a charge‐reversal capability and self‐amplifiable drug release pattern is constructed by encapsulating β‐lapachone in pH/ROS cascade‐responsive polymeric prodrug micelle. The surface charge of this micellar system would be converted from negative to positive for enhanced tumor cell uptake in response to the weakly acidic tumor microenvironment. Subsequently, the cascade‐responsive micellar system could be dissociated in a reactive oxygen species (ROS)‐rich intracellular environment, resulting in cytoplasmic release of β‐lapachone and camptothecin (CPT). Furthermore, the released β‐lapachone is capable of producing ROS under the catalysis of nicotinamide adenine dinucleotide (NAD)(P)H:quinone oxidoreductase‐1 (NQO1), which induces the self‐amplifiable disassembly of the micelles and drug release to consume adenosine triphosphate (ATP) and downregulate P‐glycoprotein (P‐gp), eventually overcoming MDR. Moreover, the excessive ROS produced from β‐lapachone could synergize with CPT and further propagate tumor cell apoptosis. The studies in vitro and in vivo consistently demonstrate that the combination of the pH‐responsive charge‐reversal, upregulation of tumoral ROS level, and self‐amplifying ROS‐responsive drug release achieves potent antitumor efficacy via the synergistic oxidation‐chemotherapy.

Angiogenesis, the formation of new blood vessels, is critical in many normal and pathological processes such as development, reproduction, tumor growth, and metastasis. Recently, exposure to moderate-intensity static magnetic fields (1 mT to 1 T) has attracted much attention for its potential therapeutic value as a noninvasive intervening method. Nevertheless, the effects of moderate-intensity and spatial gradient static magnetic fields (GSMF) on angiogenesis have not received enough attention. In this study, the effects of GSMF (0.2-0.4 T, 2.09 T/m, 1-11 days) on angiogenesis were investigated both in vitro and in vivo. An MTT assay was used as an in vitro method to detect the proliferation ability of human umbilical veins endothelial cells (HUVECs). Two kinds of in vivo models, a chick chorioallantoic membrane (CAM) and a matrigel plug, were used to detect the effects of GSMF on angiogenesis. The results showed that the proliferation ability of HUVECs was significantly inhibited 24 h after the onset of exposure. With regard to the CAM model, vascular numbers in the CAM that was continuously exposed to the GSMF were all less than those in normal condition. In accordance with the gross appearance, the contents of hemoglobin in the models exposed to GSMF for 7-9 days were also less. In addition, similar to the CAM model, the results of vascular density and hemoglobin contents in the matrigel plug also demonstrated that the GSMF exposure for 7 or 11 days inhibited vascularization. These findings indicate that GSMF might inhibit or prevent new blood vessels formation and could be helpful for the treatment of some diseases relevant to pathological angiogenesis.

The skeleton adapts to mechanical loading to promote bone formation and remodeling. While most bone cells are involved in mechanosensing, it is well accepted that osteocytes are the principal mechanosensory cells. The osteocyte cell body and processes are surrounded by a fluid-filled space, forming an extensive lacuno-canalicular network. The flow of interstitial fluid is a major stress-related factor that transmits mechanical stimulation to bone cells. The long dendritic processes of osteocytes form a gap junction channel network connecting not only neighboring osteocytes, but also cells on the bone surface, such as osteoblasts and osteoclasts. Mechanosensitive osteocytes also form hemichannels that mediate the communication between the cytoplasmic and extracellular microenvironment. This paper will discuss recent research progress regarding connexin (Cx)-forming gap junctions and hemichannels in osteocytes, osteoblasts, and other bone cells, including those richly expressing Cx43. We will then cover the recent progress regarding the regulation of these channels by mechanical loading and the role of integrins and signals in mediating Cx43 channels, and bone cell function and viability. Finally, we will summarize the recent studies regarding bone responses to mechanical unloading in Cx43 transgenic mouse models. The osteocyte has been perceived as the center of bone remodeling, and connexin channels enriched in osteocytes are a likely major player in meditating the function of bone. Based on numerous studies, connexin channels may present as a potential new therapeutic target in the treatment of bone loss and osteoporosis. This review will primarily focus on Cx43, with some discussion in other connexins expressed in bone cells.

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