Polymerization Process To Convert Monomer Molecules Into Polymer Biology Essay

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Polymers are composed of repetition of structural units, named monomers and are covalently bonded together as large molecule (macromolecule). It can be made up of identical monomer units or a mixture of two or more monomers. When only one species of monomer is used to build a macromolecule, the product is called a homopolymer. If the chain is made up of two types of monomer unit, the material is known as copolymer. Copolymers can be subdivided further into four main categories: statistical copolymers, alternating copolymers, block copolymers and graft copolymers. (1, 2)

Polymerization is the process used to convert monomer molecules into a polymer. There are basically two approaches: chain- growth and step- growth polymerization. Chain- growth polymers (also called addition polymers) are made by adding the monomers one at a time in a repetitive manner and the process is rapid. (2) The complete polymerization process takes place in three different stages: firstly, initiation, when a single reactive site which acts as a chain carrier is created; secondly, propagation, involving rapid growth of the chain end by a kinetic chain mechanism and characterized by a long sequence of identical events, namely the repeated addition of more monomer to the growing chain; and thirdly, termination, whereby the process is brought to a halt when the active center of the kinetic chain is neutralized or transferred. There are three categories of chain initiators: free- radical, cationic and anionic.(1) The choice of the most appropriate one depends on the interested monomer and the requirements of the target polymer. The most widely used process for chain- growth polymer synthesis is free- radical polymerization. It is less sensitive to the effects of adventitious impurities compared to ionic chain- growth polymerizations. Another process that is commonly used is step- growth polymerization, also known as condensation polymerization, produces a polymer by a reaction between two different functional groups which involve elimination of some smaller molecules, such as water. Condensation polymers are formed from bi- or polyfunctional monomers and the monomers usually appear in alternating sequence in the polymer chain. (1-3)

The physical behavior of a polymer depends on the microstructure (also named configuration). The physical arrangement of monomer residues along the backbone of the chain has strong influence on the other properties of a polymer. Polymer architecture can be linear or branched. A linear polymer is the simplest polymer architecture in which the repeating unit is linked only to two others in a single backbone. Branched polymers composed of monomers which are not linked solely in a linear array as the polymerization process produces one or more substituent side chains from bifunctional monomers.(1, 3)

Polymer- based nanotechnology is much of interest in pharmaceutical research especially in the design of drug delivery system. In recent years, new kind of polymeric micelles, pluronics, have attracted intensive attention of pharmacologist. (4) Pluronic block copolymers is also known as their non-proprietary name 'poloxamers' composed of hydrophilic ethylene oxide (EO) and hydrophobic propylene oxide (PO) blocks arranged in a basic A-B-A tri-block structure (Figure 1). (5-7)

Figure 1. Pluronic block copolymer molecule (A) and micelle with a solubilized drug (B). (7)

The numbers of ethylene oxide and propylene oxide units are determined by different hydrophilic-lipophilic balance (HLB).(8) Pluronics are synthesized using step-wise polymerization by repetitive addition of EO and PO monomers in assistance of sodium or potassium hydroxide as catalyst. Due to their amphiphilic nature, pluronic block copolymers display surfactant properties which enable them to interact with both hydrophilic and hydrophobic surfaces and biological membranes. (8) Surfactants are organic compounds that allow easier spreading by lowering surface tension and also lower interfacial tension between two liquids. It can also aggregates to form micelles at certain concentrations which is known as critical micelle concentration (CMC). The features of surfactants are characterized by pluronic block copolymers as Pluronics have the ability to self-assemble into spherical micelle structure. The block copolymer molecules will remain in its individual form, termed 'unimers', when concentration is below the CMC. In contrast, micelles are formed through a process called 'micellization' when the block copolymer is at concentration above CMC.(5) Micelles exhibit several morphologist such as rod-like, spherical or lamellar at different concentration of block copolymers, temperature and the length of EO and PO blocks.(9) These micelles composed of two distinctly separated phase which are a hydrophilic outer shell formed by EO chains and hydrophobic inner core formed by PO chains due to cohesive interactions in a aqueous media. (5, 10, 11) The cohesive interactions mentioned refer to hydrophobic interaction, ionic interaction and hydrogen bonding.(12)

The architecture of pluronic micelles serve important factor in drug delivery application.(12) Its hydrophobic core by itself is termed 'cargo hold' and serves as a microenvironment to incorporate hydrophobic drugs, for example anticancer drugs through hydrophobic interaction.(7, 10, 13) The process named 'solubilization' is the process where the water insoluble compounds are transferred into inner core of miceller solution. (5) As a result, polymeric micelles can served as efficient carriers by enhancing solubility and stability of compounds in physiological environment.(14) The outer hydrophilic shell on the other hand, furnishes pluronics pharmaceutical behavior greatly by ensuring the micelles in a dispersed phase. It is also responsible in reducing drug interaction between biomaterials such as cells and proteins through steric-stabilization effects, therefore, is expected to considerably control the delivery in living bodies.(7, 12)

CMC of pluronic block copolymers is significant in drug delivery. The number of micelles elevates as the concentration of block copolymers increases above CMC whereas the concentration of unimers remains constant where the number is equal to CMC. The micellization and its structure transitions can occur in a wide range of concentration in the vicinity of CMC and may as well go beyond the CMC. The acceptable CMC value for pluronic block copolymer varies 3-10 times depending on the method of measurement applied. CMC is of concern as it determines the stability of micelles in body fluids. (5, 15) The biological effects of pluronic block copolymers exert on the exposed cells are defined by the maximal target concentration of pluronic unimers which is determined by CMC. (6) The length of the PO and EO blocks has great influence in CMC. CMC decreases when the length of PO increases, hence elevates the net hydrophobicity of the pluronic molecules as well as favors the formation of the micelle core. Contrarily, an increase in the length of EO blocks result in increase of CMC. This effect excites the probability of contact between PO and EO blocks within the core of the micelles. As a result, the hydrophobicity of the core and the stability of the micelles decrease. (5, 15)

The size of the micelles greatly influences drug delivery system. The size of pluronic micelles are usually in the range of 10 nm to 100 nm. (7, 16) These micelles of pluronic block copolymers are clearly within the desired size range and the size variation strongly affects the time taken in blood circulation and the bioavailability of the substances in the body. (5) The particular size enables the micelles to survive the filtration of lung and spleen. Hence, the required serum level of the drug can be maintained as it will undergo less opsonization and prevent uptake by the macrophages of the reticuloandothelial system (RES) and therefore, the drug carriers are able to stay in the blood circulation.(10) The CMC of solution also depends on temperature. Various studies had shown that PO and EO chains will dehydrate when temperature increases. Consequently, the blocks become insoluble and aggregate to form micelles. It is important to consider temperature dependence in micelles formation in drug delivery as disintegration of micelles can occur and release solubilized drug at room temperature. Even though the disintegration process is reversible, the kinetic factors may cause difficulties to the drug to re-solubilized. (5)

Since pluronic block copolymers exhibit surfactant properties, low molecular mass hydrophobic drugs can be incorporated into inner core of pluronic micelles and enhance drug pharmacokinetics and biodistribution.(12) Hence, it serves as a good drug carrier for oral delivery drugs, to deliver CNS drugs across blood brain barrier and tumor-specific anticancer drugs. Encapsulation of drugs in micelles can enhanced the permeability and retention effect (EPR) resulting in a passive targeting property.(10, 17) Pluronic block copolymers have been widely used in formulations for treatment in drug resistance cancers.(18) Various studies had demonstrated that pluronic block copolymers sensitize resistant cancer cells which induce the cytotoxic activity of the drug b 2 to 3 fold of magnitude.(6) One of the examples that shown this effect is where the addition of P85 increases the cytotoxic effects of doxorubicin in resistant lines.(15) Treating drug resistance in cancer may not be easy as the resistance is exhibited through many mechanisms. Several mechanisms may act together or further complicate the therapy in certain cases.(15) For instance, multidrug resistance (MDR) tumour has been widely identified as one of the most difficult types to treat in cancer chemotherapy.(17, 19) Development of MDR cells is caused by overexpression of drug efflux transporter, such as P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRP). Pgp belongs to a superfamily of ATP binding cassette (ABC) proteins and a plasma membrane glycoprotein encoded by human MDR1 gene that pump a wide range of antineoplastic drugs out of cancer cells.(5, 17) In fact, there are nearly 40-50% of cancer patients exhibit overexpression of Pgp in the malignant tissue. (17) Pluronic block copolymer appeared to be a potent inhibitor of Pgp efflux pump. There is evidence to support this mechanism. It is observed that treatment with pluronic block copolymers can intracellularly accumulate doxorubicin in resistant cancer cells expressed by Pgp efflux transporter. Conversely, drug uptake in non-Pgp-expressing cancer cells was not observed in the presence of pluronic. Therefore, it can be concluded that pluronic effects specifically on the efflux of Pgp-dependent route in MDR cells. (15)

Some MDR cells display sequestration ability in anticancer drugs within cytoplasmic vesicles. These drugs serve as an addition protective mechanism by decreasing nuclear entry of the drugs. The sequestered drug will then deactivate and force out of the cell before it can perform its intended action on the cell. (7, 20) Drug sequestration can be achieved by maintaining the elevation of pH gradients across organelle membranes by activity of H+-ATPase which is an ATP-dependent pump.(5)

Pluronic block copolymers also play a role in inhibiting the glutathione/ glutathione S-transferase (GSH/GST) detoxification system by depleting GSH and inactivating GST in MDR cells. (20) Inhibition of the GST/GSH detoxification system caused reduction in glutathione conjugation of selected substrates, for example doxorubicin and further decreases the extent of elimination of these substrates from the cells through the MRP-mediated drug efflux pathway. (15)MRP exhibit different substrate properties and inhibitor specificity from Pgp.When different substrates are used, the complex drug elimination mechanism through MRP and GST/GSH detoxification systems produces different responses to pluronic. Firstly, the organic anion substrates of MRP do not require glutathione conjugation and they usually respond to pluronic in the same way as Pgp substrates and consequently the efflux decreased and substrate accumulation in the cells increased.(21) Secondly, some compounds, for example doxorubicin, that only become MRP conjugates after glutathione conjugation are known to depend on GSH levels besides MRP and GST activities. (22) Lastly, compounds that are co-transport with GSH by MRP route bypassing glutathione conjugation can also show dependence on GSH and MRP activity without exhibiting it. (15)

There is suggestion that incorporation of pluronic block copolymers are able to change membrane structures in mitochondria of MDR cells, followed by release of cytochrome C and increase of ROS levels in cytoplasm. Such effects promote mitochondria- related proapoptotic cascade in cells and prevent activation of antiapoptotic cellular defence in MDR cells. (7, 15, 20)

Various mechanisms of drug resistance required consumption of energy to exert their effects on MDR. The mitochondria are the main source of energy for metabolism activity in the cell and might serve as a promising site for pluronic block copolymers. Addition of pluronic in mitochondria membranes inhibit cellular respiration which further deplete ATP levels and constrain the energy source needed in MDR cells.(20) A study had been carried out and it shows that pluronic P85 significantly promotes reduction in ATP levels selectively in MDR cells whereas no response observed in non-MDR cells. This phenomena explained that P85 response correspond to presence of MDR in cells instead of amount of ATP available in the cells.(7) One of the reasons is that there is difference in the use of major energy source by MDR sensitive cells. It is understood that MDR cells use fatty acids as fuel source while drug-sensitive cells utilize glucose metabolism.(19) In addition, overexpression of Pgp or MRP remarkably enhances responsiveness to the pluronic regarding MDR or non-MDR cells. (7, 15)

Pluronic unimers also known to depress the microviscosity of cell membranes. The changes are due to conformational change of lipid bilayer in the efflux protein as result of immersed of block copolymer chain on the membranes. Previous studies using P85 have shown that changes in membrane lipid fluidity contribute to inhibition of Pgp efflux function. (23) It has also concluded that P85 exhibit inhibition effect on Pgp ATPase activity.(15)

Figure 2. Multiple effects of Pluronic block copolymers inMDRcells: 1) incorporation of Pluronic

molecules intomembranes and decrease of themembrane microviscosity; 2) induction ofATP

depletion; 3) inhibition of drug efflux transporters; 4) release of cytochrome C from

mitochondria and increase in ROS levels in cytoplasm; 5) increase of pro-apoptotic signaling

and decrease of anti-apoptotic defense in MDR cells; 6) inhibition of the glutathione/

glutathione S-transferase detoxification system; and 7) abolishment of drug sequestration

within cytoplasmic vesicles. (7)

In this paper, a study is carried out to explore protein-pluronic interactions in biological responses. Biomaterials are commonly used in medicine over the years and pluronics have attracted great interest in biomaterials community. Tissue engineering is a new field that concern with application of principles of engineering and biology to replace, maintain or remove damaged tissues. (24) The high-throughput material discovery can be achieved by synthesis of large library of new materials to be screen aiming to identify new polymers with desired characteristic.(25, 26) Polymer microarray had shown to be a promising method to prepare polymer libraries. The latest development in this method is the preparation of polymer microarrays by sequential printing of monomers onto the substrate with the aid of initiators. (25) Besides, protein adsorption to surfaces is remarkably important in tissue engineering and biomedical field as it can greatly affect interaction of cells with biomaterials. Protein adhesion properties to polymers can be observed by using atomic force microscopy (AFM). The amount of protein to a surface from solution is quantified by fluorescent and radioactive labeling of proteins.(27)

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