heA macromolecule which dissociates and gives polymeric ions after dissolving in aqueous or another ionizing solvent is called as polyelectrolyte. Because of the repulsion phenomenon between charges on the polymeric chains, these chains are expanded when ionized in a suitable solvent media. However, if the solvent prevents ionization of the polyelectrolyte, the chains exist in a compact, folded state. If the polyelectrolyte's chains are hydrophobic when unionized, in a poor solvent they collapse into globules and precipitate from solution. The polyelectrolyte behavior interferes between hydrophobic surface energy and electrostatic repulsion between charges. Since the degree of ionization of weak polyelectrolyte is controlled by the pH value and ionic composition of an aqueous medium, smart polymers dramatically change conformation in response to minute changes in the pH of aqueous environment. All the pH sensitive polymers bear in their structure pendant acidic or basic groups which either accept or donate protons in response to environmental pH (21).In case of pH sensitive polymers, anionic groups responsible for the increase in the swelling of polymer known as polyacids, and cationic groups responsible for the decrease in the swelling of polymer known as polybases.
' Anionic pH sensitive smart polymers are (22,23)
polyacrylic acid (PAA) (Carbopol) or its derivatives,
polymethacrylic acid (PMAA),
poly (ethylene imine), poly (L-lysine), and
polysulfonamides (derivatives of p-aminobenzensulfonamide).
' Examples of cationic polyelectrolytes are
poly (N,N-dialkylaminoethylmethacrylates), poly (lysine) (PL), poly (ethylenimine) (PEI), chitosan. sulfonamide and L-histidine whose pH responsive solubility or property originates fromthe character of the ionizable group(24).
2. Temperature sensitive smart polymers:
These are the polymers which are sensitive to temperature changes. These polymers show sol-to-gel transition as a function of environmental temperature which can be utilized to deliver the drugs in vivo. Temperature responsive polymers have ability to exhibit physiochemical or mechanical changes in presence of small temperature difference and show a phase transition at certain temperature, which cause sudden change in the solvation state. The temperature at which polymer becomes insoluble upon heating is called lower critical solution temperature (LCST). It becomes soluble upon heating is called upper critical solution temperature (UCST). The phase transition of polymer-solvent mixture is the transition from one phase to another involving mutual rearrangement of polymer molecules and its thermodynamic properties. Examples of temperature responsive polymers are poly (N-isopropylacrylamide), poly (N,N-diethylacrylamide), poly(methyl vinyl ether), poly(N-vinylcaprolactam), PEO-b-PPO (poloxamer) having LCST Value 32oC, 33oC, 37oC, 33oC and 29-85oC. PAAm/PAAc IPN having UCST 25oC. This type of systems exhibit a critical solution temperature (typically in water) at which the phase of polymer and solution is changed in accordance with their composition. Many polymers show abrupt changes in their solubility as a function of environmental temperature. This property was employed to develop aqueous solutions of these polymers which undergo sol-gel transition in response to temperature changes(21).
Figure No. 3 Polymer responds to stimuli and release the drug
Temperature-responsive polymers and hydrogels exhibit a volume phase transition at a specified temperature, due to which change in the solvation state and Polymers, which become insoluble upon heating, have a so-called lower critical solution temperature (LCST). Systems, which become soluble upon heating, have an upper critical solution temperature (UCST). LCST and UCST systems are not restricted to an aqueous solvent environment, but only the aqueous systems are of interest for biomedical applications. The change in the hydration state, which causes the volume phase transition, reflects competing hydrogen bonding properties, where intra- and intermolecular hydrogen bonding of the polymer molecules are favoured compared to a solubilisation by water. Thermodynamics can explain this with a balance between entropic effects due to the dissolution process itself and due to the ordered state of water molecules in the vicinity of the polymer. Enthalpic effects are due to the balance between intra- and intermolecular forces and due to solvation, e.g. hydrogen bonding and hydrophobic interaction. The transition is then accompanied by coil-to-globule transition. There are also systems, which exhibit both LCST and UCSTbehaviour, but that is usually not occurring within the setting of the intended biomedical applications. The corresponding hydrogels have similar transitions, the so-called lower gel transition temperature (LGTT) or upper gel transition temperature (UGTT).
Typical LCST polymers examples are
N-isopropylacrylamide (NIPAM) [25,26],
N,N-diethylacrylamide (DEAM) ,
methylvinylether (MVE) [28,29], and
N-vinylcaprolactam (NVCl) [30,31] as monomers.
A typical UCST system is
combination of acrylamide (AAm) and acrylic acid (AAc) .
PEO-b-PPO block copolymers, PEO-bPPO-b-PEO and PEG-b-PLGA-b-PEG [33'35].
The combination of a thermo-responsive monomer like NIPAM with one of a pH-responsive monomer yields double-responsive copolymers .
LCST and UCST behavior
The solubility of a polymer in aqueous solution is dependent on various factors such as molecular weight, temperature or addition of a co-solvent or additive. If the phase diagram of a polymer/solvent mixture vs. temperature shows both a one-phase and a two-phase region, one can identify the critical solution temperature: the UCST or LCST. Often the terms UCST and LCST are used in a misleading fashion, therefore, it has to be noted that they should only be used, if the phase diagram has been determined. Then it is the maximum (UCST) or the minimum (LCST), respectively, of the phase diagram. Any other transition from soluble to insoluble or vice versa (at a given concentration) should be denoted as transition temperature Ttr. However, some polymers like PNIPAM exhibit a phase transition, which is almost independent of the concentration or molecular weight. Then the Ttr at any given concentration is almost identical to the LCST. Table 2 gives a selection of polymers with either LCST or UCST behaviour in aqueous solution. These polymers have the transition temperature in the temperature region, which is interesting for biomedical applications (~20'40 ??C). It has to be noted that the transition temperature can be strongly dependent on factors such as solvent quality, salt concentration, etc. (besides molecular weight and concentration). Obviously, the transition temperature has to be determined for the setting of the intended application. One example of a pseudo-natural polymer will be discussed as well. It is the elastin-like polypeptide poly (GVGP), which is usually prepared by genetic engineering.
Selected polymers with LCST or UCST behaviour in the temperature region interesting for biomedical applications(21).
Polymer Phase transition temperature in aqueous solution
Poly(methyl vinyl ether)
(a) Strongly dependent on MW and concentration
(b) Pluronics, tetronics, poloxamer
Table No. 2 Selected polymers with LCST or UCST behaviour
3. Polymers with dual stimuli- responsiveness
These are the polymeric structures sensitive to both temperature and pH, they are obtained by the simple combination of ionisable and hydrophobic (inverse thermo-sensitive) functional groups.
4. Phase sensitive smart polymers
Phase sensitive smart polymers can be used to develop biocompatible formulations for controlled delivery of proteins in a conformationally stable and biologically active form. These smart polymeric systems have many advantages over other systems such as ease of manufacture, less stressful manufacturing conditions for sensitive drug molecules, and high loading capacity[39-40].
The phase sensitive injectable polymeric systems have many advantages such as ease of manufacture, less stressful manufacturing conditions for sensitive drug molecules, and high loading capacity. This approach was first introduced by Dunn and it employs a water insoluble biodegradable polymer, such as poly(D,L-lactide), poly(D,L-lactide-co-glycolide) and poly (D,L-lactide-co-e-caprolactone), dissolved in a pharmaceutically acceptable solvent to which a drug is added forming a solution or suspension. After injection of the formulation into the body, the water miscible organic solvent dissipates and water penetrates into the organic phase. This causes phase separation and precipitation of the polymer forming a depot at the site of injection [43,44]. Organic solvents used include hydrophobic solvents, such as triacetin, ethyl acetate, and benzyl benzoate; and hydrophilic solvents, such as N-methyl-2pyrrolidone (NMP), tetraglycol, and glycofurol. An example of phase sensitive polymer-based product is Eligard??, which employs Atrigel??as a drug carrier, and it is used for management of advanced prostate cancer. It contains LHRH agonist leuprolide acetate and PLGA 75/25 dissolved in N-methyl-2-pyrrolidone (NMP) [45-46]. This system led to suppression of testosterone levels in dogs for approximately 91 days . Clinical studies demonstrated that a depot containing 22.5 mg leuprolide maintained an effective suppression of testosterone below the medical castration level of 50 ng/dl. Another product that utilizes Atrigel?? technology is Atridox??(8.5% doxycycline), which is used for treatment of chronic periodontitis. Atridox?? is a subgingival controlled-release formulation that releases doxycycline over a week. Finding non-toxic and biocompatible solvents is a major challenge in developing phase sensitive formulations. The solvents used must be biocompatible to avoid severe tissue irritation or necrosis at site of administration. There is a controversy about the use of dimethyl sulfoxide (DSMO) and NMP in these systems. There are extensive toxicity data for oral, intraperitoneal, and intravenous administration of these solvents, but not for subcutaneous or intramuscular use.
There are several patents which use biodegradable polymers dissolved in suitable organic solvents for drug delivery[42, 50-56]. Examples of biodegradable polymers are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxy cellulose, chitin, and chitosan. The solubility of the polymers in the different solvents will vary depending on their crystallinity, hydrophilicity, hydrogen bonding, and molecular weight. Therefore, the concentration of a polymer dissolved in the various solvents will differ depending on polymer type and its molecular weight. Normally, the high molecular weight polymers will tend to solidify faster and give higher solution viscosities than the low molecular weight polymers.
5. Ultrasound-sensitive drug delivery
Cavitation or raising the local temperature responsible for release of the drug and which is given by ultrasound so it acts as a trigger for release of the drug.This processes can increase the permeability of cell membranes and accelerate polymer degradation. Ultrasound-sensitive polymers have the potential to treat tumorigenic cancers due to their invasive character, ability to penetrate deeply into the human body, and ease of control. In 2002, Pruitt and Pitt investigated ultrasound-mediated doxorubicin release using stabilized Pluronic P105 micelles. Doxorubicin was encapsulated within polymeric micelles composed of 10% Pluronic P105 and N,N-diethylacrylamide and delivered systemically to rats. Application of low-frequency ultrasound at the tumor site resulted in doxorubicin release; this resulted in a significant reduction in tumor volume. Lin et al. have investigated the physical and chemical properties of lipid membranes subjected to ultrasound treatment. They showed that high permeability resulting from ultrasound treatment is correlated with lipid packing and can be useful for efficient drug release and ultrasound-mediated DNA transfection. In 2007, Ferrara et al. reviewed that small gas bubbles, used to enhance ultrasound contrast, can be used for drug delivery applications and monitoring. When driven by an ultrasonic pulse, small gas bubbles oscillate with a wall velocity on the order of tens to hundreds of meters per second and can be deflected to a vessel wall or fragmented into particles on the order of nanometers. Also, a focused ultrasound beam can be used for disruption of delivery vesicles and blood vessel walls, which offer the opportunity to locally deliver a drug or gene. Ultrasound does not damage the surrounding tissue, making it attractive for triggering drug release.
5. Light sensitive smart polymers
Light can be applied as an external physical stimulus. Light act as a switch for drug release on and off at a target site and offering a potential for release on demandin the targeted places of the human body that is too difficult to achieve by using other stimuli. A visible light sensitive smart polymer that forms aqueous two phase systems are potentially used in industrial bioseparation techniques. Many of the problems of two phase systems like; they cannot be recycled, result in increasingly expensive bioproducts, purification processes, and environmental pollution have been overcome by the use of light sensitive smart polymers. These systems are biocompatible, biodegradable, polymerizable, and at least partially water soluble macromers.
The macromers include at least one water soluble region, at least one region which is biodegradable and at least two free radical polymerizable regions. Macromers are polymerized by free radical initiators under ultraviolet light, visible light excitation, or thermal energy. The core water soluble region can consist of PEG, poly (vinyl alcohol), polysaccharides such as hyaluronic acid, and proteins such as albumin. The biodegradable regions may be polymers made up from polylactic acid, polyglycolic acid, poly(anhydrides), poly (amino acids) and polylactones. Preferred polymerizable regions include acrylates, diacrylates, methacrylates or other biologically accepted polymerizablegroups.Initiators that can be used for generation of free radicals include ethyl eosin, acetophenone derivatives, or camphorquinone [62,22].
Macromers are polymerized by free radical initiators under ultraviolet light, visible light excitation, or thermal energy. The core water soluble region can consist of PEG, poly (vinyl alcohol), PEO-PPO, polysaccharides such as hyaluronic acid, or proteins such as albumin. The biodegradable region may be polymers made up from polylactic acid, polyglycolicacid,poly(anhydrides), poly(amino acids), and polylactones. Preferred polymerizable regions include acrylates, diacrylates, methacrylates, or other biologically accepted photo-polymerizable groups. Initiators that can be used for generation of free radicals include ethyl eosin, acetophenone derivatives, or camphorquinone [63-66].
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