Intracellular polymer

Acrylics Tubing connectors, blood set components, dental polymers, intracellular implants... 

Polyesters are known to be produced by many bacteria as intracellular reserve materials for use as a food source during periods of environmental stress. They have received a great deal of attention since the 1970s because they are biodegradable, can be processed as plastic materials, are produced from renewable resources, and can be produced by many bacteria in a range of compositions. The thermoplastic polymers have properties that vary from soft elastomers to rigid brittie plastics in accordance with the stmcture of the pendent side-chain of the polyester. The general stmcture of this class of compounds is shown by (3), where R = CH3, n = >100, and m = 0-8. 

Many bacterial polysaccharides contain phosphoric ester groups. There is a limited number of examples of monoesters. More common are phosphoric diesters, connecting an amino alcohol or an alditol to the polysaccharide chain. Another possibility is that oligosaccharide or oligosaccharide-alditol repeating units are connected to a polymer by phosphoric diester linkages. In addition to the intracellular teichoic acids, several bacteria, for example, different types of Streptococcus pneumoniae, elaborate extracellular polymers of this type. These polymers are generally discussed in connection with the bacterial polysaccharides. 

Several of the intracellular teichoic acids are polymers of glycerol phosphate or ribitol phosphate. An unusual teichoic acid, composed of d-mannitol phosphate, and with pyruvic acid linked as an acetal to 0-4 and 0-5, has been isolated from Brevibacterium iodinum. ... 

The complex polymers in feedstuffs are broken down to the constituent building blocks by a sequential process. Hydrolysis of the polymers is initiated in the lumen of the GIT by enzymes and other secretions produced by the pancreas, stomach, intestine, liver and gall bladder, and other GIT tissues, and completed by another suite of enzymes associated with the brush border membrane (BBM) or intracellular organelles. Anti-nutrient phytochemicals can decrease the hydrolysis of feedstuffs, and thereby reduce nutrient availability, either by increasing the inherent resistance of the polymers to hydrolysis or by decreasing the activities or amounts of enzymes and other secretions produced by the GIT. 

One of the most successful conjugate polymer systems was developed by Duncan and Kopecek (25). The polymer carrier used in their system is poly [N(2-hydroxypropyl) methacrylamide] a biocompatible polymer that was originally developed as a plasma extender. They have evaluated a number of polymer conjugated drugs for cancer chemotherapy with interesting results. The attachment of the drug is through a peptidyl spacer pendent to the polymer backbone. These peptides links are stable in aqueous media but are readily hydrolyzed intracellularly... 

Synthetic Polymers. Synthetic polymers are versatile and offer promise for both targeting and extracellular-intracellular drug delivery. Of the many soluble synthetic polymers known, the poly(amino acids) [poly(L-lysine), poly(L-aspartic acid), and poly(glutamic acid)], poly(hydroxypropylmethacrylamide) copolymers (polyHPMA), and maleic anhydride copolymers have been investigated extensively, particularly in the treatment of cancers. A brief discussion of these materials is presented. 

Production of poly(3HB-co-3HV) co-polymer in plants has recently been demonstrated by the PHA group of Monsanto [27], which acquired the PHA business of Zeneca in 1996. In the commercial production of poly(3HB-co-3HV) from R. eutropha, propionate is added to the growth media in order to create an intracellular pool of propionyl-CoA which can be condensed to acetyl-CoA to form 3-ketovaleryl-CoA. The 3-ketovaleryl-CoA is then reduced by the aceto-acetyl-CoA reductase to give 3-hydroxyvaleryl-CoA, which is co-polymerized with 3-hydroxybutyryl-CoA to synthesize poly(3HB-co-3HV) (Fig. 1). For the synthesis of poly(3HB-co-3HV) in plants, it was thus necessary to create an endogenous pool of propionyl-CoA which could be used by the PHA pathway. 

Polyesters, such as microbially produced poly[(P)-3-hydroxybutyric acid] [poly(3HB)], other poly[(P)-hydroxyalkanoic acids] [poly(HA)] and related biosynthetic or chemosynthetic polyesters are a class of polymers that have potential applications as thermoplastic elastomers. In contrast to poly(ethylene) and similar polymers with saturated, non-functionalized carbon backbones, poly(HA) can be biodegraded to water, methane, and/or carbon dioxide. This review provides an overview of the microbiology, biochemistry and molecular biology of poly(HA) biodegradation. In particular, the properties of extracellular and intracellular poly(HA) hydrolyzing enzymes [poly(HA) depolymerases] are described. 

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

As outlined in previous sections, escape of polyplexes from endosomes to the cytosol can be a major bottleneck in delivery. Membrane-active polymer domains or other conjugated molecules can help to overcome this barrier (see Sect. 2.3), but they may trigger cytotoxicity when acting extracellularly or at the cell surface. Therefore membrane-crossing agents either have to be inherently specific for endo-somal compartments (for example by pH-specificity), or they have to be modified to be activated in endosomes. For example, the reducing stimulus of intracellular vesicles has been used to activate formulations containing less active disulfide precursors of LLO [163] or Mel [170]. 

Carlisle RC, Etrych T, Briggs SS, Preece JA, Ulbrich K, Seymour LW (2004) Polymer-coated polyethylenimine/DNA complexes designed for triggered activation by intracellular reduction. J Gene Med 6 337-344... 

Foster S, Duvall CL, Crownover EF et al (2010) Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy. Bioconjug Chem 21 2205-2212... 

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