Rapid advances in proteomics & genomics coupled with rational drug design and rapid screening techniques have led to revolution in the drug discovery process resulting in introduction of large number of novel therapeutics at proliferative rate. However, the use of these novel therapeutics in medicine is frequently opposed by the lack of efficiency in delivery of these therapeutic agents to the target organs. Consequently, in the last three decades, there has been a great focus on the development of drug delivery systems (DDSs) for the treatment of diseases. In very simple terms, drug delivery can be defined as the process of releasing a carried bioactive agent at a specific site, at a specific rate. The drug candidates often present a multiplicity of delivery challenges, including issues of solubility, in vivo stability, poor pharmacokinetics, and undesirable toxicity and side effect profiles, all of which must be dealt with simultaneously in order for the candidate to become a successful therapeutic. Formulation scientists have always struggled to overcome these problems but with the advent of nanotechnology the conventional challenges can now be looked upon as new opportunities.
Nanotechnology deals with phenomena whose physics or chemistry differs from that of bulk materials of the same composition. Extending this interpretation, nanoparticles are particles in which the small size influences the intrinsic properties or behavior of the particle. Properties of interest may be: surface properties, quantum mechanical properties, chemical or biological reactivity, etc. The term “nanoparticles” varies greatly based on the specific definition that is used. National Science Foundation and the National Nanotechnology Initiative define nanoparticles as particles having dimensions of 1-100nm. Interestingly, much of what we know about the bulk properties of materials breaks down at these scales. For example, nanomaterials such as carbon nanotubes and gold nanoparticles have physical properties that are different from their bulk counterparts.
Therefore, such technologies generate new opportunities and applications. However, in case of drug delivery, nanoparticles are no longer confined to strict size range of 1-100nm. In fact, most of the nano based delivery systems are always above the mentioned size range. In case of drug delivery, the properties that hold premier interest are: surface properties (i.e. particle size, surface area, surface free energy and surface-to-volume ratio) and biological reactivity (circumventing opsonization). These properties can be modulated at sub micron size ranges and there’s no stringent requirement to hold on to the sizes of below 100nm. There has been a constant argument over inclusion of so called nano drug delivery systems as a part of nanotechnology as the chemists and physicist believe that to be categorized as nanoparticles the system should show some size dependent property changes (which is seen only when we go below 100nm on the size scale). Formulators however, have there own way of defining nanoparticles, where the boundaries of size ranges dissolves away and anything submicron is considered to be a part of nanotechnology.
Here we have a look at some of the fundamentals on which nanotechnology based drug delivery systems are designed.
Nanotechnology and Drug Delivery
Particle Size, Surface area, Surface Free Energy
Around 40% of drugs developed today are poor candidates for drug delivery formulations owing to their limited water solubility. Nano-sizing drug or formulating drug as a nano particulate system results in better dissolution and solubilization of drug. The “top-down” technique used for fabricating nano-structured materials results in increasing the effective surface area (surface area available for medium interaction) and imparting high free surface energy to the particles which in-turn helps in entropically driven effective solubilization.
The earliest concept for targeting therapeutic to specific site included attachment of targeting moieties to the drug molecule (Immunoconjugates). This concept was hardly considered convincing as it required attachment of one targeting moiety per drug molecule; also the attachment of immunoglobulin (targeting moiety) to naked drug molecule posed a big risk of affecting the biological activity of drug. Nanoparticles could be advantageously used to overcome these problems in targeted drug delivery. Nanoparticles act as a carrier for drug delivery with number of drug molecules encapsulated in single nanoparticle. Moreover, the enhanced surface–to-volume ratio further allows effective attachment of targeting moieties onto the surface of nanoparticles. Thus, the drug molecules are safely carried to the target site without undergoing any chemical modifications.
Particle Size & Biological System
Living organisms are built of cells that are typically 10 μm across. However, the cell parts are much smaller and are in the sub-micron size domain. Even smaller are the proteins with a typical size of just 5 nm, which is comparable with the dimensions of smallest manmade nanoparticles. This simple size comparison gives an idea of using nanoparticles as an effective tool in delivering drug to the target sites. Infact, nanoparticles are the only colloids that can be given intravenous (IV route) because they don’t settle or aggregate in the blood and thus cause no embolism. The smaller size also ensures easy and effective penetration not only through the biological membrane but also through the cellular pores achieving greater transfection and enabling manipulation at molecular level.
The trek of a “therapeutic” from the point of administration to the intended target is full of perils, biological barriers might arise in form of tight junctions between epithelial cells, Immunological hurdles are created by opsonization mediated by macrophages of RES (Reticulo Endothelial System) and biophysical obstacles include the charge related agglomeration and bio-distribution. Nanotechnology based systems presents themselves as well equipped delivery agents by overcoming various barriers and other related hurdles by the virtue of their modified properties. The small particle size and uniform particle distribution helps nanoparticles to overcome the biological barriers by effective and efficient transfer across biological membranes and tight junctions. Nanoparticles can be sized down below the cut-off range for easy penetration across the barriers and because of the hydrophobicity of the particles their journey across the membranes is not that difficult as the membranes themselves are made up of lipophilic moieties.
Opsonization which is thought to be the greatest threat to any injectable xenobiotics, leads to engulfment of foreign particles injected into the blood stream by specific macrophages cells of RES, resulting in removal of therapeutics from the circulation and ultimately decreasing efficacy and potency of the therapy. The entire process of opsonization depends on the interaction of opsonin (endogenous proteins) with the foreign object; this interaction in turn depends on the surface physiochemical properties i.e. size, shape, charge, density and surface hydrophobicity. All of these can be modulated based on the techniques used for fabrication and post fabrication modification of nanostructured particles for e.g PEGylation, which includes hydrophilic coating of Poly Ethylene Glycol on nanoparticle surface. Other non-covalent approaches include layer by layer deposition of ionic polymers, such as quantum dots. Layer-by layer methods alter the surface charge of nanoparticles resulting in prevention of particle agglomeration and regulated nanoparticle biodistribution.
Nanotechnology is an emerging field that is potentially changing the way we treat disease through drug delivery. However, significant challenges remain in pushing this field into clinically viable therapies. For drug delivery, the design and testing of novel methods dealing with controlling the interaction of nanomaterials with the body are some of the current barriers to translating these technologies to therapies. Methods of targeting nanomaterials to specific sites of the body while avoiding capture by organs, such as liver and spleen, are major challenges that need to be addressed. As Feynman had predicted, there has been plenty of room at the bottom to modify and enhance existing technologies by controlling material properties at the nanoscale. Therefore, with sufficient time and research, the promise of nanotechnology based medicine may become a reality. Drug delivery can further be benefited if we exploit true nanotechnology principles to designing of novel delivery systems.
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