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2 Stimuli-responsive Materials Used as Medical Devices in Loading and Releasing of Drugs H. Iván Meléndez-Ortiz*,1,2 and Emilio Bucio1 1Department of Radiation Chemistry and Radiochemistry, Institute of Nuclear Sciences, National Autonomous University of Mexico, Circuito Exterior, Ciudad Universitaria, Mexico City, Mexico 2Department of Pharmacy and Pharmaceutical Technology, Universidad de Santiago de Compostela, Spain Abstract Among polymers with potential use in biomedical field we can look to the stimuli-responsive polymers, also called “smart”. These materials are able to mod- ify their physical properties (for example, swelling in water) in response to a small variation of environmental factors (temperature, pH, light, magnetic and electric field, etc.). The swelling or shrinking of smart polymers in response to these small changes can be used successfully to control drug release. These polymers can be used to fabricate medical devices which have become an essential part of mod- ern medical care. However, some challenges such as, infections, inflammation, biofilm formation on surface, etc. must be taken into consideration. This chapter reviews and focuses the recent advances in the preparation and characterization of stimuli-responsive materials used as medical devices in loading and eluting of drugs. Also, some strategies are described in order to improve performance of these biomedical devices. Keywords: Stimuli-responsive polymers, medical devices, drug-eluting systems *Corresponding author: [email protected] Ashutosh Tiwari and Anis N. Nordin (eds.) Advanced Biomaterials and Biodevices, (53–78) 2014 © Scrivener Publishing LLC 53

54 Advanced Biomaterials and Biodevices 2.1 Introduction Recently, due to their potential to significantly reduce the side effects of therapeutics, there has been a remarkable growth in drug delivery sys- tems used for biomedical research. These help significantly to control the concentration and location of active drugs released in the body over long periods of time (compared to the administration of equivalent levels of free drugs). The increasing availability of biocompatible synthetic materials, together with a continuously evolving understanding of the mechanical details underlying disease pathology, have stimulated an explosion of new ideas and approaches to develop interesting medical devices used as drug delivery systems. Usually, because of their low production cost and easy manufacturing and handling, the most widely-used materials for fabri- cating medical devices are polymers. Among polymers with the greatest potential for uses in this field, we find the stimuli-responsive polymers also known as “smart”. These materials are able to modify their physical prop- erties in response to a small variation of environmental factors (tempera- ture, pH, light, magnetic and electric field, etc.). The temperature-sensitive polymers undergo an abrupt decrease of the solubility in water above a certain temperature; this temperature is known as lower critical solution temperature (LCST). The stimuli-responsive polymers can be prepared in various architectures, such as micelles, reversible hydrogels, cross-linked (permanent) hydrogels, interpenetrating networks (IPNs), modified inter- faces and comb-type and graft copolymers. The swelling or shrinking of smart polymers in response to small changes in pH or temperature can be used successfully to control drug release, because the diffusion of the drug depends on the polymer state. A thermo-responsive material can load drugs under LCST because it has the capacity to swell drug solution. Then, when temperature is increased further than LCST, it de-swells and can release the drug. However, it should be noted that temporary or permanent implanting of medical devices usually causes injury, inflammation and a wound healing response, resulting in swelling and pain at the insertion site and discom- fort for the patient. Also, some challenges such as infections, inflamma- tion, biofilm formation on surface, etc. must be taken into consideration. For example, once a medical device is inserted, a race to colonize the sur- face begins, in which proteins, host cells and microorganisms compete for adsorption onto the material. Microbial contamination is a major concern in this area because growth of bacteria on implanted medical devices can lead to development of severe infections. A potential method to prevent

Stimuli-responsive Materials Used as Medical Devices 55 microbial contamination is to coat susceptible surfaces with antimicrobial agents including polymers, which inhibit growth of microorganisms. The research discoveries reported in this chapter revise and focus the recent advances in the preparation and characterization of stimuli- responsive materials used as medical devices in loading and eluting of drugs. Additionally, some strategies are described that might help improve performance of these biomedical devices. 2.2 Classification of Materials for Bioapplications 2.2.1 Polymers Polymers are widely used in various bioapplications because they are avail- able in a variety of compositions, properties, and forms (solids, fibers, fab- rics, films, and gels), and can be fabricated readily into complex shapes and structures [1]. In recent years, there has been remarkable growth in the research and development of synthetic polymers for biomedical, micro- electronics, and other advanced technological applications. Temperature- sensitive polymers have gained much attention because of their intelligent and reversible behavior in response to environmental stimuli, in particu- lar to temperature variation. Such a behavior, on the one hand, is of great importance for theoretical and basic research, on the other hand, it can be utilized to form intelligent materials with nano- or micro- dimen- sions, such as gels, particles, micelles, and capsules. These materials in various physical formats have shown intelligent loading and release capa- bilities for drugs, proteins, nanoparticles, and DNAs under the modula- tion of temperature, ionic strength, pH values, solvents, and even light [2, 3]. Some polymers used for biomedical applications are high density polyethylene, ultrahigh molecular weight poly(ethylene), poly(urethane), poly(sulfone), poly(ethylene), poly(propylene), poly(methylmethacrylate), poly(etheretherketone), poly(acetal), poly(ethylene terephthalate) and sili- cone rubber. 2.2.2 Ceramics Traditional ceramics are of high compressive but low tensile strength. As compared to metals, ceramics often are regarded as favorable materials for joints or joint surface materials. Most types of ceramics are inherently hard and brittle materials with higher elastic moduli compared to bone. Several ceramics have been investigated as bone substitute materials due

56 Advanced Biomaterials and Biodevices to their ease of processing and forming and superior mechanical proper- ties. In the other hand, conventional ceramics such as alumina (Al2O3) and zirconia (ZrO2) have been evaluated due to their excellent properties of high strength, good biocompatibility and stability in physiological envi- ronments [4]. Also, they are non-bioactive ceramics and are covered by a non-adherent fibrous layer at the interface after implantation. In orthope- dics they are mainly used as artificial femoral heads due to their excellent mechanical strength and durability [5]. Bioactive glasses (Bioglass) have been widely used as bone void fillers in clinical settings. They mainly con- sist of sodium, calcium, silicon and phosphorous oxides [6]. However, the brittleness and low fracture toughness of bioglass hampers its application for load-bearing applications. 2.2.3 Composites Polymer-matrix composite materials are resins reinforced by fibers which have diverse applications in different industries; composite materials have potential to be manipulated to obtain materials with combination of prop- erties which cannot be obtained by conventional methods. Composite materials have been recently considered for biomedical applications, since they have mechanical and biological similarities to the human tissue being replaced [7]. 2.2.4 Metals Metals have been usually used in biomedical field as implants. Permanent metal implants based on stainless steel, cobalt– chromium (Co–Cr) alloys and titanium or its alloys have been at the forefront of classical biomateri- als research for decades. The high tensile strength and fatigue resistance of metal makes it suitable for load-bearing applications. Until now, hip, knee, spinal and dental metal implants still cover up the majority of all inserted implants worldwide. However, currently used metallic materials are afflicted with some limitations such as, corrosion which can cause tox- icity or hypersensitivity reactions. 2.3 Responsive Polymers in Controlled Drug Delivery Drug delivery systems can be classified according to the mechanism control- ling the drug release: diffusion-controlled systems, chemically controlled systems, solvent-activated systems and modulated-release systems [8]. In

Stimuli-responsive Materials Used as Medical Devices 57 modulated-release systems. The drug release is controlled by external stim- uli such as temperature, pH, ionic strength, electric and electromagnetic field, light, etc. Therefore, polymers that respond to these external stimuli can be used as controlled-release devices. Delivery applications of smart polymers have already generated an overwhelming collection of articles. The micelles are the most trivial structures used for the entrapment and subsequent release of small hydro- phobic molecules. However, the use of classic micellar structures is lim- ited to the encapsulation of hydrophobic drugs in the core. A number of other polymeric nanostructures have shown great potential in drug deliv- ery, including smart surfaces, dendrimers, and in situ forming nanogels. Stimuli-responsive polymers can mimic biological systems in response to small changes in environmental stimuli, such as, temperature, pH, ionic strength, etc. This also includes a combination of several stimuli at the same time. Stimuli-responsive polymers are also called “smart, “intelligent” or “environmentally sensitive” polymers [9]. One important feature of this type of material is reversibility, i.e. the ability of the polymer to return to its initial state upon application of a counter-trigger. These unique charac- teristics are of great interest in drug delivery, cell encapsulation and tissue engineering [10]. The most important systems from a biomedical point of view are those sensitive to temperature and/or pH of the surroundings. They present a fine hydrophobic–hydrophilic balance in their structure. pH-responsive polymers are important due to the human body exhibits variations of pH along the gastrointestinal tract, and also in some spe- cific areas like certain tissues (and tumoral areas). In the case of the tem- perature-responsive polymers, a small change around a critical solution temperature make the polymeric chains collapse or extend, responding to adjustments of the hydrophilic and hydrophobic interactions between them and the aqueous medium [11, 12]. 2.3.1 Temperature-responsive Polymers Temperature is the most widely utilized triggering signal for a variety of drug delivery systems. This is due to the fact that the human body temper- ature often deviates from the physiological value (37 °C) in the presence of pathogens or pyrogens. This deviation can be a useful stimulus to activate release of therapeutic agents from various temperature-responsive drug delivery systems for diseases accompanied by fever. Drug-delivery sys- tems responsive to temperature utilize various polymer properties, includ- ing the thermally reversible transition of polymer molecules and swelling change of networks [13].

58 Advanced Biomaterials and Biodevices Temperature-responsive polymers have a lower critical solution tem- perature (LCST), which may be defined as the critical temperature below which the polymer swells in the solution while above it the polymer con- tracts. Below the LCST, the enthalpy term, related to the hydrogen bond- ing between the polymer and the water molecules, is responsible for the polymer swelling. When the temperature is raised above the LCST, the entropy term (hydrophobic interactions) dominates, leading to polymer contraction. Therefore, these polymers can load drug at low temperature and release it at high temperature. 2.3.2 pH-responsive Polymers pH is an important environmental parameter for biomedical applications, because pH changes occur in many specific or pathological compartments, for example, there is an obvious change in pH along the gastrointestinal tract from the stomach (pH = 1–3) to the intestine (pH = 5–8). The key element for pH responsive polymers is the presence of ionisable, weak acidic or basic moieties that attach to a hydrophobic backbone [14]. Upon ionization, the electrostatic repulsions of the generated charges (anions or cations) cause a dramatic extension of coiled chains. The ionization of the pendant acidic or basic groups on polyelectrolytes can be partial, due to the electrostatic repulsion from other adjacent ionized groups [15]. Typical pH responsive polymer exhibits protonation/deprotonation events by distributing the charge over the ionisable groups of the molecule, such as carboxyl or amino groups. Swelling of a polymer increases as the external pH increases in the case of weakly acidic (anionic) groups, but decreases if the polymer contains weakly basic (cationic) groups. Most anionic pH-sensitive polymers used in drug delivery are based on poly(acrylic acid) (PAA), poly(methacrylic acid) (PMMA), poly(ethylene imine) and poly(l-lysine) [16]. Swelling of this kind of polymers in the stomach is minimal and thus the drug release is also min- imal. The swelling increases as the polymer passes down the intestinal tract due to an increase in pH leading to ionization of carboxylic groups and the drug release. In the contrary case, polymers containing cations in their back- bone swell and release a drug in the low-pH environment of the stomach. 2.3.3 Electric-responsive Polymers Electrical stimulus is widely used in research and applications, due to its advantages of precise control via the magnitude of the current, and the dura- tion of an electrical pulse [17]. Electric-sensitive polymers can be used to prepare materials that swell, shrink, or bend in response to an electric field

Stimuli-responsive Materials Used as Medical Devices 59 [18]. These polymers are an increasingly important class of smart materials because they can transform electrical energy into mechanical energy and have promising applications in energy transduction, biomechanics, chemi- cal separations, artificial muscle actuation and controlled drug delivery, [19, 20]. Electrically responsive delivery systems are prepared from poly- electrolytes (polymers that contain a relatively high concentration of ioniz- able groups along the backbone chain) and are thus pH-responsive as well. Typically, electric-sensitive polymers have been investigated in the form of polyelectrolyte hydrogels [21–24]. Polyelectrolyte gels deform under an electric field due to anisotropic swelling or deswelling as charged ions are directed toward the anode or cathode side of the gel [18]. 2.3.4 Magneto-responsive Polymers Generally, magneto-responsive polymers consist of inorganic magnetic nanoparticles which are physically entrapped within or covalently immo- bilized to a three-dimensional crosslinked network, leading to materials with shape and size distortion that occurs reversibly and instantaneously in the presence of a non-uniform magnetic field [25, 26]. As a result of the magnetic susceptibility of the particles, these materials have received significant attention for use as soft biomimetic actuators, sensors, cancer therapy agents, artificial muscles, switches, separation media, membranes, and drug delivery systems [27, 28]. Most examples of magneto-responsive polymer systems involve non-covalent interactions between polymer chains and magnetic particles [28]. However, recent advances in polymer synthesis have facilitated the covalent immobilization of polymer chains directly to the surface of magnetic particles [29]. 2.3.5 Photo-responsive Polymers Photo-responsive polymers are macromolecules that change their properties when irradiated with light of the appropriate wavelength [30]. Typically these changes are the result of light-induced structural transformations of specific functional groups along the polymer backbone or side chains [31]. Among, these functional groups (chromophores), we can find, azobenzenes [32], spi- ropyran groups [33, 34], or nitrobenzyl groups [35, 36]. Because light can be applied instantaneously and under specific conditions with high accuracy, it renders photo-responsive polymers highly advantageous for possible appli- cation which include reversible optical storage, polymer viscosity control, photomechanical transduction and actuation, bioactivity switching of pro- teins, tissue engineering, and drug delivery [37–40]. An important aspect

60 Advanced Biomaterials and Biodevices of photo-sensitive polymer systems is that using irradiation as a stimulus is a relatively straightforward, non-invasive mechanism to induce responsive behavior. However, light of UV and visible wavelengths is readily absorbed by the skin, so UV/visible-light-responsive systems have potential limita- tions for some biomedical applications. However, IR radiation can penetrate skin with less risk of damage and might be more applicable for photoactiva- tion of drug carriers within a living system [41]. 2.4 Types of Medical Devices A medical device is an instrument, apparatus, implant, in vitro reagent, or similar or related article that is used to diagnose, prevent, or treat disease or other conditions, and it does not achieve its purposes through chemical action on the body. Whereas medicinal products (also called pharmaceuticals) achieve their principal action by pharmacological, metabolic or immunologi- cal means, medical devices act by other means like physical, mechanical, or thermal means. Medical devices vary greatly in complexity and application. 2.4.1 Stents A stent is a mesh ‘tube’ inserted into a natural passage/conduit in the body to prevent or counteract a disease-induced, localized flow constriction. The term may also refer to a tube used to temporarily hold such a natural conduit open to allow access for surgery. Several small clinical studies have examined the use of drug-eluting stents for the treatment of femoropop- liteal stenosis with evidence of favorable results. Zilver PTX is a self- expanding, nitinol drug-eluting stent with polymer-free paclitaxel coating on its outer surface [42]. The most common use for stents is in coronary arteries, into which a bare-metal stent, a drug-eluting stent, or occasionally a covered stent is inserted. Coronary stents are placed during a percuta- neous coronary intervention procedure, also known as an angioplasty. In order to prevent the restenosis after stent implantation, the drug-eluting stents, which incorporate drugs that can effectively reduce the prolifera- tion and migration of smooth muscle, have been developed and several clinically proven products are currently available on market [43]. 2.4.2 Cannulas A cannula is a tube that can be inserted into the body, often for the delivery or removal of fluid or for the gathering of data. In simple terms, a cannula

Stimuli-responsive Materials Used as Medical Devices 61 can surround the inner or outer surfaces of a trocar needle thus extending needle approach to a vein by half or more of the length of the introducer. A large number of cannula devices have been designed for the adminis- tration of a drug or other chemical compound. Peripheral intravascular cannulas are indispensable in modern medical practice; there are also a growing number of patients on “home” intravenous therapy, predomi- nantly for total parenteral nutrition. Although the peripheral venous can- nulas provide necessary vascular access, their use puts patients at risk for local and systemic infectious complications, including local site infection, infusion extravasations, and cannula related blood stream infections [44]. 2.4.3 Catheters Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Catheters can be used for car- diovascular, urological, gastrointestinal, neurovascular, and ophthalmic applications. They can be inserted into a body cavity, duct, or vessel and they allow drainage, administration of fluids or gases, access by surgical instruments, and perform wide variety of other tasks depending on the type of catheter. For example, intravascular catheters are indispensable in current medical practice, particularly in intensive care units, but are no longer restricted to hospital inpatients while the central venous catheter has become a lifeline for many critically ill patients, as well as chronically ill patients who have cancer or are undergoing haemodialysis [45]. Central venous catheters are now a routine part of patient management in the intensive care unit. They provide access to large blood vessels and are used for the delivery of intravenous medication and the monitoring of central venous pressure [46]. With the recent availability of percutaneous intra- vascular central catheters, their application is likely to increase further, particularly for patients requiring intravenous therapy in the community. Unfortunately, infection continues to be a major problem associated with the use of intravascular catheters [47]. 2.4.4 Cardiac Pumps Ventricular assist devices are mechanical pumps designed to augment or replace the function of one or more chambers of the failing heart; cardiac pumps have been developed as a bridge to transplant, a bridge to recovery, and as an end stage treatment. They can be implanted to support the left ventricle or the right ventricle or two devices are used to support both left and right ventricles [48]. Over the past 10 years, pump technology has

62 Advanced Biomaterials and Biodevices changed markedly with the discovery that pulse pressure is not a funda- mental requirement in the human circulation [49]. 2.4.5 Prostheses The use of artificial prosthetic replacements has become an important sur- gical procedure in orthopedic human joint diseases. The success of this kind of procedure largely depends on the fixation of the artificial pros- thetic component after being implanted in the thighbone. The term “pros- thesis”, derived from the Greek “prosthesis” from “pro” (in place of) and “thesis” (the action of placing) is defined as “an artificial device to replace or augment a missing or impaired part of the body” [50]. The implants must maintain their shape and must require uncomplicated implantation procedures [51]. 2.4.6 Sutures The suture is a medical device used to hold body tissues together after an injury or surgery. Historically, there were few surgical options for wound closure. From catgut, silk, and cotton, there is now an ever-increasing array of sutures, approximately 5000 different types, including the absorbables poly(glycolic acid), poly(lactic acid), and poly(dioxanone) as well as the non-absorbables nylon and poly(propylene). Newer still is the idea of coating sutures with antimicrobial substances to reduce the chances of wound infection. Sutures come in very specific sizes and they must be strong enough to hold tissue securely but flexible enough to be knotted. In a surgical procedure, the choice of suture with which to close an incision is often as important as where to make the cut. Although the medical literature is replete with clinical trials of new pharmaceuti- cals and surgical devices, few efforts have been directed toward suture material. 2.5 Materials Used in Medical Devices Over many years, people have attempted to use, compounds available naturally to make tools and devices. As time progresses, polymers, alloys, ceramics and chemically modified biopolymers have been appeared thanks to the development of chemistry and materials science. Today, all sectors of human activities take advantage of compounds and systems based on artificial macromolecules.

Stimuli-responsive Materials Used as Medical Devices 63 2.5.1 Elastomers for Biomedical Devices The use of elastomers for medical devices goes back to the time when the rubber industry itself started: vulcanized natural rubber was used in medi- cal devices soon after the discovery of the rubber-vulcanization process. There are three groups of elastomers used in biomedical applications: (a) the commodity elastomers which happened to be used in the biomedi- cal field; (b) medical grades of elastomers certified for short-term physio- logical contact; and (c) a small group of elastomers suitable for longer-term physiological contact or implantation. Biomedical elastomers require high purity, desired physical, chemical and mechanical properties, easy fabrica- bility and high stability and sterilizability. When applied in possible contact with biological tissues and fluids [52–54], they must not cause thrombosis, destroy cellular elements, alter plasma protein, destroy enzymes, deplete electrolytes, cause immune response and cancer, or othersie generate toxic o alrlergic reactions.. 2.5.2 Shape-memory Polymer Systems Intended for Biomedical Devices Polymeric biomaterials are presently applied in implants, surgical instru- ments, extracorporal devices, wound covers and controlled drug deliv- ery systems. Each application requires a specific combination of material properties and functions. In many cases implants have to fulfill certain mechanical functions [55]. With respect to shape-memory polymers, bio- medical applications require certain properties or functionalities, which can be fulfilled by the appropriate choice of suitable shape-memory poly- mer architectures. An example is a covalent shape-memory polymer network in which the temporary shape is fixed only by one switching domain. Another important point to be considered from an application point of view is the processability of the different shape-memory polymer architectures [56, 57]. 2.5.3 Metallic Materials for Biomedical Devices Metallic biomaterials have the longest history among the various biomate- rials. They are exploited due to their inertness and structural functions; they do not possess biofunctionalities like blood compatibility, bone conductiv- ity and bioactivity, hence, surface modifications are required; improving their bone conductivity has been done by coating with bioactive ceramics like hydroxyapatite, or blood compatibility by coating with biopolymers.

64 Advanced Biomaterials and Biodevices Stainless steel was first used successfully as an implant material in the sur- gical field; this success was accomplished when aseptic surgery was estab- lished. Then, vitallium, a Co-based growing alloy, was put into practical use. Titanium is the newest metallic biomaterial among the three main metallic biomaterials and these remain the most popular of the metallic alloys. Titanium and its alloys have excellent biocompatibility, light weight, excellent balance of mechanical properties, excellent corrosion resistance, etc. [58, 59]. Nowadays, large number of metallic biomaterials composed of nontoxic and allergy-free elements are being developed [60, 61]. 2.5.4 Ceramic Materials for Biomedical Devices Bioceramics are special compositions of ceramic materials in the form of powders, coatings, or bulk devices, used widely to repair, augment or replace diseased or damaged tissues, usually bones, joints or teeth. Clinical use of bioceramics is rapidly expanding because of the increasing rate of failure of metallic or polymeric devices (also called prostheses or implants). Although many compositions of ceramics have been tested for medical use, very few compositions are used clinically. A12O3 and ZrO2, have been used primarily in total joint replacement. Calcium-phosphates are used as coatings on metal alloys or as particles or porous shapes for bone repair. Bioactive glasses and glass-ceramics are employed in the replacement of ear bones, teeth or vertebrae or as powders to repair bone [62, 63]. 2.5.5 Sol–gel Materials for Biomaterials Devices Sol–gel technology is a wonderful advancement in science and requires a multidisciplinary approach for its various applications. It has been used for the fabrication of optical fibers, optical coatings, electro-optic materials, nanocrystalline semiconductor-doped xerogels, colloidal silica powders for chromatographic stationary phase and as catalytic support [64, 65]. Applications utilizing sol–gel as a porous material to encapsulate sensor molecules, enzymes and many other compounds are most common; how- ever, some potential applications of sol–gel-derived materials in biomedical applications are fast emerging. Biomedical applications require the design of new biomaterials and this can be achieved by merging sol–gel chemis- try and biochemistry. Gel-derived materials are excellent model systems for studying and controlling biochemical interactions within constrained matrices with enhanced bioactivity because of their residual hydroxyl ions, micro-pores and large specific surface [66].

Stimuli-responsive Materials Used as Medical Devices 65 2.6 Stimuli-responsive Polymers Used in Medical Devices A biomaterial may be defined as any type of material (natural or synthetic) that supports or replaces a natural function. Many types of materials are used in the fabrication of biomaterials, such as polymers, ceramics, glasses, metals and alloys and composites, in devices whose purpose is, for example, to substitute heart valves, joints, tubing, or intra-ocular lenses. Biomaterials can be divided into 4 categories: a) apparatuses developed for in vitro diag- nosis, b) hybrid organs c) implants and prostheses, and d) medical devices. Depending on the duration of the contact and on the nature of the interac- tions between the material and the living medium, three different biocom- patibility levels are classified. The highest classification corresponds to the longest contact duration, which can be several weeks or longer. Polymers are widely used in the fabrication of biomaterials because of their low production cost and easy manufacturing and handling. The requirements for the biomaterials are compatibility with living tissues, good mechanical properties (elasticity, deformation, wear resistance, yield stress, ductility, toughness, hardness, etc.) and ease of production, at rea- sonable cost, including sterilization. Besides, the route selected for drug delivery has a significant effect on the drug’s therapeutic efficacy, safety, and bioavailability [67]. The ideal aim of administration should be to deliver the drug at a required concentration within the therapeutic win- dow at the right time to a specific target, in a safe and reproducible manner. However, in certain cases such as hormone delivery, diabetic treatment, and others, the preferred method of drug delivery is in the form of pulses at variable time intervals [68]. There are also instances such as the treatment of malaria, cancer, and others, wherein combination therapies involving multiple drugs to exploit the synergistic and additive potential of individ- ual drugs are required [69]. All these requirements were initially achieved by employing stimuli-responsive polymers as drug carrying matrices, wherein their diffusive, degradability, and responsive properties to exter- nal stimuli controlled the sustained release of the drug [70–73]. For that reason nowadays, research is being conducted to improve design, synthesis and fabrication of medical devices based on stimuli- responsive [74]. Stimuli-responsive polymers mimic the behavior of bio- logical molecules where external stimuli or changes in local environment can trigger a change in property: conformation, solubility, shape, charge, and size. Drug release can be regulated not only spatially via targeting, but also temporally in the presence of externally-applied stimuli [75]. One

66 Advanced Biomaterials and Biodevices class of smart polymers that can be effectively used for pulsatile/controlled drug delivery applications are responsive hydrogels. The ability of hydro- gels to respond reversibly to variations in their environment makes them viable for widespread applications in the medical field [76]. Microfluidic actuating systems have lithographically fabricated, in which the hydro- gel present at the junction of themicrochannel actuates in response to the changes in environmental conditions, thereby gating the microchannel accordingly [77, 78]. Micropumps and microvalves have synthesized using a micro-structured silicon membrane with entrapped hydrogels for envi- ronmentally sensitive fluid gating [79]. A responsive controlled-drug-release system has been prepared where the controlled release is achieved by actuating a polymeric valve system also called an artificial muscle [80]. In addition, some polymeric matri- ces have been modified with gamma radiation in order to obtain stimuli- responsive polymers which could have potential to be used as biomaterials in the fabrication of medical devices. Polypropylene (PP) films have been grafted with thermo-pH responsive polymers in order to improve loading of vancomycin [81]. Vancomycin is one of the most frequently chosen anti- biotics for the treatment of infections associated with the use of catheters. PP is widely used as component of meshes for abdominal hernias, sutures and catheters, and it can be colonized with bacteria. Grafting of acrylic acid (AA) enhanced the vancomycin loading and modified PP films reduced biofilm formation by methicillin-resistant Staphylococcus aureus [82]. PP has been modified with PNIPAAm and N-(3-aminopropyl) meth- acrylamide hydrochloride (APMA) as a suitable monomer able to electro- statically interact with anionic drugs, such as nalidixic acid. Copolymer exhibited the temperature responsiveness of PNIPAAm, while the grafting with a greater content in APMA led to load a higher amount of nalidixic acid [83]. In addition to microbial agents, these kind of stimuli-responsive polymers have been loaded with other drugs such as non-steroidal anti- inflammatory drugs (NSAIDs) [84]. Other authors have fabricated micro devices with pH responsive hydrogels encompassing enzyme glucose oxi- dase for insulin delivery applications [10, 85]. 2.6.1 Advancements in Design of Medical Device Advancements in micro- and nano-fabrication technologies have enhanced the ability to create successful implantable and oral drug delivery systems composed of silicon, glass, silicone elastomers and other polymers [86–88]. The two most used conventional drug administration methods are oral and parenteral delivery systems, however, the rate of drug delivery or the target

Stimuli-responsive Materials Used as Medical Devices 67 area of the drug is not easily controlled. In most cases, the initial drug con- centration after administration is above the toxicity level and then gradually diminishes over time to an insufficient therapeutic level. This is a very in effective and potentially dangerous way of delivering drugs. Also, the dura- tion of the therapeutic efficacy is dependent on the frequency of adminis- tration and the half-life of the drug. High dosages of non-targeted drugs are often administered to achieve an effective blood concentration for treat- ment which could be damaging to the entire body [89]. Conventional drug administration methods are also limited in providing long-term treatment, a narrow therapeutic window, complex dosing schedule, combination ther- apy, and personalization-based dosing [90]. To overcome these limitations, development of combination drug and medical device systems that have the ability to protect active ingredients, precisely control drug release kinetics (time of dose and the amount administered), and deliver multiple doses are required. New medical device and drug combination system also need to have the ability to be controlled and to adjust the release of therapeutic agents. This helps to eliminate the need for frequent injection or even sur- gery for implantable drug release systems [90]. Advances in microfabrication technology of implantable responsive drug release systems are becoming more realistic for medical applications [88]. Implantable drug delivery devices for administration of a precise amount of therapeutic agents at a specific time would be an important tool for treatment of numerous diseases that require repeat administration of drugs. However, there are some large limitations to implantable drug delivery devices, e.g., the device requires surgery for implantation and needs to have the ability to release drugs over a long period of time and therefore a large amount of drugs. Also, if a device needs to have a lifetime of a year, a high concentration of drug will need to be stored in the device safety. Therefore, the ideal implant system would protect the drug from the body until it is needed, allowing con- tinuous or time-specific delivery of therapeutic agents, and being controlla- ble externally without surgery. These requirements can be achieved by using individual drug containing reservoir microchips which have one important advantage over other designs: they have the ability to totally control drug delivery amount and timing via either continuous or palatial delivery [91]. Also, polymer microchips that are biodegradable are beneficial products because surgery would not be required to retrieve the device. 2.6.2 Drug Delivery Improved by Devices Since the 1970s, the FDA has approved over 70 controlled drug-delivery combination products [92]. During the last twenty years, drug-delivery

68 Advanced Biomaterials and Biodevices technologies became increasingly sophisticated controlled drug-delivery products diversified further into: subcutaneous implants, buccal sys- tems, vaginal rings, and wafers. Technological sophistication enabled new approaches to drug delivery systems beyond transdermal patches to address highly specific needs; in particular, therapies that stood to ben- efit from more invasive drug-delivery solutions than transdermal drug delivery. Transdermal patches account for over 60% of all controlled drug deliv- ery systems available in the market. The technology of transdermal patches has been extensively described elsewhere [93–95]. Because they offer an alternative for controlled delivery of substances into the bloodstream through the skin, this is particularly suited for the delivery of potent drugs that would be poorly absorbed or extensively metabolized when adminis- tered orally. Their initial adoption can be explained by their ease-of-use, conve- nience, and increased patient compliance. The first generation of trans- dermal patches was essentially limited by the passive methods of drug diffusion to deliver small, lipophilic, low-dose drugs [95]. However, the next generation introduced the use of chemical enhancers, noncavita- tional ultrasound, and iontophoresis to facilitate drug delivery [93, 95]. Iontophoretic systems facilitate the diffusion of larger molecules with a residual electric current that helps widen skin pores. The third generation is currently under clinical trials and is expected to revolutionize the deliv- ery of large molecules and vaccines [93–98]. 2.7 Infections Associated with Medical Devices Infection is defined as a homeostatic imbalance between the host tissue and the presence of microorganisms at a concentration that exceeds 105 organisms per gram of tissue [99]. The emergence of infection is associated with a large variety of wound occurrences, ranging from traumatic skin tears and burns to chronic ulcers and complications following surgery and device implantations. If the wound setting is able to overcome the microor- ganism invasion by a sufficient immune response, then the wound should heal via the common four-phased process of coagulation, inflammation, proliferation and remodeling [100]. If not, the formation of an infection can seriously limit the wound healing process, interfering with wound clo- sure and even leading to bacteremia, sepsis and multisystem failure. The insertion or implantation of medical devices has become an indis- pensable part in almost all fields of medicine. However, medical devices are

Stimuli-responsive Materials Used as Medical Devices 69 associated with a definite non-zero risk of bacterial and fungal infections. Device-associated infections are the result of bacterial adhesion and sub- sequent biofilm formation at the implantation site. Sources for infectious bacteria include the ambient atmosphere of the operating room, surgical equipment, resident bacteria already in the medical device, etc. [101]. In addition to human pain and suffering, direct medical costs associated with such infections are extremely high and often result in the removal of the medical device and therefore a new surgery. More than 2 million cases annually of hospital-acquired infections are reported in the USA —over half associated with medical implants. Medical devices such as end tracheal tubes, vascular and urinary catheters, and hip prosthetics are responsible for over one-half of nosocomial infections in the USA [102, 103]. In the case of joint replacements, over 800,000 surgeries (around US$4 billion) are performed annually in North America and this number is increasing [104]. Thus, there is an urgent need for significant innovation in the field of bacterial infections associated with medical devices. This innovation is especially needed with regard to polymers most commonly used to build medical devices [105]. The main goal of treating the various types of wound infections should be to reduce the bacterial load in the wound to a level at which healing processes can take place. By maintaining a high local antibiotic concentra- tion for an extended duration of release without exceeding systemic toxic- ity [106, 107], local delivery of antibiotics by topical administration, or by a local delivery device, addresses the major disadvantage of the systemic approach. Antibiotics already incorporated in controlled-release devices include amoxicillin, vancomycin, carbenicillin, tobramycin, cefamandol, and gentamicin [108]. The effectiveness of such devices is strongly depen- dent on the rate and manner in which the drug is released [109]. These are mainly determined by the material into which the antibiotic is loaded and the type of drug. If the drug is released quickly, the entire drug could be released before the infection is arrested. If release is delayed, infection may set in further, thus making it difficult to manage the wound. Also, the release of antibiotics at levels below the minimum inhibitory concentra- tion (MIC) may evoke bacterial resistance and this situation could inten- sify infectious complications [110, 111]. 2.7.1 Antibiotic-loaded Medical Devices The development of antimicrobial polymers is focused predominantly at the prevention of microbial colonization rather than microbial adherence. Antibiotic-loaded medical devices present a straightforward approach

70 Advanced Biomaterials and Biodevices for the prevention of implant-associated infections. The main principle of such devices is that an antimicrobial drug bound superficially to a medical device either directly or by means of a carrier or incorporated into the interior of the polymer. If such device comes into contact with an aqueous environment, drug release occurs in the immediate vicinity. The amount of the antimicrobial substance released is influenced by some parameters such as, loading dose, applied technique, molecular size of the drug and the physico-chemical properties of the polymeric device. Most materials exhibit a release pattern according to first-order kinetics, with an initially high drug release and subsequent exponential decrease of the released drug. Medical devices built from a material that would be antiadhesive or colonization-resistant in vivo would be the most suitable candidates to avoid colonization and subsequent infection [112, 113]. However, the most studies have focused on the incorporation or superficial coating of polymers with antimicrobials agents [114, 115]. Antimicrobials sub- stances that differ from antibacterials, such as antiseptics, have also used to develop new medical devices [116]. Also, silver has raised the interest of many investigators because of its good antimicrobial action and low tox- icity [117]. Antimicrobial polymers that contain silver represent a great challenge for academics and industry [118]. Silver is a metal known for its broad-spectrum antimicrobial activity against Gram-positive and Gram- negative bacteria, protozoa, fungi, and certain viruses [119], including antibiotic-resistant strains [120] and therefore it can be used to prevent bacterial colonization on medical devices [121–124]. Silver, as an antiseptic agent, has been effective in a variety of materials, including glass, titanium and polymers. The antimicrobial activities of commercially available silver impregnated dressings and catheters have been reported [125]. However, the use of medical devices containing silver must be undertaken with cau- tion, since a concentration-dependent toxicity has been demonstrated. 2.7.2 Biofilm Formation An ideal biomaterial should have good mechanical properties and a bio- compatible surface. Also, an acceptable biomaterial must not generate a strong foreign body or exogenous reaction or inflammation response. Nevertheless, while a few polymeric materials are truly biocompatible, only a much smaller number fulfill both requirements. Although there is a great variety of microorganisms involved as pathogens, however, staphylococci account for the majority of infections. Their ability to adhere to materials and promote formation of a biofilm comprise the

Stimuli-responsive Materials Used as Medical Devices 71 most important aspects of their pathogenicity. The host defense mecha- nisms often seem unable to handle the infection and, in particular, to eliminate the microorganisms from the infected device. These biofilms are considered the primary cause of implant-associated infection [126]. At the same time, however, the formation of a biofilm is necessary when the biomaterial is considered as a part of the body (orthopedic prosthe- sis) in order to enhance its long-term incorporation and bio-mechanical answer. On the other hand, biofilm formation is not necessary in a) temporary materials (tubes, drains, patch, pumps), b) light-transmitting biomateri- als (intra-ocular lens), c) vessel materials used for cells culture, d) medico- surgical tools, to avoid any bacterial transmission, e) medical analytical tools, f) semi-permeable membranes, used for microfiltration (kidney dialysis), g) bio-artificial pancreas (permeation of glucose and insulin) and h) artificial cornea (oxygen and water permeation). In the last case, biofilm formation implies pore obstruction and decrease of permeability. Another worrying feature of biofilm-based infections [127, 128] is rep- resented by the higher resistance of bacterial and fungal cells growing as biofilms as compared with planktonic cells [129]. It has been found that killing bacteria in a biofilm sometimes requires approximately 1000 times the antibiotic dose necessary to achieve the same results in a cell suspension [130]. The mechanisms involved in the increased drug resistance of biofilms [131] presumably include the following: (1) slow or incomplete penetration of antimicrobial agents through the biofilm matrix and (2)  physiological response of microorganisms to the heterogeneous chemical environment existing in biofilms [132]. Another critical issue of biofilm-based infections is that biofilms are polymicrobial communities in which both bacteria and fungi often occur. Polymicrobial biofilms comprising Candida albicans and Staphylococcus epidermidis have demonstrated an altered sensitivity of each species to antimicrobial agents as a result of their mutual interaction [133]. The occurrence of polymicrobial infections has significant implications for patient management owing to the related difficulties in selecting the most appropriate antimicrobial therapy, especially when multidrug-resistant pathogens are involved. Temperature-responsive polymer poly(N,N’- dimethylaminoethyl methacrylate) (PDMAEMA) has been grafted onto some films such as silicone rubber (SR) and poly(ethylene) in order to make them less susceptible to microbial biofilm formation. The quaternization of grafted PDMAEMA chains permitted to reduce Candida albicans and Staphyloccus aureus biofilm formation by 99% compared to pristine materi- als. These materials had the ability to inhibit microbial biofilm formation and at the same time acted as nalidixic acid-eluting systems [134].

72 Advanced Biomaterials and Biodevices 2.7.3 Approaches for the Prevention of Device-related Infections A very interesting approach to prevent biofilm in medical devices has been the application of an external stimulus, for example an electric field together with antibacterials [135]. Under these conditions, the killing of biofilm-embedded bacteria is dramatically enhanced. Besides, related approaches aimed at eradica- tion of biofilms include the combined use of ultrasound together with antibac- terials [136, 137] and, possibly, the bactericidal effect of extracorporeal shock waves on S. aureus [138]. Another approach to create anti-infective surfaces has been developed on the basis of so-called ‘intelligent polymers’. Polymeric films have been modified by means of gamma radiation and loaded with antimicro- bial agents in order to prevent colonization of bacterial agents. A sequential interpenetrating polymer network grafted onto PP film was prepared with the aim of developing medicated coatings for medical devices. The smart polymers (PAAc and PNIPAAm) were used in order to load vancomycin. Drug-loaded films sustained the delivery for several hours at pH 7.4 and provided release rate values adequate for killing bacteria attempting to adhere the surface of the films [139]. In other case, PP films grafted with N,N’-dimethylacrylamide (DMAAm) and NIPAAm were prepared in order to improve the hemo- compatibility and elution of antimicrobial for medical devices. The (PP-g- DMAAm)-g-NIPAAm films had significantly hemolytic and thrombogenic activity. The DMAAm promoted the loading of norfloxacin, an antimicrobial drug, when the copolymer was swollen and then NIPAAm shrink allowed a sustained delivery at 37°C. These temperature-responsive PP films have poten- tial as hemo- and cyto-compatible materials for medical devices [140]. Acknowledgements This chapter was supported by DGAPA-UNAM Grant IN202311 and CONACYT-CNPq Project 174378, and the Ibero-American Programme for Science, Technology and Development of CYTED — RIMADEL (=Red iberoamericana de nuevos materiales para el diseño de sistemas avanzados de liberación de fármacos en enfermedades de alto impacto socioeconómico ). References 1. S. Ramakrishna, J. Mayer, E. Wintermantel, and K.W. Leong, Compos Sci Technol, Vol. 61, p. 1189, 2001. 2. C. Gao, H. H. Möhwald, and J. Shen, Polymer, Vol. 46, p. 4088, 2005. 3. E. Bucio and G. Burillo, Radiat Phys Chem, Vol. 76, p. 1724, 2007. 4. K. S. Katti, Colloid Surface B, Vol. 39, p. 133, 2004.

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3 Recent Advances with Liposomes as Drug Carriers Shravan Kumar Sriraman1 and Vladimir P. Torchilin1,* 1Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, USA Abstract Liposomes are artificially-prepared bilayered phospholipid vesicles. Since their discovery, they have emerged as a promising vehicle for the efficient delivery of active biological compounds. They can be loaded with hydrophilic drugs in their aqueous interior and/or hydrophobic drugs in the lipid membrane while simultaneously protecting the incorporated drug from degradation or inactiva- tion and changing drug pharmacokinetics and bio-distribution in a favorable fashion. The coating of the liposome surface with polyethylene glycol (PEG) gave rise to long-circulating liposomes. This coating helps prevent liposomal uptake by the mononuclear phagocyte system. Longer circulation times allow for an increased concentration of the liposomes in the blood and when combined with active tar- geting through the attachment of targeting ligands, lead to efficient liposomal delivery to the target sites increasing thus drug concentration in the required zone and decreasing toxicity. This chapter aims to provide the reader with a clear understanding of the advantages and limitations of different types of liposomes and bring to light the recent advances in the use of liposomes in the field of drug delivery. *Corresponding author: [email protected] Ashutosh Tiwari and Anis N. Nordin (eds.) Advanced Biomaterials and Biodevices, (79–120) 2014 © Scrivener Publishing LLC 79

80 Advanced Biomaterials and Biodevices Keywords: Liposomes, passive targeting, active-targeting, dual-targeted liposomes, antibody-targeted liposomes, multifunctional liposomes, drug delivery, drug carriers 3.1 Introduction Liposomes are artificially prepared bilayered nanoparticles and are mainly composed of phospholipids thus conferring upon them a high degree of biocompatibility. Liposomes were discovered by Bangham et al. in 1965 and were first described as ‘phospholipid liquid crystals’[1]. Soon after, their use as drug carriers was recognized [2]. Since then the field of liposomal drug delivery has made significant progress and as a result a number of liposomal formulations have entered the clinic [3] (See table  3.1). Many of the current drug therapies like anticancer therapy etc. are fraught with toxicity issues resulting from non-specific drug accumulation in healthy cells. Liposomes are fast becoming the carrier of choice for a number of ‘promiscuous’ drug candidates and the liposomal encapsulation of these drugs can help address most of these issues. Hydrophilic drugs can be trapped in their aqueous interior while hydrophobic drugs remain associated in their lipid bilayer. This allows for improved solubility of the drug, sustained release kinetics, protection from the degrading action of enzymes in the body thereby increasing the drug’s half-life and accumulation at the target site and allowing for therapeutic effects at lower doses. In addition, drug-loaded liposomes can be surface modified to incorporate added functions like longevity, triggered release, and specific targeting of different tissues, cell types and intracellular organelles amongst others. One of the first attempts to review the developments in the field of lipo- somes as drug carriers was done by Gregoriadis [4]. Since then there have been a number of developments and numerous reviews have been pub- lished in order to keep abreast [5, 6]. To further the development of this field, the current state and trends in research need to be identified. The aim of this chapter is to equip the reader with a clear knowledge of the different types of liposomes and highlight the specific use of these in different disease models thus demonstrating the versatility of these drug carriers. In order to better understand the direc- tion in which the field of liposomal drug delivery is heading, it is important to be well aware of the current developments and strategies being used by researchers, as well as to address the associated challenges [7]. With this in mind this chapter has mainly focused on the developments in liposomal drug delivery within a six-year window.

Table 3.1 Some liposomal drugs used in clinical application or undergoing clinical evaluation. Trade Name Drug Indication Company Doxil/Caelyx Doxorubicin Ovarian Cancer Janssen-Cilag (Marketed) Myocet Doxorubicin Metastatic Breast Cancer Enzon Pharmaceuticals (Marketed) Recent Advances with Liposomes as Drug Carriers 81 DaunoXome Daunorubicin Kaposi’s Sarcoma, Breast Cancer, Galen Ltd. (Marketed) Lung Cancer Amphotec Amphotericin B Leishmaniasis, Fungal Infections Kadmon Pharmaceuticals (Marketed) AmBisome Amphotericin B Fungal Infections Astellas Pharma (Marketed) Marquibo Vincristine Acute Lymphoblastic Leukemia Talon Therapeutics Inc. (Marketed) and Melanoma Abelcet Amphotericin B Fungal Infections Sigma-Tau Pharmaceuticals (Marketed) Visudyne Verteporphin Wet Macular Degeneration Valeant Pharmaceuticals (Marketed) DepoCyt Cytarabine Cancer therapy Sigma-Tau Pharmaceuticals (Marketed) Topex-Br Terbutaline Sulfate Asthma Ozone Pharma (Marketed) Onco TCS Vincristine Non-Hodgkins Lymphoma INEX Pharmaceuticals (Continued)

Table 3.1 (Cont.) 82 Advanced Biomaterials and Biodevices Trade Name Drug Indication Company ThermoDox Celsion Corporation Thermosensitive Doxorubicin Breast Cancer, Liver Cancer Aronex Pharmaceutical Aronex Pharmaceutical Platar Platinum Compounds Solid Tumors Celator Pharmaceuticals Nyotran Nystatin Fungal Infections Alza CPX-1 Irinotecan Colorectal Cancer Introgen Therapeutics SPI-077 Cisplatin Head and Lung Cancer Neopharm INGN-401 FUS1 Lung Cancer Chong Kun Dang Pharmaceutical Corp. LE-SN38 SN38 Colorectal Cancer S-CKD602 CKD602 Variety of Cancers

Recent Advances with Liposomes as Drug Carriers 83 3.2 Passive Targeting of Liposomes For any therapeutic nanoparticle to function properly, it is necessary to evade uptake by the mononuclear phagocyte system (MPS) and stay in sys- temic circulation for a prolonged period of time. The first generation of lipo- somes, termed classical liposomes underwent rapid clearance by the MPS and on further optimization over the years, resulted in the development of long circulating liposomes. Being in the nanometer size range, they were also able to preferentially accumulate at target sites via the enhanced per- meability and retention (EPR) effect [8]. This effect relates to the enhanced extravasation of macromolecules into tumor tissues (also due to lack of lymphatic drainage), regions of inflammation and infarcts due to the pres- ence of leaky vasculatures. This thus forms the basis for passive targeting. 3.2.1 Plain and Cationic Liposomes Classical liposomes have been known to be excellent drug carriers for a long time now and their initial success has fuelled further studies with many of the newer drug types. They have been used extensively for the delivery of anaesthetics like bupivacaine [9], cholinesterase inhibitors like rivastigmine [10], water-soluble antibiotics like ciprofloxacin [11], clarithromycin [12], novel NSAIDS [13], reverse transcriptase inhibitors [14] and supplements like s-adenosyl methionine [15]. They have been predominantly used for the delivery of hydrophobic anticancer drugs like gemcitabine [16], curcumin [17–19], autocystin D [20], and vincristine sulfate [21]. They have also been used for the delivery of small molecule drugs like fasudil for the treatment of pulmonary arterial hypertension (in a rat model) [22]. Liposomes loaded with gold nanoparticles have also been shown to enhance radiation therapies by selective delivery to tumors [23]. Classical liposomes have also been used for the delivery of proteins and peptides [24] [25]. Recently, liposomes have been used for the deliv- ery of growth factors like epidermal growth factor [26] and vascular endo- thelial growth factor [27]. ATP-loaded liposomes have also shown to be effective therapeutic strategies for protection against ischemic-reperfusion [28]. TRAIL-loaded liposomes were used for the treatment of rheumatoid arthritis and its efficiency was confirmed in a rabbit model [29]. In the field of gene delivery, neutral phosphatidylcholine liposomes were used to deliver shRNA as well as siRNA to melanoma cells [30]. These proved to be more effective than cationic liposomes and were associated with less toxic- ity. Classical liposomes have also played a big role in the field of imaging.

84 Advanced Biomaterials and Biodevices Gadolinium was conjugated to a lipid chain and incorporated into the lipo- somal membrane [31]. The formulation was shown to possess favorable relaxivity and stability and thus serves as a good contrast agent for MRI imaging. Liposomes have also been successfully used in topical applications. Recently, a liposomal benzocaine gel was developed as a topical anaes- thetic [32]. Topical delivery of liposomal colchicine was successfully evaluated in a rat model [33]. Inhalable liposomal vasoactive intesti- nal peptide (VIP) has also been shown to be an effective approach for the treatment of various lung diseases [34]. It makes use of a ‘peptide depot’ thus allowing for sustained delivery of VIP. Cationic liposomes have been preferred over conventional/classical liposomes especially in the field of gene delivery because of their positive charge. This allows for the efficient complexing of the genetic cargo further shielding it from the degrading actions of enzymes in the body. However, they have known to be less stable than the conventional neutrally charged liposomes as they are likely to bind the negatively charged proteins in the blood and increase uptake by MPS. They have also been known to cause toxicity to the cell due to their non-specific binding. Still, numer- ous cationic liposomal formulations have been developed for the deliv- ery of siRNA [35], short hairpin RNA (shRNA) [36], DNA [37–40] and other oligonucleotides [41–43]. Cationic liposomes encapsulating siRNA targeting protein kinase N3 was shown to significantly inhibit tumor progression in a murine orthotopic model [44]. Recently, lipo- somes encapsulating DNA enzymes were shown to efficiently down- regulate the target c-jun gene in osteosarcoma cells [45]. The gene encoding vascular endothelial growth factor (VEGF) was delivered to skeletal myoblast cells for the treatment of acute myocardial infarc- tion [46]. It was further evaluated in a rat model and was found to significantly improve neovascularization and facilitate cardiac repair. Cationic liposomal formulations have not just been restricted to the delivery of genes. Recently they have been used for the delivery of anti- cancer drugs like paclitaxel as well as for photodynamic therapy [47]. By virtue of their charge-mediated interactions, they have also been very useful in inducing antigen specific responses [48]. 3.2.2 Polymer-Coated Long-Circulating Liposomes One of the main drawbacks in using classical liposomes is the fact that they are very quickly removed from circulation mainly by the liver and also by the cells of the MPS. Coating of these liposomes prevents this and

Recent Advances with Liposomes as Drug Carriers 85 considerably improves circulation time which allows for better accumula- tion at the target site. The most common and well established approach has been to PEGylate the liposome, i.e. attach polyethylene glycol (PEG) to the liposome surface. This sterically stabilizes the liposome and allows the liposome to circulate longer in the blood by preventing the association of the liposome to blood proteins called opsonins, as well as preventing the uptake by cells of the MPS [49]. It also alters the kinetics of drug release allowing for slower release rates [50]. PEG-coated stealth liposomes have been used extensively for the delivery of a variety of anti-cancer drugs like mitomycin C [51], doxorubicin [52, 53], ganciclovir [54], paclitaxel [55], flavopiridol [56], CKD-602 (a camptothecin analog) [57], cisplatin [58] and oxaliplatin [59]. In a novel approach, doxorubicin was conjugated to one end of a PEG chain and incorporated into liposomes and was found to inhibit tumor growth more effectively than conventional drug-loaded liposomes [60]. The effectiveness of a relatively new anti-cancer drug, Honokiol, incorporated into PEGylated liposomes was evaluated on cis- platin-resistant human ovarian cancers in mice [61]. The formulation sig- nificantly reduced tumors by almost 90% and increased the survival time considerably when compared to untreated controls. These liposomes were also used for the delivery of glucocorticoids like prednisolone disodium phosphate to investigate their anti-tumor activity [62]. PEGylated lipo- somes were also used recently to study the tissue distribution and kinetics of short chain ceramides [63]. Though used mainly in anti tumor thera- pies, PEG-coated liposomes have also been used for the delivery of other non-cancer drugs like zoledronic acid for the treatment of neuropathic pain [64], superoxide dismutase for rheumatoid arthritis [65], asialo- erythropoietin for repair of cerebral damage [66], hemoglobin and coen- zyme Q10 to reduce the effects of ischemic stroke [67, 68], minocycline for treatment of neurovascular injury [69], glucocorticoids to prevent the relapse of multiple sclerosis [70], recombinant factor VIII for hemo- philia [71], vasoactive intestinal peptide [72] and neurotensin-degrading enzyme inhibitors [73]. In the field of gene delivery, PEG-liposomes have been used for the efficient delivery of DNA [74], siRNA [75–79] and other oligonucleotides [80]. PEGylation also provides for a better biodistribution profile of other- wise labile drugs. Recently, the effect of different PEGylation densities on the biodistribution of lipid-Mu-peptide DNA was evaluated in vivo [81]. Though the PEGylation of liposomes has been the most common approach for the coating of liposomes to render it the ‘long circulating’ function, a number of other polymeric materials have been tested as well [82]. Silk fibroin was used to coat liposomes with emodin (a receptor