Polymersomes Another Representation Of Vesicles Similar Natural Liposomes Biology Essay

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The term "Polymersomes" for block copolymers forming vesicles was coined in 1999[1]. Polymersomes (also known as polymeric vesicles)[2-4] has had rapidly growing interest over the last decade. The motivation behind this pursuit of research is due to its intriguing aggregation phenomena, cell and virus mimicking dimensions and functions[3, 5], together with its tremendous potential applications in medicine, pharmacy and biotechnology[4, 6-9]. Polymersomes are another representation of a class of vesicles similar to that of natural liposomes[10], these Polymersomes structures also resemble that of liposome architectures. Vesicles in this case can be described as a small hollow bubble/sphere that can enclose an aqueous solution in their core, the size of a typical Polymersomes vesicle membrane can range in radii size from 50nm to 5µm or even more[11]. Liposomes are self assembled low molecular weight lipids where on the other hand Polymersomes structures are formed from synthetic amphiphilic diblock[12-14], triblock[15, 16], graft[17, 18], dendritic[19] copolymers that self assemble in water into bilayer structures and vesicle membranes (Figure ) [20].

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-Bilayer structure

-Hydrophobic head group

-Hydrophilic tail group

Figure Amphiphilic copolymer vesicle[21]

Polymersomes have many properties comparable to natural liposomes e.g. phospholipid bilayers, however, also show many advantages over its counterparts. Polymersomes have increased membrane thickness compared to liposomes hence their mechanical and thermodynamic stability, this is also a consequence to their larger molecular weight[22, 23]. Polymersomes have a wide range of uses due to the capacity to transporting hydrophobic and hydrophilic species, versatility, permeability and tunable membrane properties[1, 9]. Polymersomes uses range from drug carriers to nanometre scale enzymatic reactors. Polymersomes facilitate the encapsulation of various drugs and diagnostic agents aimed at controlled delivery information for cellular and therapeutic targets[23]. Many other environmentally sensitive molecules such as DNA and RNA fragments, enzymes and other proteins and peptides can also be encapsulated and protected using Polymersomes. A physical barrier is provided by the Polymersomes membrane that helps isolate the encapsulated compound from external factors, such as those found in biological systems[1]. Furthermore, the synthetic choice of polymer(s) and choice of molecular weight of the polymer is vital, as a broad range of manipulation on the characteristics of the membrane can be made[24].

Polymersomes synthesis

Many synthesis techniques have been undergone into the preparation of Polymersomes up to date. Polymersomes can be prepared using the methods used for preparing liposomes, these include dissolution methods, film rehydration and direct injection methods[10]. A study by Bermudez et al reported the synthesis of a series of molecular weights of PEO-PBD and PEO-poly(ethylethylene) is carried out using standard living anioinic polymerization techniques. H1 NMR analysis was used to determine the number of monomer units in each block. To determine the number-average molecular weights alongside the polydispersity indices, polystyrene standards with gel permeation chromatography. The preparations of the actual polymeric vesicles were made by standard film rehydration techniques. The experimental technique used to prepare the polymeric vesicles was by coating the inside of a glass vial uniformly with copolymer in chloroform solution followed by evaporation of the chloroform under vacuum[25].

A method used for synthesising Polymersomes in BioNanotechnology is the synthesis of a particular class of Polymersomes named polymer nanotubes. They are synthesised directly by pulling the membranes on the Polymersomes using optical tweezers or a micropipette. The length on these nanotubes is unusually stretched (approximately 1cm), however they are quite stable and maintain their shape indefinitely. Once the nanotubes have been pulled they are stabilised by subsequent chemical cross linking. The compositions of these Polymersomes are diblock copolymers with an aqueous core which is connected to the aqueous Polymersomes interior. There are many advantages these nanotubes offer due to their aqueous core and robust character[23].

Recently Polymersomes that respond to internal or external stimuli (for example pH, temperature, redox potential, light, and magnetic field etc) whether they are reversible or not has had immense effort focussed for their development [8, 15, 26-30].the release of encapsulated species inside Polymersomes can be readily modulated by the stimuli-sensitive Polymersomes which have emerged as novel programmable delivery systems[30]. On the application of appropriate stimuli to the Polymersomes in water, the feasibility of construction and/or deconstruction of the Polymersomes are viable. The possible outcomes of the stimuli sensitive Polymersomes is enhanced therapeutic efficacy and minimal side effects[9].

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One of the most popular stimuli utilized for the construction of these is temperature. The main reason is that temperature is a factor that naturally occurs in the body and temperature can be adjusted externally with ease (for example hypothermia). Although this sounds like a very attractive and promising field to research only a couple of studies on thermal sensitive Polymersomes have been reported [13, 31, 32]. A recent study carried out by McComick et al. reported on the diblock copolymer poly(N-(3-aminopropyl)-methacrylamide hydrochloride)-b-poly(N-isopropylacrylamide)(PAMPA-PNIPAM) by increasing the LCST (Lower Critical Solution Temperature) for the development of thermal sensitive Polymersomes[31]. Another example is reported by Discher et al. on Polymersomes poly(ethylene gylcol)-b-poly(N-isopropylacrylamide) (PEO-PNIPAM)[13].

Self assembled structures such as Polymersomes also have their limitations in stability especially when used for i.v administration as they lead to premature drug release. An example o generating a robust Polymersomes is by the cross-linking of their membranes. Discher et al reported a study on redox initiated cross linking of Polymersomes membrane using poly(ethyleneglycol)-b-butadiene[33]. However, in targeted drug delivery, once the response to an internal stimulus is received, it is desirable to have reversible cross links which are stable in circulation but then degradable. For biomedical applications, the most interesting is probably the redox potential and perhaps on of few promising used for internal stimuli. This is mainly due to the existence of high redox potential in the cellular properties. The extracellular space is mildly oxidising and the intracellular space is reducing[34]. A study by Xu et al reports on novel reversibly cross-linked temperature sensitive Polymersomes used for triggered protein and drug release [9].

Polymersomes forming polymers are particularly attractive when biocompatible copolymers such as PEG poly(ethylene glycol) or PEO poly(ethylene oxide) are employed, being attached to hydrophobic blocks such as PLA (polyactic acid), PEE poly(ethylethylene), and PPS poly (propylene sulfide). In particularly, the PEG-PPS block copolymer offers many advantages as reported by Napoli et al[35]. The synthesis of PEG-PPS is reported using gel permeation chromatography (GPC)[36]. Narrow polydispersity and ease of polymerization via an anionic mechanism was employed. A low glass transition temperature is also reported, an indication of avoiding kinetic "traps" which is common in the use of glassy hydrophobes. Finally it has been shown that they respond to the oxidative environment, which is a possibly a way to render them responsive to some biological signals[35].

PEGPPS Polymersomes

Polyethylene glycol- polypropylene sulphide (PEGPPS) polymer chains are utilized for the purpose of this research to build the copolymer membrane. The choice PEGPPS is owing to its immense number of advantages it holds. PEGPPS is easily synthesized using an anionic mechanism for polymerization with narrow polydispersity. To avoid the kinetic traps for example when using glassy hydrophobes PEGPPS has a comparably low glass transition temperature of ≈230K [15, 37, 38]. Finally PPSPEG also respond to the oxidative environment, this could perhaps be a way render these polymers to biological signals [39]. The polymer PEGPPS is amphiphilic in property. Ethylene glycol monomers account for the hydrophilic segments of the polymer chain and the propylene sulphide account for the hydrophobic segments of the polymer chain.

Polyethylene glycol (PEG)

The synthetic polymer polyethylene glycol (PEG) (Figure ) also known as polyethylene oxide (PEO) is commercially available in a wide range of molecular weights. Polyethylene glycol id produced with the interaction of ethylene oxide with water. A more preferred method for the production of PEG is reaction ethylene glycol with its oligomers or functionalizing the PEG end groups. The reason for this being a much more preferred method for production is that it produces polymers with low polydispersity and the molecular weight can be controlled. The chain lengths are dependant on the ratio of the reactants used. Both cationic and anionic mechanisms can be utilized for the polymerization of PEG depending on the catalyst used. The most widely used mechanism in recent studies has been anionic polymerization [40].

Figure PEG monomer

PEG is a non-ionic hydrophilic polymer that is soluble in water as well as many organic solvents of which include methylene chloride, ethanol, acetone and chloroform. Low molecular weight PEG (Mw<1000) is a colourless viscous liquid; however the higher molecular weight PEG is a more waxy white solid. The melting points of these are proportional to the molecular weight with the highest temperature being around 67°. PEG has non-toxic characteristics, for this reason it is found in many food, cosmetic and pharmaceutical products. The success of this PEG in biotechnological applications has had great success over the past few years due to the mild action of this polymer on the biological activity of cell components. PEG is easily modified and attached to other molecules and surfaces. The size of the attached molecule to the attached molecule to PEG is readily increased along with its solubility. PEG can be characterized for a wide range of applications, some of which include protein and nucleic acid purification, drug coupling, drug release and many others [41].

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Polypropylene sulphide (PPS)

Polypropylene sulphide (PPS) is a newcomer to the biomedical field possessing interesting properties that could be useful for the purpose of this project. It is selected due to its extreme hydrophobicity and its low glass transition temperature, most importantly PPS has oxidative conversion abilities from hydrophobe to hydrophile [15, 38]. PPS in the crystal state adopts an all Trans conformation. The melting point for this is 53°C and is soluble in a variety of solvents. PPS has an asymmetric carbon in the repeating unit for the polymer chain, this results in two possible stereochemical arrangements, which include R and S enantiomers (Figure Figure ) respectively.

PPS is prepared using a ring opening polymerization, using anionic, cationic and coordinate catalyst. The coordinate catalyst system for example cadmium salts produces an isotactic or crystalline polymer. The anionic and cationic systems produce amorphous atactic polymers. When the polymers are prepared, they undergo polymerization via an anionic mechanism with basic initiators [42].

Figure Polypropylene sulphide (S) enantiomer

Figure Polypropylene sulphide (R) enantiomer

PPS has elastic properties that compares with styrene-butadiene rubbers, however this polymer has not yet achieved any commercial production. PPS offers values of good solvent and weather resistance, that make this polymer a suitable material for use in solvents, adhesives etc [42].

Bilayer computational studies

There has been a wide range of experimental research carried out on Polymersomes in the last decade, however, only very few detailed study of Polymersomes using computational simulations have been reported. Due to the high molecular weights instrinsic to polymers alongside with the requirement for large amounts of water to observe the hydrophobic effects and system size being so large, precise atomistic computer simulations have become a challenge on these systems. Before the 1990's very few atomistic molecular dynamics (AMD) studies were carried out on block copolymer systems due to their complexity given the limitations of length and timescale. Systems generally only contained a single polymer chain in a box of solvent[43].

Nevertheless, even today with the increase in efficiency over atomistic systems, the underlying problem of the limitations associated with system sizes and timescales still exist. In the early studies, block copolymers with only short chain lengths ranging from 2 to about 30 were focused on. The first paper was published in 1996 on the self assembly of A-B amphiphilic block copolymers by Khalatur et al [44].

To overcome these problems associated with large systems and timescales, the development of a wide variety of coarse grained (CG) models have been undergone for the simulation of block copolymer systems. The basic concept behind CG models is representing a single sphere for a large group of atoms (e.g a monomer in a polymer chain). In the context of this simplification, a detailed chemical observation cannot be made. However the valuable interactions among the spheres can imitate some key features represented in real polymers for example the amphiphilic properties in copolymer chains.

For the purpose of this study a full atomistic molecular dynamics (AMD) on a PPS-PEG poly(propylene sulfide)-poly(ethylene glycol) bilayer system is proposed. Due to the lack of previous studies of Polymersomes, lipid bilayer studies are revised and the simulation run parameters are followed for the initial setup of the atomistic simulation.

There have been many molecular dynamic studies on lipid bilayers of similar properties to PPSPEG. One study included, is the lipid bilayer simulation of DPPC lipids[45], the simulation involved 128 (DPPC) lipids, 64 per leaflet surrounded by 4310 water molecules making it a lipid to water ratio of about 1:33 ratio sufficiently hydrating the lipids. Simple point charge water molecules were used and Gromos96 force field was adopted. A constant temperature of 323K and a constant pressure of 1.0 atmosphere were used. The system was equilibrated for 2ns keeping a constant number of particles adopting an NPT ensemble. 3D periodic boundary conditions were used with the z-axis lying in a direction normal to the bilayer. Pressure was controlled semi-isotropically so that the x, y and z sizes of the simulation box were allowed to fluctuate independently to each other, keeping the total pressure constant. Thus, membrane area and thickness were therefore free to adjust under NPT ensemble conditions. Tau_p and tau_t were 0.1ps and 1.0ps respectively. Electrostatic interactions were simulated using PME with a PME long range cut-off of 1.8nm and also keeping the LJ cut -off the same at 1.8nm. LINCS routine was used to keep all bond lengths in the DPPC and solute constant. The simulation was carried out using GROMACS version 3.0 for 50ns with an integration timestep of 2fs.

The distribution of pentachlorophenol in phospholipids bilayer is another molecular dynamics study that involves a POPE bilayer consisting of 126 lipids and 6032 water molecules. GROMACS version 3.0 was used to run the simulations. A leap frog integrator was used with a 2fs integration time step. The SETTLE algorithm was used to constrain bonds to their equilibrium values for water and the LINCS algorithm used for al other bonds. Electrostatic interactions were simulated using again PME with cut-off value of 0.9 and 0.12nm grid with fourth order spline interpolition. The simulation was performed using anisotropic pressure coupling at 1.0 independently in the x, y and z directions that lets the lipids to fluctuate independently during the simulation. The lipid force field parameters were taken from Berger et al. The Lennard Jones parameters were taken from the OPLS-all atom force field and GROMOS87 force field was used for the bonded parameters. Two initial simulations were carried out for 15ns and then two runs were followed for 30ns and 50ns respectively[46].

Finally the molecular dynamics simulation of dipolmitoyl phosphatidylcholine (DPPC) bilayer is another study that is covered in atomistic detail. This study has shown that an increased integration timestep of 5 fs for the simulations of (DPPC) lipid bilayers can be safely adopted due to the properties being less sensitive to the details of the pressure coupling algorithm. Lindahl and Edholm[47] reported the first 100ns simulation of a bilayer consisting of 64 DPPC molecules, and a larger system containing 1024 lipids with a linear size of 20nm was simulated for 10ns. 128 DPPC molecules surrounded by 3726 water molecules therefore corresponding to 29 water per lipid and a fully hydrated state. For the force field, variations on the united atom DPPC force field described by Berger et al was used. PME electrostatics with a cut-off of 1nm was applied, grid fourier transformed 3D FFT algorithm using a maximum spacing of 1.2Å for the FFT grid. Constant pressure (1bar) and temperature(323K) is applied through the simulation adopting an NPT ensemble. Simulations were carried out on GROMACS version 2.1 and 3.0 and they both gave the same results. Periodic boundary conditions were applied in all three dimensions therefore multi-lamellar system is simulated. Bond lengths are kept constant using LINCS routine and the water geometry is maintained using the SETTLE algorithm. The efficiency and stability of both algorithms allow a time step of 5fs. The equilibration time took10-20ns and the simulation time was extended to 150ns[48].