Barrier Cellular

Kinsey, ST Locke, BR Penke, B Moerland, TS, Diffusional Anisotropy Is Induced by Sub-cellular Barriers in Skeletal Muscle, NMR in Biomedicine 12, 1, 1999. 

The simplest case of pharmacokinetics is intravenous injection [1]. In this case the drug is injected directly into the bloodstream. The drug may permeate to different tissues depending on its ability to get across the blood vessel walls and the cellular barriers in the particular tissue targets (Fig. 1). If the drug has small molecular weight and adequate... 

Low therapeutic index Anatomical or cellular barriers Commercial... 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

Table 1 Transport Mechanisms Common to Cellular Barriers...

In order to probe these mechanistic aspects of solute transport, simplified models of the respective cellular barriers have been developed in recent years. In many cases, the cells that comprise these barriers, or cells that serve to mimic the barrier of interest, can be maintained in culture. The ability of the cells to... 

In conclusion, Eqs. (140) and (141) are applicable to quantify not only the transmonolayer kinetics of highly membrane interactive permeants, but also the kinetics of less membrane interactive compounds. Notably, the examples emphasize the importance of simultaneously measuring the disappearance of a compound from the donor solution and its appearance in the receiver and demonstrate how interactions with proteins on either side of the cellular barrier influence permeability. 

Raub TJ, CL Barsuhn, LR Williams, DE Decker, GA Sawada, NFH Ho. (1993). Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers. J Drug Targeting 1 269-286. 

Sawada and coworkers [25-27] studied the iso-pH 7.4 MDCK permeabilities of very lipophilic molecules, including chlorpromazine (CPZ) [25], These authors included 3% wt/vol bovine serum albumin (BSA) on the apical (donor) side, and 0.1-3% BSA on the basolateral (acceptor) side, and found that plasma protein binding greatly affected the ability of molecules to permeate cellular barriers. They observed cell tissue retention of CPZ ranging from 65 to 85%, depending on the... 

Passage through the epithelium and endothelial cellular barriers likely represents the greatest challenge to absorption. Although the molecular details remain unclear, this absorption process appears to occur via one of two possible means transcytosis or paracellular transport (Figure 4.6). 

Figure 4.6 Likely mechanisms by which macromolecules cross cellular barriers in order to reach the bloodstream from (in this case) the lung. Transcytosis entails direct uptake of the macromolecule at one surface via endocytosis, travel of the endosome vesicle across the cell, with subsequent release on the opposite cell face via exocytosis. Paracellular transport entails the passage of the macromolecules through leaky tight junctions found between some cells...

As mentioned earlier, there is an interaction of fullerene derivatives with cytochrome c (Witte et al., 2007). The importance of these interactions is quite evident, considering that drags, before reaching their target, interact with serum proteins, cross cellular barriers, and come in contact with enzymes of the metabolic path such as cytochrome P450. Therefore, these studies are really important to develop new fullerene derivatives as potential drags. 

There are two principal routes by which the actinides can enter the body uptake can occur either via inhalation or by oral uptake as contaminants of food. However, as both routes of uptake require the actinides to cross a variety of cellular barriers it is necessary to be familiar with some of the chemistry of these elements. 

Tuma PL, Hubbard A. Transcytosis crossing cellular barriers. Physiol Rev 2003 83 871-932. 

From the environmental point of view, the three principal routes of entry of xenobiot-ics into the human body are percutaneous, respiratory, and oral. In multicellular animals, the extracellular space is filled with interstitial fluid. Thus, regardless of how a compound enters the body (with the exception of intravenous administration), it enters interstitial fluid after penetrating the initial cellular barrier (such as skin, intestinal mucosa, or the lining of the respiratory tract). From the interstitial fluid, the compound penetrates the capillaries and enters the bloodstream, which distributes it throughout the body. 

Polymers that are protease inhibitors and polymer-inhibitor conjugates are now widely investigated for their ability to protect proteins and peptides from proteolytic degradation. These molecules are effective in the immediate area surrounding the delivery device, so the effects on proteins that have diffused far from the delivery device are limited. Due to the fact that bioadhesives were used as the conjugating polymer, the delivery device may adhere to the intestinal lining. If this does happen, the diffusional distance of the protein from the device to the intestinal wall will be quite short. One barrier that the protease inhibitors do not affect is the cellular barrier. Biomacromolecules must still find a method to enter the cells or be taken up by phagocytosis. 

The cellular barriers include macrophages, eosinophils, phagocytes and natural killer (NK) cells. Some of these cells internalize macromolecules that they encounter in circulation or in tissues. This internalization takes place either by pinocytosis, receptor-mediated endocytosis or phagocytosis. The pinocytosis involves nonspecific membrane invagination. In contrast, receptor-mediated endocytosis involves specific macromolecules that are internalized after they bind to respective cell surface receptors. Endocytosis is not cell-specific and is carried out probably by all cells. 

In this chapter, a brief overview of the cellular barriers to gene delivery is presented. Special emphasis is given to those events that compromise the translocation process of plasmid DNA from the cytosol into the nucleus. In addition, the strategies developed by viruses to efficiently bypass these cellular barriers and target their genomic DNA into the nucleus of infected cells will be discussed. 

While isolation of a specific inhibitor will be necessary to assess the definitive role of the cytosolic nuclease in the low transfection efficiency in vivo, circumstantial evidence suggests that the metabolic instability of plasmid DNA represents one of the cellular barriers to gene transfer. Microinjection of DNA complexes with PEI has augmented the transfection efficiency (Pollard et al., 1998). Although the stability of the PEI-complexed DNA has not been determined in vivo, it has been demonstrated that the nuclease resistance of plasmid DNA is dramatically increased upon complex formation in vitro (Cappaccioli et al., 1993 Chiou et al., 1994 Thierry et al., 1997). Therefore, it is conceivable that faster diffusional mobility and decreased nuclease susceptibility jointly lead to the enhanced nuclear targeting efficiency of the PEI-condensed plasmid DNA. 

Figure 12.1 Cellular barriers to gene delivery. Extracellular DNA, delivered to cells in either viral particles, liposomes, or other vehicles, must traverse the plasma, endosomal, and nuclear membranes before any transcription, replication, or integration can occur.

Figure 16.1 Conceptual multi-component peptide and major cellular barriers in gene transfer. DBS DNA binding signal CTS cytosolic translocation signal NLS nuclear localization signal CRS cell recognition signal, and PEG polyethylene glycol.

Conceptual multi-component peptide and major cellular barriers in gene transfer 305... 

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

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