No abstract

The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by "bottom up" or "top down" technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.

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Cell-microstructure surface interactions play a significant role in tissue engineering to guide cell spreading and migration. However, the mechanisms underlying cell-topography interactions are complex and remain elusive. To address this topic, microsphere array patterns were prepared on silk fibroin films through polystyrene microsphere self-assembly, followed by culturing rat bone marrow derived mesenchymal stem cells on the films to study cell-substrate interactions. Filopodia sensed and anchored to the microspheres to form initial attachments before spreading. Importantly, the anchored filopodia converted into lamellipodia, and this conversion initiated the directional formation of lamellipodia. Therefore, the conversion of exploratory filopodia into lamellipodia was the main driving force for directional extension of the lamellipodia. Correspondingly, cell spreading, morphology, and migration were modulated by pseudopodial recognition and conversion. This finding demonstrated that filopodia not only act as an antenna to detect microenvironment but also serve as skeleton to guide lamellipodial extension for directing cell motions. The micropatterned films promoted cell adhesion and proliferation due to accelerated lamellipodia formation and cell spreading, with recognition and conversion of filopodia into lamellipodia as a critical role in cell response to surface topography.

The signaling pathway of dishevelled-associated activator of morphogenesis 1 (Daam1) triggered by Wnt5a drives cell movement and migration during breast cancer metastasis. However, Wnt5a signaling in glioblastoma progression remains poorly defined. Wnt5a expression and activations of RhoA, Cdc42, and Rac1 were detected in human glioblastoma tissues by using ELISA assays and small G-protein activation assays, respectively. The cell invasion rate and Daam1 activation of glioblastoma U251 and T98MG cells were determined by cell invasion assays and pull-down assays, respectively. According to our experiments, Wnt5a expression and RhoA activation were upregulated in invasive glioblastoma tissues, with a significant positive correlation between them. Wnt5a activated Daam1 and RhoA, and subsequently promoted the invasion of glioblastoma U251 and T98MG cells. This process was abolished by secreted frizzled-related protein 2 (sFRP2), an antagonist that directly binds to Wnt5a. Specific small interfering RNA (siRNA) targeting Daam1 markedly inhibited Wnt5a-induced RhoA activation, stress fiber formation and glioblastoma cell invasion. CCG-1423, a RhoA inhibitor, decreased Wnt5a-induced stress fiber formation and glioblastoma cell invasion. Finally, siRNA targeting Daam1 or CCG-1423 treatment did not alter the cell proliferation of glioblastoma U251 and T98MG cells. We thus concluded that Wnt5a promoted glioblastoma cell invasion via Daam1/RhoA signaling pathway.