Inducing a Transient Increase in Blood-Brain Barrier Permeability for Improved Liposomal Drug Therapy of Glioblastoma Multiforme.

The blood-brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nanocarrier-based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within 4 h. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.

Data of continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surfaces.

This data article contains two figures and one table supporting the research article entitled: "Continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surface" [1]. The table shows coating conditions of three copolymers, poly(styrene-co-acrylic acid) grafted with oligovitronectin, poly(styrene-co-N-isopropylacrylamide) and poly(styrene-co-polyethylene glycol methacrylate) to prepare thermoresponsive surface. XPS spectra show the nitrogen peak of the polystyrene surface coated with poly(styrene-co-acrylic acid) grafted with oligovitronectin. The surface coating density analyzed from sorption of poly(styrene-co-acrylic acid) grafted with oligovitronectin by UV-vis spectroscopy is also presented.

Continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surfaces.

Stem cell culture is typically based on batch-type culture, which is laborious and expensive. Here, we propose a continuous harvest method for stem cells cultured on thermoresponsive nanobrush surfaces. In this method, stem cells are partially detached from the nanobrush surface by reducing the temperature of the culture medium below the critical solution temperature needed for thermoresponse. The detached stem cells are harvested by exchange into fresh culture medium. Following this, the remaining cells are continuously cultured by expansion in fresh culture medium at 37 °C. Thermoresponsive nanobrush surfaces were prepared by coating block copolymers containing polystyrene (for hydrophobic anchoring onto culture dishes) with three types of polymers: (a) polyacrylic acid with cell-binding oligopeptides, (b) thermoresponsive poly-N-isopropylacrylamide, and (c) hydrophilic poly(ethyleneglycol)methacrylate. The optimal coating durations and compositions for these copolymers to facilitate adequate attachment and detachment of human adipose-derived stem cells (hADSCs) and embryonic stem cells (hESCs) were determined. hADSCs and hESCs were continuously harvested for 5 and 3 cycles, respectively, via the partial detachment of cells from thermoresponsive nanobrush surfaces.

Recent developments in ß-cell differentiation of pluripotent stem cells induced by small and large molecules.

Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (ß)-cells. Small and large molecules play important roles in each stage of ß-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional ß-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-α), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of ß-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for ß-cell differentiation.