3.MICRO AND NANO DRUG DELIVERY SYSTEMS
One of the most attractive areas of micro and nano research is drug delivery. This includes the design of micro and nano carriers, synthesis of nanomedicines and production of nanosystems that are able to deliver therapeutic drugs to the specific organs or tissues in the body for appropriate periods. For drug delivery vehicles it is very important that these systems have good blood and biocompatibility properties. They themselves or the degradation products should not have any toxic, allergic or inflammatory effects. The systems should also protect the activity of the drugs and improve their transport through the biological barriers. If some specific functionality is added on the system, it would also be possible to deliver the drug to the target site where the system is
stimulated by an appropriate signal.In the design and formulation of delivery systems, the key parameters are the size of the device, entrapment method, stability of drug, degradation parameters of the matrix and release kinetics of drugs. Nanosystems have many advantages over the micro systems such as circulation in blood stream for longer periods without being recognized by macrophages, ease of penetration into tissues through capillaries and biological membranes, ability to be taken up by cells easily, demonstrating high therapeutic activity at the target site, and sustaining the effect at the desired area over a period of days or even weeks. In the last decades, numerous publications came up to describe the design of delivery systems with novel preparation methods, physicochemical properties, and bioactivities.Drug delivery is an interdisciplinary area of research that aims to make the administration of complex drugs feasible. Over the recent years there has been an increasing interest in developing new delivery systems by collaborative research of basic scientists, engineers, pharmacologists, physicians and other health related scientists. The main purpose is to deliver the drug to the desired tissue in the biological system so that it would achieve higher activity for prolonged period at the site without risk of side effects. Micro and nano drug delivery systems are developed for these purposes especially to target the drugs to a specific area or organ in a more stable and reproducible controlled way.Entrapment or conjugation of a drug to a polymeric system may protect the drug from inactivation and help to store its activity for prolonged durations, decrease its toxicity, as well as may achieve administration flexibility.
Various delivery systems, such as emulsions, liposomes, micro and anoparticles, are of major interest in the field of biomedicine and pharmaceutics. Generally biodegradable and bioabsorbable matrices are preferred so that they
would degrade inside the body by hydrolysis or by enzymatic reactions and does not require a surgical operation for removal.Targeted delivery can be achieved by either active or passive targeting. Active targeting of a therapeutic agent is
achieved by conjugating the therapeutic agent or the carrier system to a tissue or cell-specific ligand. Passive targeting is achieved by coupling the therapeutic agent to a macromolecule that passively reaches the target organ. Muvaffak et al (2002, 2004a, 2004b, 2005) prepared anticancer drug- containing gelatin microspheres and conjugated antibodies on the surfaces of these biodegradable microspheres. It was reported that the systems prepared in this way demonstrated specific activity towards its antigen. Monsigny et al (1994) reviewed the main properties of neoglycoproteins and glycosylated polymers which have been developed to study the properties of endogenous lectins and to carry drugs which can form specific ligands with cell surface receptors. The glycocon- jugates have been successfully used to carry biological response modifiers such as N-acetylmuramyldipeptide which is hundreds of times more efficient in rendering macrophages tumoricidal when it is bound to this type of
carriers. Complexes of polycationic glycosylated polymers with plasmid DNA molecules are also very efficient in transfecting cells in a sugar-dependent manner.Bioactive agents can be incorporated in micro and nano systems or in systems which have microporous structures. Local delivery of drugs or growth factors which are embedded in microporous gelatin structures was
reported by Ulubayram and coworkers (2001, 2002). They examined release kinetics of bovine serum albumin proteins from gelatin matrices (Ulubayram et al 2002) and also reported fast and proper healing of full skin defects on rabbits with application of gelatin sponges loaded with epidermal growth factor (EGF) (Ulubayram et al 2001). EGF was added in gelatin microspheres which were crosslinked with various amounts of crosslinkers (Ulubayram et al 2001, 2002). Similar systems were studied by Sakallioglu and colleagues (2002, 2004) and
positive effects of low-dose EGF loaded gelatin microspheres in colonic anastomosis were reported. Uguralp et al (2004) also reported positive effects of sustained and local administration of EGF incorporated to biodegradable
membranes on the healing of bilateral testicular tissue after torsion. Guler et al (2004) examined the effects of locally applied fibroblast containing microporous gelatin sponges on the testicular morphology and blood flow in
rats.There are a large number of studies investigating the drug releasing responses to various stimuli such as pH, temperature, electric field, ultrasound, light, or other stresses. Kim et al (2000) prepared nanospheres with core-
shell structure from amphiphilic block copolymers by using PEO-PPO-PEO block copolymer (Pluronic) and poly(-caprolactone). Release behaviors of indomethacin from Pluronic/PCL block copolymeric nanospheres showed
temperature dependence and a sustained release pattern. Chilkoti et al (2002) described recursive directional ligation approach to synthesis of recombinant polypeptide carriers for the targeted delivery of radionuclides,
chemotherapeutics and biomolecular therapeutics to tumors by using a thermally responsive, elastin-like polypeptide as the drug carrier. Determan et al (2005) synthesized a family of amphiphilic ABCBA pentablock
copolymers based on the commercially available Pluronic® F127 block copolymers and various amine containing methacrylate monomers. The systems exhibited both temperature and pH responsiveness. They suggested that
the copolymers have high potential for applications in controlled drug delivery and non-viral gene therapy due to their tunable phase behavior and biocompatibility. Micro and nano systems for drug delivery applications can be
studied in the classes of micelles, liposomes, dendrimers, and particles of polymeric and ceramic materials as explained in the following sections.
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
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