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Carriers for Brain Targeting
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nanocarriers for Brain Targeting, 2019
Md. Sahab Uddin, Mst. Marium Begum
Conversion of prodrug to the drug in plasma is regarded as an obstacle in prodrug. Another way to enter into BBB is reversible disruption which makes junctions of the endothelial cells leaky and thus provides access for biological elements to the brain (Gabathuler, 2010). Osmotic disruption, ultrasound disruption, and disruption by bradykinin analogue are some techniques that have been used for disruption. In the process of osmosis, it shrinks endothelial cells, thus disrupting the tight junctions (TJs). An effective example of this is administration of mannitol solution with subsequent administration of drugs that increase drug concentration in brain, which is not possible if taking of drug alone (Gabathuler, 2010). Another fruitful process is magnetic resonance imaging-guided based ultrasound technique to enter BBB. A recent study has shown that Evans Blue (EB) extravasation can be enhanced by the application of repeated sonication, where 1-MHz frequency was applied (Yang et al., 2011). Sonications were applied at an ultrasound frequency of 1 MHz and a repetition frequency of 1 Hz. EB extravasation in double sonication groups was increased approximately twofold compared with the single sonication group. In the study, it was seen that compared to groups where no sonication has been applied, extravasation was high with both the cases. In BBB, B2 bradykinin receptor agonist and cereport (i.e., RMP-7, a bradykinin B2 agonist) have increased permeability of drugs. There are confirmations of increased CNS delivery when carboplatin, loperamide, and cyclosporin-A are administered with RMP-7 (Borlongan and Emerich, 2003). The main two obstacles to enter BBB are brain uptake of plasma albumin and other protein components of blood, which are noxious to brain cells (Vykhodtseva et al., 2008).
A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
Published in Science and Technology of Advanced Materials, 2019
Kristina N Ekdahl, Karin Fromell, Camilla Mohlin, Yuji Teramura, Bo Nilsson
Thrombin, which is generated from prothrombin at the last stage of the coagulation cascade, drives cellular activation via protease-activated receptors (PAR) 1, 3 and 4 which are expressed on platelets, leukocytes, smooth muscle cells, and ECs. This results in, e.g., the upregulation of cell adhesion molecules on these cells and the release of pro-inflammatory cytokines and reactive oxygen compounds, which overall promotes atherogenesis. BK is generated within the contact system by kallikrein which digests HMWK and thereby releases this nine-amino acid residue long peptide. The activity of BK is mediated via bradykinin receptor (BKR) 1 and 2. BKR2 is expressed constitutively on ECs, smooth muscle cells and leukocytes such as PMNs and lymphocytes. BK mediates inflammation and anaphylactoid reactions via BKR2, leading to chemotaxis (recruitment of leukocytes), increased vascular permeability, smooth muscle cell contraction, and pain. Over a longer time period, BK also leads to increased angiogenesis, thereby representing a potential link to cancer. Under physiological conditions, BKR1 shows low expression, but it is upregulated under inflammatory conditions and induces, e.g., further activation of ECs and PMNs which induce the PMNs to bind to the endothelial surface, and such adhesion is a major feature in artherogenesis.