Intracellular uptake

Table 1 Cytotoxicity towards A2780, A2780cisR, HT29 and A549 cancer cells, and ECRF24 endothelial cells, and intracellular uptake in A2780 cells and logP0/w values of 1 - 3. Errors represent the standard error of the mean (SEM)...

A highly stable and shielded polyplex should circulate in the blood stream without undesired interactions until it reaches the target cell. At that location, specific interactions with the cell surface should trigger intracellular uptake. While lipid membrane interaction is undesired at the cell surface, it should happen subsequently within the endosomal vesicle and mediate polyplex delivery into the cytosol. During or after intracellular transport to the site of action, the polyplex stability should be weakened to an extent that the nucleic acid is accessible to exert its function. 

The fluorescent labels reported for investigation of intracellular uptake and distribution by CLSM comprise Nile red [13], Texas Red, and 6-coumarin [14]. Not only for fluorescence microscopy but also for transmission electron microscopy (TEM), the loading of markers proved to be useful. Osmium tetroxid as an electron dense marker and bovine serum albumin (BSA) as a model protein were entrapped in PLGA-nanoparticles to elucidate their uptake and intracellular distribution in human vascular smooth muscle cells [15]. 

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in intemeuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine. 

Figure 5.6. Metabolism of proteins by proteases found at the cell surface and internal cellular organelles. Intracellular uptake of proteins often involved receptor-mediated endocytosis initial surface binding can be specific for a hormone (e.g., insulin, glucagon).

White DL, Saunders VA, Dang P et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107) reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006 108 697-704. 

Metal reclamation from acid mine drainage and contaminated surface- and groundwater and wastewaters has been extensively studied. Technologies for metal removal from solution are based on the microbial—metal interactions discussed earlier the binding of metal ions to microbial cell surfaces the intracellular uptake of metals the volatilization of metals and the precipitation of metals via complexation with microbially produced ligands. 

Intracellular uptake of glucose itself raises certain problems. How is metabolic breakdown of glucose prevented if passage of the sugar from the lumen to blood proceeds via an intracellular route Do transporting cells contain diffusion barriers to prevent access of glucose to the metabolic machinery The metabolism-linked membrane permeability mechanism, used by certain other cells (2, 41), would be self-defeating in this case. 

Isberg, R.R. Discrimination Between Intracellular Uptake and Surface Adhesion of Bacterial Pathogens. Science, 934 (May 17. 1991). 

The high hydrophilicity and corresponding low lipophilicity of both EDTA and DTP A result in very low uptake of these chelating agents into cells. In an endeavour to increase intracellular uptake of DTPA, Rahman et al.98 injected liposomally entrapped DTP A into mice which had hepatic accumulations of 239Pu. Although this was an effective treatment for mice it proved to be unsatisfactory for hamsters99. ... 

Increased intracellular uptake of adriamycin by mouse NIH 3T3 cells 621... 

Proteolytic enzymes such as proteases and peptidases are ubiquitous throughout the body. Sites capable of extensive peptide and protein metabolism are not only limited to the liver, kidneys, and gastrointestinal tissue, but also include the blood and vascular endothelium as well as other organs and tissues. As proteases and peptidases are also located within cells, intracellular uptake is per se more an elimination rather than a distribution process [13]. While peptidases and proteases in the gastrointestinal tract and in lysosomes are relatively unspecific, soluble peptidases in the interstitial space and exopeptidases on the cell surface have a higher selectivity and determine the specific metabolism pattern of an organ. The proteolytic activity of subcutaneous tissue, for example, results in a partial loss of activity of SC compared to IV administered interferon-y. 

Paraliei to FAAH inhibition, similar results can also be observed by pharmacologically blocking the AEA transport system, which is responsible of the intracellular uptake of AEA from the synaptic cleft. 

Insulin is an endogenous hormone produced by fi-cells of islets of Langerhans of the pancreas, which consist of two chains of amino acids. It is required to be administered by a parenteral routes as it is destroyed when given orally. Insulin is used for the control of IDDM and in the emergency management of diabetic ketoacidosis.30 Insulin promotes the intracellular uptake of potassium and is used in hyperkalemia. Baker et al.31 have used insulin and glucagon in the treatment of liver disorders. Recent evidence indicates that the effects of insulin with glucose and potassium in ischemic heart disease have proved beneficial.32 It also is used in acute myocardial infarction.32... 

Fig. 3.2. General mechanisms for the uptake and transport of macromolecules by an enterocyte. Intracellular uptake-, after absorption and endocytosis by the microvillous membrane, macromolecules are transported in small vesicles and larger phagosomes. Intracellular digestion occurs when lysosomes combine to form phagolysosomes. Intact molecules that remain after digestion are deposited in the intercellular space by exocytosis. Intercellular uptake-, alternatively, macromolecules may cross the tight junction barrier between cells and diffuse into the intercellular space. (After Walker, W. A. Isselbacher, K. J. Uptake and transport of macromolecules by the intestine possible role in clinical disorders. Gastroenterology, 6T. 531-50, by Williams Wilkins (1974).)...

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