Degeneration of the hippocampus is associated with Alzheimer’s disease, and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer’s are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apopotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive towards increases in activity and regions subject to modification. We have discovered compounds that are orally available, non-toxic, stable in mice, rats and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photocrosslinking.
Synthesizing highly efficient red-emissive carbon dots (CDs) is a challenge that still impedes widespread applications of CDs in bioimaging. Herein, we demonstrate a facile, isolation-free synthesis of deep red (600−700 nm) emissive nitrogen-doped CDs (nCDs) based on microwave-assisted pyrolysis of citric acid and ethylenediamine. The duration of pyrolysis, the molar ratio of acid to amine, and the concentration of reactants were optimized using Central Composite Design and Response Surface Methodology to yield deep red fluorescence. We demonstrated their applicability on three different cell lines (retinal epithelial, lens epithelial, and Chinese hamster ovary cells). We measured the viability, the generation of reactive oxygen species, and percentage of apoptotic cells to determine their level of toxicity in cell culture. Confocal images showed that the nCDs fluoresced at different wavelengths depending upon the excitation wavelength and were excitable up to 635 nm. Furthermore, the ex vivo imaging of porcine ocular globes and postmortem imaging of a whole mouse exemplified the utility of nCDs.
The vitreous humor of the eye is a biological hydrogel principally composed of collagen fibers interspersed with hyaluronic acid. Certain pathological conditions necessitate its removal and replacement. Current substitutes, like silicone oils and perfluorocarbons, are not biomimetic and have known complications. In this study, we have developed an in situ forming two-component biomimetic hydrogel with tunable mechanical and osmotic properties. The components are gellan, an analogue of collagen, and poly(methacrylamide-co-methacrylate), an analogue of hyaluronic acid; both endowed with thiol side groups. We used response surface methodology to consider seventeen possible hydrogels to determine how each component affects the optical, mechanical, sol-gel transition temperature and swelling properties. The optical and physical properties of the hydrogels were similar to vitreous. The shear storage moduli ranged from 3 to 358 Pa at 1Hz and sol-gel transition temperatures from 35.5 to 43 °C. The hydrogel had the ability to remain swollen without degradation for four weeks in vitro. Three hydrogels were tested for biocompatibility on primary porcine retinal pigment epithelial cells, human retinal pigment epithelial cells, and fibroblast (3T3/NIH) cells, by electric cell-substrate impedance sensing system. The two-component hydrogels allowed for the tuning and optimizing of mechanical, swelling, and transition temperature to obtain three biocompatible hydrogels with properties similar to vitreous. Future studies include testing of the optimized hydrogels in animal models for use as a long-term substitute, whose preliminary results are mentioned.
For targeted delivery with nanoparticles (NPs) as drug carriers, it is imperative that the NPs are internalized into the targeted cell. Surface properties of NPs influence their interactions with cells. We examined the responses of retinal pigment epithelial cells, NIH 3T3 fibroblast cells, and Chinese hamster ovary cells to gold nanoparticles (Au NPs) in their nascent form as well as coated with end-thiolated hyaluronate (HS-HA). The grafting density of HS-HA on Au NPs was calculated based on total organic carbon measurements and thermal gravimetric analysis. We imaged the intracellular NPs by 3D confocal microscopy. We quantified viability and generation of reactive oxygen species (ROS) of the cells to Au NPs and monitored cell-surface attachment via electrical cell-substrate impedance sensing. The results confirmed that receptors on cell surfaces, for HA, are critical in internalizing HS-HA-Au NPs, and HA may mitigate ROS pathways known to lead to cell death. The 50- and 100-nm HS-HA-Au NPs were able to enter the cells; however, their nascent forms could not. This study shows that the delivery of larger Au NPs is enhanced with HS-HA coating and illustrates the potential of HA-coated NPs as a drug delivery agent for inflamed, proliferating, and cancer cells that express CD44 receptors.
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