Protein delivery release mechanisms

Fig. 6 Preparation of core-shell drug delivery micelles, (a) Unfolding of globular protein to prepare protein-derived polypeptide copolymers with exposed internal ftmctitmal groups, (b) Preparation of onion-type core-shell drug delivery micelles from albumin-derived polypeptide copolymers and the two step release mechanism (adopted and modified from Wu et al. [44])...

Reservoir delivery systems have been developed in a variety of styles, ranging from microcapsules to hollow fibers to liposomes. Hayashi et al. (1994) produced delivery systems by encapsulating proteins and hormones inpoly-L-lactide microspheres by a solvent evaporation method. The release mechanism for hormones entrapped in liposomes was studied by Ho et al (1986). Progesterone and hydrocortisone skin permeation was enhanced by the presence ofthe liposomes no penetration ofthe liposomes was observed. Examples ofthe most common hydrogels employed in reservoir systems are crystalline-rubbery PEG, PAAm, celluloses, PAA, and PHEMA. 

Scheme 1. Mechanism of protein drug release from pH/thermo-sensitive beads made of polymers with increasing molecular weight. Top - swelling and drug diffusion mechanism results in slow release suited for colon targeting. Bottom - bead dissolution results in fast release suited for duoden delivery. Center - combination of both mechanisms results in intermediate release suited for lower small intestine targeting.

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

The mechanism and sequence of events that control delivery of protons and electrons to the FeMo cofactor during substrate reduction is not well understood in its particulars.8 It is believed that conformational change in MoFe-protein is necessary for electron transfer from the P-cluster to the M center (FeMoco) and that ATP hydrolysis and P release occurring on the Fe-protein drive the process. Hypothetically, P-clusters provide a reservoir of reducing equivalents that are transferred to substrate bound at FeMoco. Electrons are transferred one at a time from Fe-protein but the P-cluster and M center have electron buffering capacity, allowing successive two-electron transfers to, and protonations of, bound substrates.8 Neither component protein will reduce any substrate in the absence of its catalytic partner. Also, apoprotein (with any or all metal-sulfur clusters removed) will not reduce dinitrogen. 

Silicones are frequently used in transdermal drug delivery. Recently, the use of loosely cross-linked silicone elastomer blends for this application was surveyed.537 The mechanisms of controlled drug release in the silicone-based systems have been studied,538 as silicones are evaluated for relatively new protein drug-delivery systems.5... 

Hydrophobic polymers are often used to deliver biomacromolecules regardless of the route of administration. The rapid transit time of approximately 8 hours limits the time of a device in the gastrointestinal (GI) system, consequently the mechanisms possible for oral drug release are limited. The predominant method of release from hydrophobic polymers has been degradation, or biodegradation, of a polymeric matrix by hydrolysis (Figure 11.1). In fact, all of the hydrophobic polymers described in this chapter for use as oral protein or peptide delivery are hydrolytically unstable. 

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