Polymeric liposomes bilayer

Polycondensation reactions in oriented monolayers and bilayers proceed without catalysis, and simply occur due to the high packing density of the reactive groups and their orientation in these layers. Bulk condensation of the a-amino acid esters at higher temperatures does not lead to polypeptides but to 2,5-diketopiperazines. No diketopiperazines are found in polycondensed monolayers or liposomes. Polycondensation in monolayers and liposomes leading to oriented polyamides represents a new route for stabilizing model membranes under mild conditions. In addition, polypeptide vesicles may be cleavable by enzymes in the blood vessels. In this case, they would represent the first example of stable but biodegradable polymeric liposomes. 

Early in the development of liposomes, it was recognized that their plasma instability could be a serious detriment in certain applications. Consequently, there were efforts to Lrst incorporate polymerizable lipids into the liposomal bilayers, and then initiate polymerization by, for example, photolysis, to form interchain crosslinks to stabilize the bilayer. The most commonly used polymerizable lipids have been PCs-containing diacetylene or butadiene moieties in the tailgroups... 

In pursuit of enhanced liposomal stability, Ringsdorf, Regen, Chapman, and O Brien pioneered the use of polymerized liposomes. These liposomes were prepared from polymerizable lipid molecules. Polymerized liposomes demonstrated uniform size distribution and are considerably more stable compared to their unpolymerized counterparts. Various polymerizable groups (e.g., butadiene, dia-cetylene, vinyl, or methacryloyl ) have been used to achieve the polymerization of the lipid bilayers. These reactive groups on the lipid may be in the head group region, the hydrocarbon core, or at the hydrocarbon termini. 

The activity increase in the polymeric liposomes compared to the monomer c in be ascribed to a structural change in the bilayer organization during polymerization. DSC data indicate residual monomeric domains" in the polymerized liposomes, so that the ATPase is most probably embedded in these domains, stabilized by the polymer matrix as schematically shown in fig. 20. 

While most vesicles are formed from double-tail amphiphiles such as lipids, they can also be made from some single chain fatty acids [73], surfactant-cosurfactant mixtures [71], and bola (two-headed) amphiphiles [74]. In addition to the more common spherical shells, tubular vesicles have been observed in DMPC-alcohol mixtures [70]. Polymerizable lipids allow photo- or chemical polymerization that can sometimes stabilize the vesicle [65] however, the structural change in the bilayer on polymerization can cause giant vesicles to bud into smaller shells [76]. Multivesicular liposomes are collections of hundreds of bilayer enclosed water-filled compartments that are suitable for localized drug delivery [77]. The structures of these water-in-water vesicles resemble those of foams (see Section XIV-7) with the polyhedral structure persisting down to molecular dimensions as shown in Fig. XV-11. 

Figure 1 Schematic structures of micelle and liposome, their formation and loading with a contrast agent, (a) A micelle is formed spontaneously in aqueous media from an amphiphilic compound (1) that consists of distinct hydrophilic (2) and hydrophobic (3) moieties. Hydrophobic moieties form the micelle core (4). Contrast agent (asterisk gamma- or MR-active metal-loaded chelating group, or heavy element, such as iodine or bromine) can be directly coupled to the hydrophobic moiety within the micelle core (5), or incorporated into the micelle as an individual monomeric (6) or polymeric (7) amphiphilic unit, (b) A liposome can be prepared from individual phospholipid molecules (1) that consists of a bilayered membrane (2) and internal aqueous compartment (3). Contrast agent (asterisk) can be entrapped in the inner water space of the liposome as a soluble entity (4) or incorporated into the liposome membrane as a part of monomeric (5) or polymeric (6) amphiphilic unit (similar to that in case of micelle). Additionally, liposomes can be sterically protected by amphiphilic derivatization with PEG or PEG-like polymer (7) [1].

This leakage can also be reduced by chemical modification of the external surface of the bilayers in order to introduce polymeric components into the interfacial structure (see the section on surface modified liposomes). 

Aqueous dispersions of polymerizable lipids and surfactants can be polymerized by UV irradiation (Fig. 18). In the case of diacetylenic lipids the transition from monomeric to polymeric bilayers can be observed visually and spectroscopically. This was first discussed by Hub, 9) and Chapman 20). As in monomolecular layers (3.2.2) short irradiation brings about the blue conformation of the poly(diacetylene) chain. In contrast, upon prolonged irradiation or upon heating blue vesicles above the phase transition temperature of the monomeric hydrated lipid the red form of the polymer is formed 23,120). The visible spectra of the red form in monolayers and liposomes are qualitatively identical (Fig. 19). 

Principles to stabilize lipid bilayers by polymerization have been outlined schematically in Fig. 4a-d. Mother Nature — unfamiliar with the radically initiated polymerization of unsaturated compounds — uses other methods to-stabilize biomembranes. Polypeptides and polysaccharide derivatives act as a type of net which supports the biomembrane. Typical examples are spectrin, located at the inner surface of the erythrocyte membrane, clathrin, which is the major constituent of the coat structure in coated vesicles, and murein (peptidoglycan) a macromolecule coating the bacterial membrane as a component of the cell wall. Is it possible to mimic Nature and stabilize synthetic lipid bilayers by coating the liposome with a polymeric network without any covalent linkage between the vesicle and the polymer One can imagine different ways for the coating of liposomes with a polymer. This is illustrated below in Fig. 53. 

Diacyllipid-polyethyleneoxide conjugates have been introduced into the controlled drug delivery area as polymeric surface modiLers for liposomes (Klibanov et al., 1990). Being incorporated into the liposome membrane by insertion of their lipidic anchor into the bilayer, such molecules can ster-ically stabilize the liposome against interaction with certain plasma proteins in the blood that results in signiLcant prolongation of the vesicle circulation time. The diacyllipid-PEO molecule itself represents a characteristic amphiphilic polymer with a bulky hydrophilic (PEO) portion and a very short but extremely hydrophobic diacyllipid part. Typically, for other PEO-containing amphiphilic block... 

Vineland, NJ) or over-the-counter cosmetic creams promoted for improved hydration (L Oreal, Paris and Dior, Paris). More recently, parenteral liposome formulations of amphotericin B, doxorubicin, and dau-norubicin have been approved and marketed (ABELCET, Elan, the Liposome Co., Inc, Princeton, NJ AmBisome and DaunoXome, Nexstar/Fujisawa, Deerfield Park, IL Amphotec and Doxil, Sequus/ Alza, Menlo Park, CA), with others on the horizon for applications in photodynamic therapy. Although the vast majority of liposome preparations are constructed from phospholipids, other nonphospholipid materials can be used either alone or in mixtures to form bilayer arrays. One such example is Amphotec, which utilizes sodium cholesteryl sulfate as the primary lipid. Other liposome forming materials may include but are not limited to fatty-acid compositions, ionized fatty acids, or fatty acyl amino acids, longchain fatty alcohols plus surfactants, ionized lysophospholipids or combinations, non-ionic or ionic surfactants and amphiphiles, alkyl maltosides, a-tocopherol esters, cholesterol esters, polyoxyethylene alkyl ethers, sorbitan alkyl esters, and polymerized phospholipid compositions. ° ... 

Prepolymerized lipids form vesicles only if the disentanglement of the polymer main chain ( = hack hone) and the membrane forming side-chains is simplified hy a hydrophilic spacer between them . Efficient decouplings of the motions of the polymeric chain and the polymeric bilayer are thus achieved and stable liposomes with diameters of around 500 nm were formed upon ultrasonication (Figure 4.28a). Their bilayer showed a well-defined melting behaviour in DSC. The ionene polymer with C12, C16 and C20 intermediate chains also produced vesicles upon sonication (Figure 4.28b). Here, the amphiphilic main chain is obviously so simple that ordering to form membranes produces no problems whatsoever . ... 

BMA and EGDMA monomers and UV-initiated polymerization to generate a cross-linked poly(methacrylate) network in the POPC bilayer. The substrate, ampicillin, diffused into liposomes through the OmpF channels and was converted to ampi-cillinoic acid. Thus a polymer-stabilized, vesicle-sized bioreactor with selective permeability was created, allowing for retention of the enzyme and ingress/egress of substrate and product. 

The potential of polymersomes in biomedical applications have been extensively discussed in several reviews [19,22-26], so they are mentioned here only briefly. Mainly due to the high molecular weight of their amphiphiles they differ from liposomes in several aspects, which makes them beneficial for certain purposes. (1) Typically, they have a much thicker shell. For the vesicles shown in Fig. 2c the hydrophobic core thickness is d = 21 nm, while for lipid membranes typically dm 3 nm. (2) Due to the larger thickness, polymeric membranes are much less susceptible to fluctuations and defects, and they can withstand larger deformations than lipid systems. It is remarkable that, while lipid bilayers can be stretched only 5%... 

Next we intended to improve the stability of the liposome as the carrier of the por-phinatoirons, which will bring about a highly concentrated, physically and mechanically stable and storageble solution of the porphinatoirons just like as or superior to blood. To accomplish this intention, we apply a new concept which makes liposomes stable by the polymerization of the lipid bilayer The double bond of the phospho-... 

Some encapsulation processes have limited variability with regards to payload. For example, the payload capacity of molecular encapsulation or complexation in cyclodextrins is limited by affinity equilibrium of the active molecule to the host molecule. Conversely, the payload for some of the common emulsion-based processes, such as interfacial polymerization, will remain high due to the inability to increase shell thickness set by the diffusion limits of the reactive monomers used to form the shell. While liposomes can also have a core-shell structure, their formation process and structure severely limit payload. Lipophilic active ingredients can be entrapped within the lipid bilayer of the liposome but are limited to low percentages to avoid disrupting the bilayer structure. Hydrophilic active ingredients can be entrapped in the core of the liposome, but payload is again limited by their solubility or concentration in the inner aqueous environment. 

Rrocess, which results in a separation of the octadecyl groups previously eld in close contact within the polymeric micelles 3. upon saturation coverage of the liposome surface, coated liposomes and free polymeric micellar structures coexist in solution 4. the phase of the lipidic bilayer plays a role, it seems, during the adsorption process. This last observation, based primarily on preliminary DSC measurements, should be clarified by monitoring the spectroscopic response of the labeled... 

The use of bilayer coatings was reported from Kapnissi et al. [31], where a permanently adsorbed coating of a cationic polymer salt [poly(diaIlymethylammo-nium chloride)] was covered with a dynamically adsorbed polymeric surfactant [poly (sodium undecylenic sulfate)]. In contrast to the stable coatings, the adsorbed layers can be easily prepared. Traditionally, polymeric surfactants have been used in MEKC [38] and the separation principle can therefore be transferred to o-CEC. However, several other types of dynamically attached pseudo-stationary phases (PSPs) exist, such as cyclodextrins [39], dendrimers [40], proteins [41], liposomes [42], ionenes [43], siloxanes [44] micelles [3, 38] and microemulsions [45]. Comparisons between MEEKC and MEKC are often made, as their separation basis is similar [46-48]. In MEKC, surfactant molecules form micelles and solutes dissolve in them, which facilitates separation. Solutes can penetrate a microemulsion droplet more easily than a more rigid micelle and the loadability of a droplet compared with a micelle is much higher. 

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