Interaction with plasma protein

Biomedical Applications Due to their excellent blood compatibility (low interaction with plasma proteins) and high oxygen and moisture permeabilities, siloxane containing copolymers and networks have been extensively evaluated and used in the construction of blood contacting devices and contact lenses 376). Depending on the actual use, the desired mechanical properties of these materials are usually achieved by careful design and selection of the organic component in the copolymers. 

Heparin has been reported to complex with a variety of basic species, including biogenic amines and drugs for reviews, see Refs. 10 and 391. For its possible relevance to the pharmacological properties of heparin and complexed species, mention is made here of complexes with histamine392,393 and anthracycline antibiotics.394 C.d. studies on the interaction of basic homopolypeptides with heparin and other glycosaminogly-cans have shown that heparin is able to induce an ordered, helical conformation in the polypeptide.395 397 Similar, and even more dramatic, effects were observed with mixed basic polypeptides, presumed to represent better models for the biologically relevant interactions with plasma proteins.368... 

As already noted in Fig. 5.1, the ring opening of /3-lactam antibiotics is not only a major event in their interaction with bacterial enzymes, but occurs also in the mammalian body. Chemical hydrolysis in body fluids, metabolism by mammalian enzymes and interactions with plasma proteins, all influence the pharmacological activity of these antibiotics. These aspects will be considered below. We begin with the discussion of the chemical reactivity of the /3-lactam nucleus, which plays a key role in these events. 

Senior J, Delgado C, Fisher D, Tilcock C, Gregoriadis G. Influence of surface hydiophilicity of liposomes on their interaction with plasma-protein and clearance from the circulation— studies with poly(ethylene glycol)-coated vesicles. Biochim Biophys Acta 1991 1062 ... 

Hence, concerning the interaction with plasma proteins, covalently immobilized heparin performs identically to heparin in solution, and this results in the enrichment of the HCP surface with the most thrombogenic plasma components fibrinogen and thrombin. 

As with normal hydrocarbon-based surfactants, polymeric micelles have a core-shell structure in aqueous systems (Jones and Leroux, 1999). The shell is responsible for micelle stabilization and interactions with plasma proteins and cell membranes. It usually consists of chains of hydrophilic nonbiodegradable, biocompatible polymers such as PEO. The biodistribution of the carrier is mainly dictated by the nature of the hydrophilic shell (Yokoyama, 1998). PEO forms a dense brush around the micelle core preventing interaction between the micelle and proteins, for example, opsonins, which promote rapid circulatory clearance by the mononuclear phagocyte system (MPS) (Papisov, 1995). Other polymers such as pdty(sopropylacrylamide) (PNIPA) (Cammas etal., 1997 Chung etal., 1999) and poly(alkylacrylicacid) (Chen etal., 1995 Kwon and Kataoka, 1995 Kohorietal., 1998) can impart additional temperature or pH-sensitivity to the micelles, and may eventually be used to confer bioadhesive properties (Inoue et al., 1998). 

Size measurements can be done to study the interaction of polymeric micelles with biological media (Jones and Leroux, 1999). For instance, PERP -bPEO micelles were found to maintain their initial size in the presence of antibodies and bovine serum albumin, suggesting the apparent absence of interaction with plasma proteins (Kabanov et al., 1992). 

In this study we have attempted to investigate the effective chemical composition at the surfaces of two commercially available polyurethanes, Biomer and Avcothane, with the objective of identifying chemical species which would interact with plasma proteins. 

Figure 14.1. Fate of plasmid DNA in vivo after intravascular (left) or tissue (right) injection. Upon administration, plasmid DNA can be taken up by various cells, including mononuclear phagocytes such as macrophages. It also interacts with plasma proteins and extracellular matrix (ECM) components. In some cases, extravasation (intravascular route) or diffusion (tissue injection) is required for plasmid DNA to reach the target cell. Cellular uptake of DNA occurrs via an endocytotic route (solid lines) as well as a nonendocytotic route (dashed lines), depending on the vector and delivery method used for gene transfer. When endocytosis occurs, a means of endosomal escape is needed. Only plasmid DNA entering the nucleus has a chance to produce therapeutic protein.

Several polymers were evaluated in the form of a surface coating on glass beads packed in columns to determine their ability to retain platelets when whole human blood passes over the surface. This ability was measured as the platelet retention index p, the fraction of platelets retained on the column. Lowest values of p were found for poly(ethylene oxide), polypropylene oxide), poly(tetramethylene oxide) (in the form of polyurethanes), and polydimethylsiloxane. Highest values (around 0.8) were found for cross-linked poly(vinyl alcohol) and the copolymers of ethylenediamine with diisocyanates. Intermediate values were found for polystyrene and its copolymers with methyl acrylate, for polyacrylate, and for poly(methyl methacrylate). The results are interpreted in terms of possible hydrophobic and hydrogen bonding interactions with plasma proteins. 

On the other hand non-viral vectors, which have only been used for the past two decades, have yet to become a marketing reality because they still do not meet adequate safety profiles, the standards for efficient delivery, or the rigorous testing of clinical trials. Non-viral vectors involving cationic liposomes have been most widely used in pre-clinical and clinical trials however, apart from the non-viral delivery of genetic material, which is inefficient when compared to the delivery associated with viral vectors, non-viral vectors stiU suffer from some of the same toxicity issues from which viral vectors suffer. Some of the delivery issues such as hpoplex instability in the blood stream, interaction with plasma proteins, and non-specific cellular interactions persist, despite the extensive investigations and corrective maneuvers that have been conducted over the past decade. Therefore, currently, the only advantage with cationic lipids seems to be their inability to transform host cells into cancerous cells (3,4). 

There are a variety of pathways by which NPs enter the bloodstream and their interaction with plasma proteins is inevitable. It is currently unclear whether the NP-blood protein interactions are specific or nonspecific so we included a range of essential proteins in our study. Below, we summarize the proteins considered and summarize briefly some of their essential functions. 

As mentioned above, the presence of positive charges at the surface of DNA complexes promotes non-specific interactions with plasma proteins and cell... 

Senior,]., Delgado, C., Fisher, D., Tilcock, C., and Gregoriadis, G. (1991) Influence of surface hydrophilicity of liposomes on their interaction with plasma proteins and clearance from the circulation Studies with polyethylene glycol-coated vesicles, Biochim. Biophys. Acta 1062, 77-82. 

Diamond-like carbon interaction with plasma proteins and cell adhesion proteins/molecules... 

Several polymers have been characterized for their ability to form PM and PICM and are presented in Table 4.1. The hydrophilic segment can consist of polysaccharides, such as chitosan. and pullulan, or synthetic polymers, such as poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone) (PVP), poly(N-isopropylacrylamide) (PNIPAM), poly(2-ethyl-2-oxazoline) and poly(acrylic acid). Of all hydrophilic polymers, PEG (with a molecular weight of 1-20 kD) is undoubtedly the most widely used shell forming component of both PM and PICM. The neutrality, hydrophilicity and flexibility of PEG diminish the possibility of undesirable electrostatic interactions with plasma proteins. Furthermore, the presence of reactive groups at both chain ends... 

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