One of the areas
in which bioorthogonal chemistry—chemistry
performed inside a cell or organism—has become of pivotal importance
is in the study of host–pathogen interactions. The incorporation
of bioorthogonal groups into the cell wall or proteome of intracellular
pathogens has allowed study within the endolysosomal system. However,
for the approach to be successful, the incorporated bioorthogonal
groups must be stable to chemical conditions found within these organelles,
which are some of the harshest found in metazoans: the groups are
exposed to oxidizing species, acidic conditions, and reactive thiols.
Here we present an assay that allows the assessment of the stability
of bioorthogonal groups within host cell phagosomes. Using a flow
cytometry-based assay, we have quantified the relative label stability
inside dendritic cell phagosomes of strained and unstrained alkynes.
We show that groups that were shown to be stable in other systems
were degraded by as much as 79% after maturation of the phagosome.
Reversine or 2-(4-morpholinoanilino)-N6-cyclohexyladenine was originally identified as a small organic molecule that induces dedifferentiation of lineage-committed mouse myoblasts, C2C12, and redirects them into lipocytes or osteoblasts under lineage-specific conditions (LISCs). Further, it was proven that this small molecule can induce cell cycle arrest and apoptosis and thus selectively lead cancer cells to cell death. Further studies demonstrated that reversine, and more specifically the C2 position of the purine ring, can tolerate a wide range of substitutions without activity loss. In this study, a piperazine analog of reversine, also known as aza-reversine, and a biotinylated derivative of aza-reversine were synthesized, and their potential medical applications were investigated by transforming the endoderm originates fetal lung cells (MRC-5) into the mesoderm originated osteoblasts and by differentiating mesenchymal cells into osteoblasts. Moreover, the reprogramming capacity of aza-reversine and biotinylated aza-reversine was investigated against MRC-5 cells and mesenchymal cells after the immobilization on PMMA/HEMA polymeric surfaces. The results showed that both aza-reversine and the biofunctionalized, biotinylated analog induced the reprogramming of MRC-5 cells to a more primitive, pluripotent state and can further transform them into osteoblasts under osteogenic culture conditions. These molecules also induced the differentiation of dental and adipose mesenchymal cells to osteoblasts. Thus, the possibility to load a small molecule with useful “information” for delivering that into specific cell targets opens new therapeutic personalized applications.
In the treatment of cancer, targeting of anticancer drugs to the tumor microenvironment is highly desirable. Not only does this imply accurate tumor targeting but also minimal drug release en route to the tumor and maximal drug release once there. Here we describe high-loading, “stealth-like” doxorubicin micelles as a pro-drug delivery system, which upon light activation, leads to burst-like doxorbicin release. Through this approach, we show precise spatiotemporal control of doxorubicin delivery to cells in vitro.
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