The Future Technologies of Drug Delivery Systems - Essay Example

The Future Technologies of Drug Delivery Systems To biotechnology has produced more than 200 new therapies and vaccines including products usedin the treatment of cancer, diabetes, HIV/AIDS and autoimmune disorders. There are numerous biotech drug products and vaccines that are currently under clinical trials. These several figures depict the significance of biotechnological methods and techniques which are increasingly dominating the process of drug research and development. Well established molecular biology techniques for protein engineering including phage display, construction of fusion proteins or synthetic gene design have matured to the level where they can transferred to industrial applications in recombinant protein design (Kayser & Warzecha, 2012). On the basis on genetic code, numerous proteins that have been approved for clinical use are subjected to alterations. These changes occur in amino acid substitution so as to improve the pharmacokinetic and pharmacodynamic activity. In addition, these changes also lead to the development of antagonist functionality. These derived proteins with site directed mutations are referred to as muteins and display good pharmacological attributes. Several approved recombinant therapeutic products are engineered post-biosynthesis. From the molecular biology background, post-translational engineering is associated with glycosylation or lipidation post-biosynthesis (Kayser & Warzecha, 2012). A drug delivery system (DDS) is defined as a formulation or device that allows the introduction of a therapeutic substance in the body, such a system is capable of improving the efficacy as well as safety of the substance by controlling the rate, time and place of release of the drug in the body. This process includes the administration of the therapeutic product, the release of active ingredients across the biological membrane to the site of action (Jain, 2008). The majority of the pharmacological attributes of classic drugs can be enhanced by the use of drug delivery systems. These include particulate carriers mostly comprising of polymers and lipids as well as their associated therapeutics. Drug delivery systems are devised to change the biodistribution and pharmacokinetics of the drugs. Alternatively, these drug delivery systems function as reservoirs for the associated drugs (Allen & Cullis, 2004). Fig. 1. Approaches to achieve passive targeting, long-circulating carriers for prolonged drug release and target-specific carriers The main objective of medicine and pharmacy is the delivery of any medication at the right time in a safe and reproducible fashion to a particular target and at the appropriate level. However, this requirement is often faced by challenges. For instance, although the oral administration is the preferred route of drug delivery due to its non-invasive attributes, adequate delivery of protein drug cannot be achieved via this route. This is mainly attributed to the acidic conditions within the stomach, the first-pass effect and resistance from intestines. All these factors can change, destroy or decrease the absorption of molecules from the intestine thereby reducing their bioavailability (Allen & Cullis, 2004). The other commonly used routes of drug administration include injection and nasal drug delivery systems. Injections as a form of drug administration are always linked to pain and the reluctance of the patients to use this route. Nasal drug delivery often displays poor absorption of polar molecules. Therefore, the lack of appropriate delivery systems for drugs not only bears implications for classical administration of drugs and dosage forms but also form a major setback for the advancement of novel therapeutic strategies. For instance, in gene therapy technology, a virus is used as a vector for the delivery of corrective and active genes into the cell of the patient. However, if the vector attaches itself to the genes of the cell, it can result into uncontrolled genetic alterations thus lead to carcinogenesis. It is therefore, recommended that if the promise of RNAi therapies is to achieved, researchers must develop ingenious systems that offer protection to the small interfering RNAs (siRNAs) in the bloodstream. Instead, these small interfering RNAs must be targeted within the right cells (Allen & Cullis, 2004). The major advances in drug delivery systems have been displayed by numerous biotech companies and pharmaceutical manufacturing firms. In oral drug delivery, a number of research groups have examined novel ways on how to enhance the protection and absorption of peptides following oral administration. For example, the use of bioadhesives has been assessed to promote the penetration of drugs through and between intestinal cells. Polymers including polyanhydrides attach to the gut and cross the intestinal epithelia, thus resulting into improved bioavailability of the therapeutic agent. Protein or peptide drugs can also be conjugated to macromolecule carriers such as a protein or polymer. Presently, polyethylene glycol is the commonly used polymer used in the alteration of the proteins with therapeutic potential. This polymer has attributes of low toxicity, affordability and commercially available compared to other molecular weight alternatives. This has been used by Nobex corporation in the development of insulin that can be administered orally (Allen & Cullis, 2004). The application of nasal routes as drug delivery systems has led to increased interest within the pharmaceutical industry over the past years. Several absorption enhancers have been examined, and which are capable of improving the absorption of polar therapeutic agents. For instance, formulations based on chitosan powder have been assessed for the nasal administration of morphine and insulin. Moreover, the use of lipids, poly-L-arginine and cyclodextrins as absorption enhancers is under examination. A number of pharmaceutical and biotech companies are examining the novel strategies of developing nasal drug delivery systems. For example, Aradigm, has come up with a disposable nozzle- containing element that ensures superior aerosol performance whenever the patient inhales the drug (Allen & Cullis, 2004). Transdermal drug delivery is another area of future drug delivery system, and is a relatively direct route into the bloodstream. In regard to transdermal drug delivery, there are two different physical mechanism involved as exemplified by iontophoresis and ultrasound. These strategies are under development, and are geared towards circumventing the physical barrier of the skin. By using iontophoresis, Iomed Inc, has come up with Phoresor, which is used in the administration of iontocaine for local dermal anesthesis. Another strategy used in transdermal drug delivery is the use of micro-needles which create micro-scale pathways across the skin thus improving its permeability (Orive, Hernandez, Gascon, Dominguez-Gil & Pedraz, 2003). Encapsulation methods also form a critical component of next generation drug delivery systems in biotechnology. The inclusion therapeutic active molecules in micro-particulate delivery systems also constitute another way of protecting and transporting therapeutic agents to the right place. These methods can be exemplified by liposomes, micelles and micro-particles. Liposomes are as a result of concentric spherical phospholipid bilayers that occur in the inner compartment. They can be sued for encapsulation of numerous therapeutic agents. By applying the technology of micro-encapsulation, researchers are examining the possibility of introducing cells that can function as factories releasing therapeutic molecules. In order to achieve full efficacy, the microcapsules must be coated with semi-permeable immuno-barriers that can exert double protective roles. This allows for immuno-isolation of the transplanted tissues from the immune response generated by the host. Additionally, the coating offers protection to the host from any biological risk (Orive, Hernandez, Gascon, Dominguez-Gil & Pedraz, 2003). Fig. 2: Mechanisms of absorption promoting effect of lipids The encapsulation of cells offers numerous benefits in comparison to the encapsulation of peptides. This strategy allows for de novo secretion of the produced therapeutic proteins as well as regulation of peptide delivery as a physiological role. Therefore, numerous encapsulated cells have been designed for the treatment of a variety of diseases. These include the development of bio-artificial pancreas and liver, treatment of cancer and treatment of classical Mendelian disorders resulting from deficiencies in gene or enzymatic products. Recent studies have pointed towards the development of ciliary neurotrophic factor cells that can be encapsulated in dogs suffering from retinitis pigmentosa (Orive, Hernandez, Gascon, Dominguez-Gil & Pedraz, 2003). Following the discovery of RNA interference (RNAi) in mammalian cell, there continues to be an enormous interest in harnessing this pathway for disease treatment. Essentially, RNAi is an endogenous pathway for post-transcriptional silencing of gene expression. It is stimulated by double-stranded RNA (dsRNA) such as the endogenous microRNA (miRNA) and synthetic short interfering RNA (siRNA). Through activation of the pathway, siRNAs can virtually silence the expression of any gene with high specificity and efficiency. The therapeutic potential of this technique is far reaching, and siRNAs-based therapeutics are under advancement for the treatment of a wide variety of diseases (Kanasty, Dorkin, Vegas & Anderson, 2013). A particular and common pathway through which siRNA leaves the bloodstream is through the kidney. The glomerulus offers a physical filtration barrier which allows water and small molecules to pass into the nascent urine while larger molecules remain in circulation. The majority of delivery systems are larger than 20nm, and therefore, they are capable of evading renal clearance. Most siRNA drug delivery systems undergo cellular internalization via endocytosis. Numerous delivery systems aim to improve the frequency of cellular uptake by incorporating targeting ligands that attach to receptors on target cells. Therefore, they are able to trigger receptor-mediated endocytosis (Kanasty, Dorkin, Vegas & Anderson, 2013). The adsorption of serum proteins on the nanoparticle surface may hinder the ligand-receptor association. Other delivery systems use cell penetrating peptides that can trigger cell uptake through endocytosis. A number of delivery systems are also designed to incorporate materials which respond to low pH environment. These materials become membrane disruptive so as to stimulate the release of siRNA from the cytoplasmic endosomes. The cyclodextrins polymer (CDP)-based nanoparticles have been used in clinical trials for siRNA delivery systems. Although the nano-complexes composed of only CDP and siRNA are able to mediate efficient delivery in vitro, these complexes require additional formulation components for stabilization and efficacy. The CDP-siRNA delivery system has been assessed in a couple of therapeutically appropriate animal models. In a xenograft representation for Ewing’s sarcoma, CDP nano-particles were formulated with siRNA targeting the oncogenic EWS-FLI1 fusion gene (Kanasty, Dorkin, Vegas & Anderson, 2013). These stimulated gene knockdown and had anti-proliferative effects with no measured innate immune responses when administered intravenously. In yet another syngeneic subcutaneous mouse tumor model, the targeted CDP delivery system showed potent silencing against the validated cancer target ribonucleotide reductase subunit 2 (Kanasty, Dorkin, Vegas & Anderson, 2013). The activity of liposomal siRNA formulations was first reported in non-human primates in 2006. Following such a report, numerous lipid nano-particle (LNP) RNAi drugs have been evaluated for clinical trials. The drugs that have been developed in this approach target the treatment of transthyretin-mediated amyloidosis, cancer and hypercholesterolemia. In the research of these diverse systems, a number of features have been developed especially in effective siRNA delivery systems. These features include the use of cholesterol, targeting ligands, ionizable or cationic lipids as well as shielding lipids (Kanasty, Dorkin, Vegas & Anderson, 2013). Fig 3. Fate of water soluble, chemically labile molecules in the gut (left), protection against enzymatic degradation by lipid–drug conjugate (LDC) nanoparticles (middle) and suggested mechanism of absorption enhancement Several promising systems have been devised by directly conjugating delivery material to the siRNA complex. This approach results to well-defined, single-component systems that use only equimolar amounts of delivery material and siRNA. The first conjugate delivery systems to show efficacy in vivo consisted of siRNA conjugated to cholesterol and other lipophilic molecules. Other conjugate delivery systems have been designed by attaching siRNA to peptides, polymers, aptamers, small molecules and antibodies. The development of siRNA-polymer conjugates delivery systems that are designed to respond to intracellular environments, referred to as Dynamic Poly-Conjugates (DPCs) was first reported in 2007 (Kanasty, Dorkin, Vegas & Anderson, 2013). These conjugates incorporate numerous components each intended to play a particular function in the process of delivery. The siRNA complex is bound to a membrane-disrupting polymer by a hydrolysable disulphide linker. The DPC delivery systems have been indicated to be effective in the silencing of two different genes within the liver when administered intravenously. The two genes were apolipoprotein B (ApoB) and Peroxisome proliferator-activated receptor alpha (ppara). Poly-Conjugates have been developed to target the liver through the incorporation of GalNAc ligands. These ligands attach to the asialoglycoprotein receptor (ASGPR) on liver cells (Kanasty, Dorkin, Vegas & Anderson, 2013). Fig.5 mechanism of RNA-based drug delivery system Targeted aptamers can also be used as vehicles to deliver specific therapeutic agents to target areas. Alternatively, targeted aptamers can also be used along detection procedures to ascertain for the presence or absence of particular targets in heterogeneous backgrounds. Chimeric molecules including aptamers-oligonucleotide conjugates have been reported to improve the delivery and suppression of the complex to certain cells. In particular, prostate-specific membrane antigen aptamers is complexed to siRNA so as to suppress nonsense-mediated mRNA. This acts as a surveillance strategy which prevents the expression of mRNAs containing premature termination amino acid set. There are novel aptamers under development which target specific tumors or the tumor associated antigen (CEA). Aptamers have also been designed for the delivery of specific drugs. An example is the aptamers-insulin complex from which insulin may be released by an innocuous, oral administration form, such as quinine (Grijalvo, Avino & Eritja, 2014). Another significant technology that offers a promising future in regard to drug delivery systems is nanotechnology. It is defined as a field that applies the principles of nano-scale and techniques so as to understand and transform biosystems. This field uses the principles of biology and materials in the creation of novel devices and systems that are integrated with the nano-scale (Roco, 2003). Fig 4. Mechanism of in vitro stability increase by transforming soluble drugs to drug nanocrystals The designing of three-dimensional nanoparticles of defined composition from nucleic acids has led to great interest due to their unique ability of producing a population of molecularly identical nanoparticles with strictly defined attributes. This method has been adopted to deliver siRNA molecules. Oligonucleotide nanoparticles (ONPs) comprise of complementary fragments of DNA designed to hybridize into pre-defined three dimensional conformational structures. The Oligonucleotide nanoparticles are distinguished from other nanoparticle delivery systems by the exceptional control over particle structure. The particle shape, size and surface chemistry have been shown to affect the performance of these nanoparticles. However, the heterogeneity of numerous systems precludes the study of specific structure-function associations. Oligonucleotide nanoparticle delivery system offers a platform to gain information on structure-function that may be beneficial in drug delivery systems incorporating siRNA (Kanasty, Dorkin, Vegas & Anderson, 2013). References Allen, T., & Cullis, P. (2004). Drug Delivery Systems: Entering the Mainstream. Science, 1818-1822. Grijalvo, S., Avino, A., & Eritja, R. (2014). Oligonucleotide delivery: a patent review (2010 - 2013). Expert Opinion in Therapeutic Patents, 1-19. Jain, K. (2008). Drug Delivery Systems. New York: Springer. Kanasty, R., Dorkin, J., Vegas, A., & Anderson, D. (2013). Delivery materials for siRNA therapeutics. Nature Materials, 967-977. Kayser, O., & Warzecha, H. (2012). Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications. New Jersey: John Wiley & Sons. Muller, R., & Keck, C. (2004). Challenges and solutions for the delivery of biotech drugs - review of drug nanocrystal technology and lipid nanoparticles. Journal of Biotechnology, 151-170. Roco, M. (2003). Nanotechnology: convergence with modern biology and medicine. Current Opinion in Biotechnology, 337–346. Read More