Tumor growth inhibition through targeting liposomally bound curcumin to tumor vasculature

Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~ 500 μg/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures.     

CAF cellular glycolysis: linking cancer cells with the microenvironment

Cancers have long being hallmarked as cells relying heavily on their glycolysis for energy generation in spite of having functional mitochondria. The metabolic status of the cancer cells have been revisited time and again to get better insight into the overall carcinogenesis process which revealed the apparent crosstalks between the cancer cells with the fibroblasts present in the tumour microenvironment. This review focuses on the mechanisms of transformations of normal fibroblasts to cancer-associated fibroblasts (CAF), the participation of the CAF in tumour progression with special interest to the role of CAF cellular glycolysis in the overall tumorigenesis. The fibroblasts, when undergoes the transformation process, distinctly switches to a more glycolytic phenotype in order to provide the metabolic intermediates necessary for carrying out the mitochondrial pathways of ATP generation in cancer cells. This review will also discuss the molecular mechanisms responsible for this metabolic make over promoting glycolysis in CAF cells. A thorough investigation of the pathways and molecules involved will not only help in understanding the process of activation and metabolic reprogramming in CAF cells but also might open up new targets for cancer therapy.     

Biomaterial characterization of off‐the‐shelf decellularized porcine pericardial tissue for use in prosthetic valvular applications

Fixed pericardial tissue is commonly used for commercially available xenograft valve implants, and has proven durability, but lacks the capability to remodel and grow. Decellularized porcine pericardial tissue has the promise to outperform fixed tissue and remodel, but the decellularization process has been shown to damage the collagen structure and reduce mechanical integrity of the tissue. Therefore, a comparison of uniaxial tensile properties was performed on decellularized, decellularized‐sterilized, fixed, and native porcine pericardial tissue versus native valve leaflet cusps. The results of non‐parametric analysis showed statistically significant differences (p < .05) between the stiffness of decellularized versus native pericardium and native cusps as well as fixed tissue, respectively; however, decellularized tissue showed large increases in elastic properties. Porosity testing of the tissues showed no statistical difference between decellularized and decell‐sterilized tissue compared with native cusps (p > .05). Scanning electron microscopy confirmed that valvular endothelial and interstitial cells colonized the decellularized pericardial surface when seeded and grown for 30 days in static culture. Collagen assays and transmission electron microscopy analysis showed limited reductions in collagen with processing; yet glycosaminoglycan assays showed great reductions in the processed pericardium relative to native cusps. Decellularized pericardium had comparatively low mechanical properties among the groups studied; yet the stiffness was comparatively similar to the native cusps and demonstrated a lack of cytotoxicity. Suture retention, accelerated wear, and hydrodynamic testing of prototype decellularized and decell‐sterilized valves showed positive functionality. Sterilized tissue could mimic valvular mechanical environment in vitro, therefore making it a viable potential candidate for off‐the‐shelf tissue‐engineered valvular applications.     

Preliminary experience with diffusion tensor imaging before and after re-irradiation treatments in children with progressive diffuse pontine glioma

Purpose

The purpose of this study is to evaluate quantitative changes in diffusion tensor imaging (DTI) tractography and fractional anisotropy (FA) of the pons along with clinical correlation, in patients who receive re-irradiation for progressive diffuse intrinsic pontine glioma (DIPG).

Methods

A retrospective case review of children with progressive DIPG who received re-irradiation at our institution from 2007 to 2011 after approval from the Institutional Review Board was performed. Tractography analysis and FA were analyzed pre and post-re-irradiation, and correlation with clinical features and MR imaging was performed.

Results

DTI analysis showed reduced values of FA on tumor progression. Increase in the FA values was noted after re-irradiation in these patients. This correlated with clinical improvement. These changes were concordant with the 3D tractography analysis which showed better visualization of the corticospinal tracts as they course through brainstem and posterior transverse pontine fibers following re-irradiation.

Conclusion

Serial changes in the FA values using DTI could provide clinically more correlative information in patients with progressive DIPG, who receive re-irradiation. Though the use and results of this modality has been reported in the newly diagnosed DIPG before, evaluation of DTI in children who receive re-irradiation for progressive DIPG has not been reported earlier. Though limited by the small sample size and treatment variability, this study for the first time shows the preliminary experience, potential, and likely efficacy of complementing DTI analysis to routine neuroimaging also in patients re-irradiated for progressive DIPG to better assess treatment response.     

A low-cost and scalable process for harvesting microalgae using commercial-grade flocculant

A low-cost and scalable harvesting process was demonstrated for Chlorella sp. FC2 IITG, which offered an improved process economy for the production of a microalgal biomass feedstock via (i) the utilization of a cheaper commercial grade chemical flocculant; (ii) the recycling of post-harvested nutrient-rich spent water for the successive growth of the FC2 cells and (iii) the modulation of the flocculant dose, resulting in the non-requirement of a pH adjustment of the spent water and separate inoculum development step. Ferrous sulphate and ferric chloride were screened from a pool of four commercial grade flocculants, resulting in high harvesting efficiencies of 99.83% and 99.93% at the lower flocculant doses (g of flocculant g of dry biomass⁻¹) of 2.5 and 3, respectively. The effect of the recycled nutrient-rich spent water and treated non-flocculated microalgal cells after harvesting was evaluated for the growth performance of the FC2 cells in six successive batches. It was found that ferrous sulphate was superior over ferric chloride in terms of the recyclability of the spent water for more number of batches, offering similar growth kinetics and nutrient recovery efficiency as compared with that of the control sample. The scale-up feasibility of the harvesting process was evaluated with a 5 L photobioreactor under indoor conditions and a 350 L open raceway pond under outdoor conditions with a modulated flocculant dose of 1.5 g ferrous sulphate. g dry biomass⁻¹. The harvesting cost of 1 kg biomass using commercial grade ferrous sulphate was estimated to be in the range of 0.17–0.3 USD and was significantly lower as compared to that of analytical grade ferrous sulphate.

A low-cost and scalable microalgal harvesting process with high harvesting efficiency has been demonstrated using a commercial flocculant and spent-water recycling.