Application in Drug Delivery:
Drug Delivery is mainly the process of drug transport from its application (oral, transdermal or nasal) to the final target in cell and tissue receptors. The efficiency of delivering drugs to the target site is influenced by various factors like relative solubility of drugs in body fluids, relative susceptibility to enzyme degradation, relative chemical instability of drugs in body fluids, preferred enrichment in tissues and biological barriers (e.g., blood-brain barrier). Nanotechnology provides various materials to address the issues such as protecting, targeting and enhanced pharmacokinetic profile. The use of nanotechnology to develop new drug delivery systems will enhance the delivery which results in superior performance characteristics of the product and also aid in resurrection of the blockbuster drugs. Examples of various nanotech based drug delivery systems are listed below.
Nanotechnology based Drug Delivery systems:
Polymer Micelles: They are nano-sized particles made up of polymer chains and are usually formed when amphiphilic block copolymers are self associated in aqueous solution. They have been of growing interest in recent years due to high drug loading capacity in the inner core and the unique disposition characteristics (Kataoka et al., 2001). They are considered to be advantageous over conventional drug carriers due to their small size (10-100nm), ability to dissolve water insoluble drugs in its core, ability to control size and morphology by varying molecular weight, chemical composition and block length ratios, prolonged blood circulation times and in vivo stability. The drugs are enclosed in the hydrophobic core of the block copolymer micelles which is surrounded by the hydrophilic shell and are transported to target sites. "Pluronic" is the most commonly used block copolymer of poly(ethylene glycol) (PEG) and poly(propylene oxide) (PPO).
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Figure: Polymer Micelles a) prepared from self-assembling amphiphillic block copolymers & b) in aqueos solution. The micelles can target the drugs to specific siteswhile the hydrophobic outer shell protects the reactive moieties during circulation. Source: Wisconsin Alumni Research Foundation (WARF)
Liposomes: They are a form of vesicles that consists of one or more phospholipid bilayers. The inner liquid core of the liposome encapsulates the polar drugs, where as the phosopholipid bilayer is used for carrying the hydrophobic drugs. Once administered, the lipid bilayer of the liposome fuses with the target cell membrane and delivers the drugs into the cell causing the cell death. Liposomal membranes can be engineered by modifying the polymer chains, targeting moieties and antibodies that are specific to the target cells to enhance the uptake. They have found wide range of applications as drug carriers due to their biodegradability and non-toxic nature. Currently, several classes of drugs like antimicrobial, anti-viral, antifungal, anti-tubercular, vaccines and genes are being administered by the use of liposomes (Samad et al., 2007).
Figure: Liposomes are small vesicles that are used as drug carriers and are loaded with various molecules such as proteins, nucleic acids and drug molecules. They are extremely versatile as shown in the figure and can be used in many applications. (Source: Pharmainfo.net)
Dendrimers: They are nanometer-sized macromolecules with symmetrical structure and are highly branched. The structure consists of a central core that is surrounded by a series of branches. The ease of preparation and functionalization, the size and ability to display multiple surface groups for the reorganisation of biological processes make dendrimers the attractive systems for drug delivery. The terminal groups control the interaction of dendrimers with the molecular environment. By creating modifications in its termini, the interior of the dendrimer may be made hydrophobic while the exterior hydrophilic or vice versa. By attaching the targeting ligands on the surface groups the cell specificity is achieved whilst the decreased toxicity, enhanced solubility, stability and biocompatibility is achieved by functionalising the surface groups with PEG. The molecules can be synthesized in a divergent (working from the central core to the periphery) or a convergent series (starting from outermost residues to the inner core). The drugs can be loaded in the inner core or attached to the surface groups. The 5-Fluorouracil which has extraordinary anti-tumour activity is known to be highly toxic. But after formation of dendrimer-5FU conjugates by acetylation of PAMAM dendrimers, the conjugates upon hydrolysis release free 5FU minimizing toxicity (P.K. Tripathi et al., 2002).
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Figure: Dendrimers that may function as combined drug delivery and imaging agents for targeting tumour cells (Source: AAPS Journal, 2007)
Molecular Imprinting: This technology holds an enormous potential in pharmaceutical industry for creating drug dosage forms. It is a technique to create template-shaped cavities in polymer matrices that are to be used in recognition of molecules. They are formed by the self assembly of functional monomers around the template molecule by interaction between their functional groups which are then polymerised to form a molecular imprinted polymer (MIP). This obtained cavity can act as a binding site for specific target molecule.
Figure: Schematic of one type of molecular imprinting where several different monomers are bound to a template molecule. The template bound to the monomers is immobilized within a polymer matrix and the template is removed, without removing the monomers. The remaining cast can then be used to either identify specific target molecules. (Source: Institute of Environmental research, 2007)
Few examples of MIP based drug delivery systems include: a) Activation modulated drug delivery where the release of drug is triggered by chemical, physical and biochemical processes, b) rate programmed drug delivery where diffusion of drug is based on specific rate profile, c) feedback-regulated drug delivery where the concentration of triggering agent affects the rate of drug release. Though the application of MIP's to drug delivery systems is in an initial stage, significant progress will occur in this field in next few years allowing MIP's to become the potential drug delivery systems (Carmen et al., 2006).
Drug Delivery Devices: The ultimate goal in controlled release is the development of a microfabricated device with the ability to store and release multiple chemical substances on demand. Recent advances in micro-, nano-fabrication techniques and Micro-Electro-Mechanical Systems (MEMS) have allowed the fabrication of minute biochemical devices like microneedles for diffusion of larger molecules (e.g., proteins), Modern stents which release anti-neoplastic drugs directly into the tissue, and MEMS based biochips which are mainly aimed at Heart attack, Stroke and Diabetes. The controller in the chip calculates the appropriate and effective amount of the drug based on the real time measurement from micro sensors and is then released by micro-actuators/mechanisms in time. The major advantages of using these controlled release biochips are (i) a variety of potent drugs can be delivered in a safe manner, (ii) Storage and release of any form of multiple chemicals (solid, liquid or gel), (iii) Achievement of complex release patterns and (iv) Local chemical delivery of the drug achieving high concentration at target site (Kaparissides et al., 2006).
PROBLEMS WITH CURRENT TECHNOLOGY:
a) Drug Loading Efficiency in Nano Vehicles: Drug loading efficiency is one of the key factors in the development of nanotech-based drug delivery systems. When compared to macro-sized drug delivery systems the volume of a nano-sized drug reservoir is extremely limited. For example, the micellar nanoparticles can hold only a maximum of 20-30% (drug weight / total weight of carrier) of hydrophobic drug. The drug loss during the loading process is also not negligible. So far, only few studies have been done for this inherent problem and one approach employed hydrotropic polymers to improve the aqueous solubility of the drug. A highly potent anti-cancer drug Paclitaxel (PTX) has a water solubility of less than 0.3Âµg/ml. In a conventional micelle composed of PEG-b-PLA, a maximum of 27.6% of PTX can be loaded but it is increased to 37.4% when a hydrotropic polymer, PEG-b-poly(2-(4-vinylbenzyloxy)-N, N-diethyl-nicotinamide)) (PEG-b-PDENA) is attached (Huh et al., 2005)
b) Complexity of Nanocarriers: Efforts to develop more intelligent and efficient drug carriers have resulted in more complicated drug delivery systems. Integration of multiple components on a single nano-sized carrier involves multiple formulation processes and multiple chemical synthetic steps which inevitably increases the production cost and lower the yield. Moreover, the scale up of the production becomes difficult with complications in manufacturing process. It is also hard to predict the fate and action mechanisms of these complex systems in the human body due to their variations in the physicochemical properties.
c) Interface between Synthetic Materials and Biological Tissues/Components: One of the most important issues in developing nanodevices is biocompatibility. Due to lack of proper testing on biocompatibility, most of the new materials being developed by researchers for effective drug delivery are not being used in clinical applications. For clinical applications of these new drug delivery systems it is important to carefully examine the interactions between the biological components and engineered materials. Today, fast advances in drug delivery systems are not being accompanied with proper biocompatibility tests. In 1986, harmonised standards for biocompatibility tests (IS0 10993) were began by International Standards Organisation (ISO) and until now 20 parts of ISO 10993 have been established and are under harmonisation process (ISO, 2007). ISO 10993 has made it difficult for researchers to follow the FDA guidelines due to a large number of protocols. Hence, reasonable guidelines are required urgently for researchers to rely on which will allow them to consider biocompatibility issue from the beginning of design of the drug delivery systems.
NANOTECHNOLOGY FOR FUTURE DRUG DELIVERY SYSTEMS:
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Nanotechnology and its applications in drug delivery are advancing very dynamically and as we are in the middle of the revolution it is not a simple task to predict its future. As the nano drug delivery vehicles continue to improve, much simpler systems can be achieved. It is believed that the recently introduced LBL (Layer-by-Layer) coating technique to generate multifunctional polymer coating layers will have many applications in the development of a variety of composites (De Geest et al., 2006). The current nano/micro manufacturing and fabrication technology is highly advanced and it has the ability to develop mass production of nano/microparticles with high drug loading efficiencies in the coming years as well. In future, nanotechnology is expected to integrate the technologies relating to material science (targeting ability of DDS), biology (finding right ligands for target interaction), physics (monitoring the location of the systems) and chemistry (releasing the drug in proper time and place) for production of efficient drug delivery systems and hence revolutionizing the current systems. These broad prospects and possibilities will make the researchers to combine their efforts in the field of nanotechnology to make it successful, efficient and practical.