Cells as delivery vehicles for cancer therapeutics

Cell-based therapeutics have advanced significantly over the past decade and are poised to become a major pillar of modern medicine. Three cell types in particular have been studied in detail for their ability to home to tumors and to deliver a variety of different payloads. Neural stem cells, mesenchymal stem cells and monocytes have each been shown to have great potential as future delivery systems for cancer therapy. A variety of other cell types have also been studied. These results demonstrate that the field of cell-based therapeutics will only continue to grow

Nanoscopic surfactant behavior of the porin MspA in aqueous media

The mycobacterial porin MspA is one of the most stable channel proteins known to date. MspA forms vesicles at low concentrations in aqueous buffers. Evidence from dynamic light scattering, transmission electron microscopy and zeta-potential measurements by electrophoretic light scattering indicate that MspA behaves like a nanoscale surfactant. The extreme thermostability of MspA allows these investigations to be carried out at temperatures as high as 343 K, at which most other proteins would quickly denature. The principles of vesicle formation of MspA as a function of temperature and the underlying thermodynamic factors are discussed here. The results obtained provide crucial evidence in support of the hypothesis that, during vesicle formation, nanoscopic surfactant molecules, such as MspA, deviate from the principles underlined in classical surface chemistry

Naïve rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses

Background: Un-engineered human and rat umbilical cord matrix stem cells (rUCMSC) attenuate growth of several types of tumors in mice and rats. However, the mechanism by which UCMSC attenuate tumor growth has not been studied rigorously. Methods- The possible mechanisms of tumor growth attenuation by rUCMSC were studied using orthotopic Mat B III rat mammary tumor grafts in female F344 rats. Tumor-infiltrating leukocytes were identified and quantified by immunohistochemical image analysis. Potential cytokines involved in lymphocyte infiltration in the tumors were determined by microarray and Western blot analysis. The Boyden chamber migration assay was performed for the functional analysis of identified cytokines. Results: rUCMSC markedly attenuated the tumor growth; this attenuation was accompanied by considerable lymphocyte infiltration. Immunohistochemical analysis revealed that the majority of infiltrating lymphocytes in the rUCMSC-treated tumors were CD3+ T cells. In addition, treatment with rUCMSC significantly increased infiltration of CD 8+ and CD4+ T cells and NK cells throughout tumor tissue. CD68+ monocytes/macrophages and FoxP3+ regulatory T cells were scarcely observed, only in the tumors of the PBS control group. Microarray analysis of rUCMSC identified that monocyte chemotactic protein (MCP)-1 is involved in rUCMSCinduced lymphocyte infiltration in the tumor tissues. Discussion: These results suggest that naïve rUCMSC attenuated mammary tumor growth at least in part by enhancing host anti-tumor immune responses. Thus, naïve UCMSC can be used as powerful therapeutic cells for breast cancer treatment, and MCP-1 may be a key molecule to enhance the effect of UCMSC at the tumor site

Cell Based Drug Delivery: Micrococcus luteus Loaded Neutrophils as Chlorhexidine Delivery Vehicles in a Mouse Model of Liver Abscesses in Cattle

Citation: Wendel, S. O., Menon, S., Alshetaiwi, H., Shrestha, T. B., Chlebanowski, L., Hsu, W. W., . . . Troyer, D. L. (2015). Cell Based Drug Delivery: Micrococcus luteus Loaded Neutrophils as Chlorhexidine Delivery Vehicles in a Mouse Model of Liver Abscesses in Cattle. Plos One, 10(5), 13. doi:10.1371/journal.pone.0128144The recent WHO report on antibiotic resistances shows a dramatic increase of microbial resistance against antibiotics. With only a few new antibiotics in the pipeline, a different drug delivery approach is urgently needed. We have obtained evidence demonstrating the effectiveness of a cell based drug delivery system that utilizes the innate immune system as targeting carrier for antibacterial drugs. In this study we show the efficient loading of neutrophil granulocytes with chlorhexidine and the complete killing of E. coli as well as Fusobacterium necrophorum in in-vitro studies. Fusobacterium necrophorum causes hepatic abscesses in cattle fed high grain diets. We also show in a mouse model that this delivery system targets infections of F. necrophorum in the liver and reduces the bacterial burden by an order of magnitude from approximately 2.10(6) to 1.10(5)

Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes

Citation: Ohta, N., Ishiguro, S., Kawabata, A., Uppalapati, D., Pyle, M., Troyer, D., . . . Tamura, M. (2015). Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes. Plos One, 10(5), 17. doi:10.1371/journal.pone.0123756Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naive UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression

Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection

Citation: Udukala, D. N., Wang, H. W., Wendel, S. O., Malalasekera, A. P., Samarakoon, T. N., Yapa, A. S., . . . Bossmann, S. H. (2016). Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection. Beilstein Journal of Nanotechnology, 7, 364-373. doi:10.3762/bjnano.7.33Additional Authors: Ortega, R.;Toledo, Y.;Bossmann, L.;Robinson, C.;Janik, K. E.;Koper, O. B.;Motamedi, M.;Zhu, G. H.Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(carboxyphenyl) porphyrin (TCPP)) that is tethered to the central nanoparticle by means of a protease-cleavable consensus sequence and a second dye (Cy 5.5) that is directly linked. Based on the protease activities of urokinase plasminogen activator (uPA), MMPs 1, 2, 3, 7, 9, and 13, as well as CTS B and L, human breast cancer can be detected at stage I by means of a simple serum test. By monitoring CTS B and L stage 0 detection may be achieved. This initial study, comprised of 46 breast cancer patients and 20 apparently healthy human subjects, demonstrates the feasibility of protease-activity-based liquid biopsies for early cancer diagnosis

Porcine umbilical cord matrix stem cells

Since their discovery in 2000, pig umbilical cord stem cells have been studied at KState. The studies have been expanded to included other species, including humans. In addition, other research groups around the world have published scientific studies with these cells. Their unique attributes include being plentiful, easily collected, and (in humans) non-controversial. Initial work in the pig has concentrated on characterizing the cells to understand how they compare with other populations of stem cells. Results indicate that they have several characteristics in common with other primitive stem-cell populations, and that they are relatively easy to work with in the laboratory