Page - (000360) - in Biomedical Chemistry: Current Trends and Developments

the construction of stalks that were covalently attached to the nanopore openings, and the same stalks were bonded to a capping agent, in this case β-cyclodextrin (β-CD), that responded to the changes in the pH environment by opening or closing the nanopore accordingly in a reversible manner. In addition, the authors were able to demonstrate that this nanosystem was taken-up into the acidic endosomal compartments in THP-1 and KB-31 cells, showing also an efficient entrapment of dye molecules and anticancer drug doxorubicin inside the nanopores at physiological pH. In contrast, when the pH was decreased to values below 6, it caused dissociation of the β-CD caps and released the entrapped cargos, leading to apoptotic events of the cells. The opposite systems was also designed, having the β-CD rings immobilized and the stalks movable, making also possible the storage and delivery of different payloads (Zhao, 2010). Other stimuli-responsive approaches are related to the use of pH- sensitive linkers that connect the drug molecule with the nanoparticle itself. Lee created a delivery system that linked doxorubicin to the MSN surface by hydrazone bonds, which were sensitive to the pH environmental changes, cleaving at low pH values from 4−6 (compatible with pH in the lysosome) and being intact at physiological pH, thus maintaining the drug molecules safely connected to the carrier during circulation in the bloodstream (Lee, 2010). Polymer coatings have also been used as coating agents to prevent the fast release of drug payloads. For example, Liu used poly(4-vinyl pyridine) (PVP) as a pH-responsive capping nanoshell to coat MSNs, where the releasing kinetics of the molecules was dependent on the protonation degree of PVP at different pH values. As the pH decreased, the drug release rate increased, since the protonated polymer became swollen and permeable to the trapped molecule. This approach may be useful to deliver drug cargos into microenvironments with lower pH, such as the tumor region and/or even the endosomal organelles (Liu, 2011). Redox-responsive drug delivery approaches have also been recently exploited for cancer therapy applications (Remant, 2014; Shi, 2014), taking advantage of the fact that tumor cells have greater reducing features compared to healthy tissues, thus showing a much higher concentration of glutathione in the cytosol of tumor cells (Kuppusamy,