A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery.
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ABSTRACT:
SUBMITTER: Choi YR
PROVIDER: S-EPMC8442875 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study evaluated transcriptional effects of nanomaterials that have been proposed for use as platforms for drug delivery. We tested SiO2 that had been surface modified to have a positive zetapotential of different geometries as well PAMAM dendrimers with different surface charges. We tested these materials on human aortic endothelial cells (HAECs) since we were interested in determining if there was a toxicogenomic response in endothelial cells that may come into contact with drug delivery nanoplatforms. The most pronounced transcriptional response resulted from the SiO2 treatement - the most prevelant responses were cell cycle, lipid metabolism and pro-inflammatory responses - with fewer responses from the PAMAM dendrimers. The lipid metabolism responses may relate to teh positive surface character as this response was not observed in the G3.5-COOH dendrimers. Indeed, the G3.5-COOH dendrimers were non-toxic and did not demonstrate any consistent transcriptional response. Primary human aortic endothial cells (HAECs) were grown in 6 well plates (in 2 ml of medium) until they were >80% confluent by visual inspection. Daily media changes allowed continued growth for HAECs that demonstrate contact inhibition. The cells were then incubated with nanomaterials: surface modified SiO2 with worm and sphere goemetries (the spheres were 200 nm in diameter and the worm's cylindrical diameter 200 nm and the length was ~ 1000 nm); and PAMAM dendrimers with different surface charges (G3.5-COOH are negative and G4-NH2 are positive). RNA was collected after 4 and 24 hrs (one SiO2 worm sample was at 1.5 hrs due to space available on the 4-pack microarrays). Triplicate biological samples (indicated by the 'a', 'b', and 'c' designations in the sample names) were evaluated for gene expression changes by microarray analysis.
2013-12-20 | E-GEOD-35142 | biostudies-arrayexpress
Project description:Material-based tactics have attracted extensive attention in driving the functional evolution of organisms. In aiming to design steerable bioartificial organisms to scavenge pathogenic waterborne viruses, we engineer Paramecium caudatum (Para), single-celled microorganisms, with a semiartificial and specific virus-scavenging organelle (VSO). Fe3O4 magnetic nanoparticles modified with a virus-capture antibody (MNPs@Ab) are integrated into the vacuoles of Para during feeding to produce VSOs, which persist inside Para without impairing their swimming ability. Compared with natural Para, which has no capture specificity and shows inefficient inactivation, the VSO-engineered Para (E-Para) specifically gathers waterborne viruses and confines them inside the VSOs, where the captured viruses are completely deactivated because the peroxidase-like nano-Fe3O4 produces virus-killing hydroxyl radicals (•OH) within acidic environment of VSO. After treatment, magnetized E-Para is readily recycled and reused, avoiding further contamination. Materials-based artificial organelles convert natural Para into a living virus scavenger, facilitating waterborne virus clearance without extra energy consumption.
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Project description:OBJECTIVE: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve-electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active. METHODS: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-? (TNF-?) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo. RESULTS: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-? in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results. CONCLUSION: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects.
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Project description:Mechanobiologic signals play critical roles in regulating cellular responses under both physiologic and pathologic conditions. Using a combination of synthetic biology and tissue engineering, we developed a mechanically-responsive bioartificial tissue that responds to mechanical loading to produce a pre-programmed therapeutic biologic drug. By deconstructing the signaling networks induced by activation the mechanically-sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we synthesized synthetic TRPV4-responsive genetic circuits in chondrocytes. These cells were then engineered into living tissues that respond to mechanical compression to drive the production of the anti-inflammatory drug interleukin-1 receptor antagonist. Mechanical loading of these tissues in the presence of the cytokine interleukin-1 protected constructs from inflammatory degradation. This “mechanogenetic” approach enables long-term autonomous delivery of therapeutic compounds that is driven by physiologically-relevant mechanical loading with cell-scale mechanical force resolution. The development of synthetic mechanogenetic gene circuits provides a novel approach for the autonomous regulation of cell-based drug delivery systems.
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