Covalent Encapsulation Systems

Duncan and co-workers also created one of the first covalently linked DDS based on a dendrimer scaffold [52]. Carboxylated (COOH) PAMAM dendrimers were used to attach cisplatin, a common chemotherapeutic in clinical use. The covalent attachment of the drug increases the specific solubility of cisplatin ten-fold, and enables a loading of approximately 25% to be achieved for the PAMAM dendrimer. However, dendrimer clusters form as a consequence of the multiple COOH groups on the dendrimer scaffold and intermolecular reactions involving cisplatin. In vitro evaluation has shown that the covalent conjugation to the dendrimer results in a lower toxicity, and in vivo experiments have shown that the blood clearance rate is lower, with higher intra-tumoral concentrations of platinum than those achieved with the free drug. 

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Most DDS belong to one of two main categories physical encapsulation systems and covalent encapsulation systems. These two DDS will be described in more detail in... 

Recently, Ciba Specialty Chemicals introduced nanocapsules with antimicrobial products. Washing durabihty is obtained by engineering the cotton surfaces with a covalently bonded encapsulation system, which enables the controlled dehvery of antimicrobials. As a consequence of a slow-release mechanism, a small quantity of active material is released step-by-step. In short, the new system captures the best of both worlds permanently fixed capsules to achieve durability, and mobile antimicrobials to inhibit bacterial growth on the entire surface (Fig. 7.14). 

As has been described in Chapter 4, random copolymers of styrene (St) and 2-(acrylamido)-2-methylpropanesulfonic acid (AMPS) form a micelle-like microphase structure in aqueous solution [29]. The intramolecular hydrophobic aggregation of the St residues occurs when the St content in the copolymer is higher than ca. 50 mol%. When a small mole fraction of the phenanthrene (Phen) residues is covalently incorporated into such an amphiphilic polyelectrolyte, the Phen residues are hydrophobically encapsulated in the aggregate of the St residues. This kind of polymer system (poly(A/St/Phen), 29) can be prepared by free radical ter-polymerization of AMPS, St, and a small mole fraction of 9-vinylphenanthrene [119]. 

As we saw in the previous sections, inclusion compounds have many structural properties which relate them to other systems based on the hierarchy of non-bound interactions, like enzymes or enzyme-substrate complexes. As a matter of fact, most of the so-called artificial enzymes are based on well-known host molecules (e.g. P-cyclodextrin) and are designed to act partly on such bases 108>109). Most of these models, however, take advantage of the inclusion (intra-host encapsulation) phenomena. Construction of proper covalently bound model molecules is a formidable task for the synthetic chemistuo>. Therefore, any kind of advance towards such a goal is welcomed. 

The first intravascular sensor for simultaneous and continuous monitoring of the pH, pC>2, and pCC>2 was developed by CDI-3M Health Care (Tustin CA)14 based on a system designed and tested by Gehrich et al.15. Three optical fibres (core diameter = 125 pm) are encapsulated in a polymer enclosure, along with a thermocouple embedded for temperature monitoring (Figure 3). pH measurement is carried out by means of a fluorophore, hydroxypyrene trisulfonic acid (HTPS), covalently bonded to a matrix of cellulose, attached to the fibre tip. Both the acidic ( eXc=410 nm) and alkaline ( exc=460 nm) excitation bands of the fluorophore are used, since their emission bands are centred on the same wavelength (/-cm 520 nm). The ratio of the fluorescence intensity for the two excitations is measured, to render the sensor relatively insensitive to fluctuations of optical intensity. 

Similarly to the phospholipid polymers, the MPC polymers show excellent biocompatibility and blood compatibility [43—48]. These properties are based on the bioinert character of the MPC polymers, i.e., inhibition of specific interaction with biomolecules [49, 50]. Recently, the MPC polymers have been applied to various medical and pharmaceutical applications [44-47, 51-55]. The crosslinked MPC polymers provide good hydrogels and they have been used in the manufacture of soft contact lenses. We have applied the MPC polymer hydrogel as a cell-encapsulation matrix due to its excellent cytocompatibility. At the same time, to prepare a spontaneously forming reversible hydrogel, we focused on the reversible covalent bonding formed between phenylboronic acid and polyol in an aqueous system. 

For reasons that are probably unrelated to their technical performance, these covalent protein-polysaccharide conjugates have not yet been used commercially in food systems. But it seems that it is only a matter of time before the impressive potential of these highly functional ingredients becomes exploited on a commercial scale in various food applications — not just for emulsification, but also for foaming, gelation, waterholding, and encapsulation. 

Tawfik and Griffith (1998) reported an in vitro selection strategy for catalytic activity using compartmentalization. Here, each member of the DNA library is encapsulated in an aqueous compartment in a water in oil emulsion. The compartments are generated from an in vitro transcription-translation system, and contain the components for protein synthesis. The dilution is chosen such that, on average, the water droplets contain less than one DNA molecule. The DNA is transcribed and translated in vitro in the presence of substrate, which is covalently attached to the DNA. Only translated proteins with catalytic activity convert the substrate to the product. Subsequently, all DNA molecules are recovered from the water droplets and the DNA linked to the product is separated from the unmodified DNA linked to the educt, which requires a method to discriminate between both. The modified DNA can then be amplified by PCR and used for a second selection cycle. The principle of this approach is depicted in Figure 6. 

The encapsulation of chemical space on the scale of simple molecules has been a topic of considerable interest for more than two decades. For the formation of capsules two independent strategies have emerged covalent synthesis and self-assembly. The groups of Cram [8], Collet [9], and Sherman [10] have synthesized capsules capable of encapsulating up to three small molecular guests [11]. Rebek and co-workers pioneered the use of self-assembly to produce a variety of assemblies held together by hydrogen bonds [12-15], Multi-component systems have... 

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