The Encapsulation Efficiency of a Targeted Drug Delivery System - Literature review Example

Herceptin Drug Encapsulation By Introduction Na chnology is the designing, characterization, synthesis and application of structures, materials, systems, and devices by regulating size and shape at the nanometre scale. Materials exhibit unique features at the nanoscale of 1 to 100 nanometre (nm). These changes in property are due to the increase in surface area and dominance of quantum effects that is related to tiny particles with large surface area to volume ratio (Capek, 2010). On the other hand, nanoparticles are compounds that are between 1 and 100 nanometers in size. According to nanotechnology, a single particle can be viewed as a small object in size that behaves like a unit with respect to its characteristics. There is enough evidence on nature on nanotechnology. For instance, the DNA molecules width is about 2.5nm, the thickness of the human hair is about 10,000nm thick, and the diameter of a hydrogen atom is about 0.1nm that is too small to be seen by human eyes. Nature also produces nanostructures that offer functional proteins, which are of great significance at the cellular level. It is argued that one of the functions of these proteins found in cells is nanotechnological separations. Molecular motors that comprise the human muscles are complex nanomachines that convert chemical energy to mechanical energy with high efficiency. Ribosomes can also produce protein molecules with high precision and photosynthesis is carried out in plants by nanosize cells that use energy to synthesize organic compounds with the use of cheap raw materials (Bender & Nahta, 2008). Herceptin (Trastuzumab) Pharmacists have confirmed the effectiveness of using Herceptin. Although the medication has raised controversies among scholars, it is confirmed that the medication is of paramount importance in the process of healing. According to Sauter et al. 2009, Herceptinis anticancer medication used mainly to treat early stage malignant cancer of the breast and in some cases cancer of the stomach. This is a condition that has for a long time given medical researchers sleepless nights as many of the medications used currently have been found to have severe side effects. In the process of treatment, Herceptin acts on those tumors which produce the Human Epidermal growth Receptor (HER2 protein) more than the normal amount. Human Epidermal growth Receptor 2 is a protein which enhances the growth of cancer cells. The presence of the cancerous cells leads to excessive production of the HER2 protein hence promoting the metastasis of the cancerous cells to a larger part of the affected area. The presence of the disease is confirmed when one tests positive for the HER2 protein (Press, Sauter, Bernstein, et al 2005). The medication interferes with the multiplication of the cancer cells in the body by attacking the human epidermal receptor protein, whereby the attack reduces the rate of multiplication of the protein hence reducing the effects of the condition. The drug has been proven of importance in cancer treatment since its proper administration with careful monitoring has ‘been seen to reduce metastasis of cancerous cells. Amplification of HER2 receptors occurs in 30% of early-stage breast cancers and encodes transmembrane tyrosine kinase. Although signaling pathways induced by these receptors are incompletely characterized, the activation of P13K/Akt pathway is very significant. This pathway is associated with mitogenic signaling related to MAPK pathway. Herceptin is a monoclonal antibody that binds to the extracellular segment of the HER2 receptor (Yarden, 2000). Exposure of cells to Herceptin results in their arrest in the G1 phase of the cell cycle and experience a reduction in proliferation. According to Tisdale & Millera (2010) Herceptin induces some of its effects through down- regulation of HER2 receptors resulting in disruption of receptor dimerization and signaling through the downstream P13K cascade .Then phosphorylation of P27 fails and hence it enters the nucleus where it hinders cdk2 activity, causing cell arrest. Herceptin also suppresses angiogenesis by inducing anti-angiogenic factors and repressing of pro-angiogenic factors. Studies have shown that the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2 receptors that results in the release of the extracellular domain. Some of the effects of Herceptin are inhibiting HER2 ectodomain cleavage in breast cancer cells (Gennari, Menard, Fagnoni, et al, 2004). Recently, it was shown that Herceptin reduces the chance of relapse in breast cancer patients by 50%, hence standing out as a significant weapon against cancer. Nano-sized drug delivery systems have been used widely as carriers for different formulations due to their ability to overcome biological barriers. They also deliver the drug in a controlled manner at the desired place (Musolino, Naldi, Bortesi, et al 2008). Herceptin actively targets HER-positive cancer cells. Its surface encapsulation is made up of monoclonal antibodies. Herceptin has an isoelectric point of 8.45 and therefore, it is positively charged at acidic pH. Under such conditions the antibody reacts with the negatively charged surface nanoparticles through electrostatic interactions hence forming a coating that may result in improved particle uptake through receptor-mediated endocytosis (Mcdonagh, 2011). Several clinical studies have shown the therapeutic benefits of Herceptin in patients with breast cancer. However, a small number of patients have expressed Herceptin-related cardiotoxicity. This occurrence is characterized by an asymptomatic decrease in the left ventricular ejection or congestive heart failure. Concomitant anthracycline administration significantly increases the risk of cardiotoxicity during Herceptin treatment (Beano, Signorino, Evangelista, et al 2008). Herceptin inhibits HER2 cardiac signaling mechanism. HER2 play an important role in cardiomyocte survival and development. Reduced HER2 exposes the heart to cardiomyopathy, reduced adaptation to pressure overload and are very sensitive to anthracycline toxicity. At cellular level overexpression of HER2 provides high protection against oxidative stress and hinders apoptosis from occurring. It is for this reason that individuals with chronic heart failure have high serum levels of HER2. Thus, while cardiac stress increases HER2 expression. Inhibition of HER2 by Herceptin stimulates ventricular dysfunction (Broekx, Hond, Torfs, et al 2010). Several strategies have been developed to counter Herceptin related cardiotoxicity without significantly compromising its therapeutic efficacy as well as shortening duration of treatment and monitoring patients. One the major proposals is the use of Herceptin-toxin conjugates. This technique makes use of monoclonal antibodies that are tumor-specific but insufficiently cytotoxic.in themselves (Patterson & Willis, 2012). These antibodies are chemically bound to cytotoxic agents to lead them to specific antigens on target tumors. This provides more control over apoptosis in cancerous cells and greater selectivity in their action. For example, Herceptin coated with DM1 that is obtained from the fungal toxin maytansine, results in low toxicity. Research has also proven that Herceptin’s efficacy and tolerability of Herceptin-DM1 conjugate to treat patients with breast cancer (Strauss, 2013). This technique has offer great relief in the medical field; its popularity has been adapted by many medical practitioners. Using short-term regimens is another method of handling cytotoxicity. Considerable interest has developed in the short-term treatment regimens due to their higher safety and better cost-benefit ratio. For instance, when Herceptin is administered before other cardiotoxic drugs to test the hypothesis of cardiotoxicity reduction while maintaining antineoplastic efficacy remarkable results are obtained. There is a strong association between low cardiotoxicity and short Herceptin treatment regimens. Other techniques include individualized anthracycline therapy and administration of Trastuzumab without anthracyclines (Mozaffari, Lindemalm, Choudhury, et al 2007). These treatments have reduced mortality and improved the quality of life of patients too. A study conducted by Vivek, R, Thangam R, et al. on Herceptin, the researchers sought to realize targeted delivery and proper release of the drug in efforts to kill the cancer cells in breasts. In the study, the researchers used tamoxifen (Tam), recyclable antibody conjugated polymeric nanoparticles. In the process, copolymer polyvinyl-pyrrolidone (PVP) conjugateed herceptin (antibody) as well as PLGA NPs to make better intracellular release of Tam alongside HER2 receptor numerous cells. It was notable therefore that nanocarrier drug delivery system made the therapy process more efficient by boasting the target and ensuring continuous discharge of therapeutic agents (Vivek et al, 2014). Effects of Herceptin Herceptin just like any other drug is not recommended for use to every individual. It is contraindicated individuals who have heart disease, those who are allergic to the drug and to pregnant women since it can cause harm to the unborn child and also to the lactating mothers since the content of the drug is expelled together with the breast milk. The drug has serious side effects which include heart problems that is reduced heart function and heart failure where by the pumping mechanism of the heart is impaired leading to reduced tissue ‘perfusion. Since the drug is administered intravenously the individual may experience infusion reaction during administration these may include dizziness, itching at the site, swelling of the face and tongue. Other side effects follow within 24 hours of Herceptin administration these include, shortness of breath, sudden onset of respiratory distress and pneumonitis. When the drug is used for the treatment of breast cancer the patient will report fever, loss stools, weight loss, feeling tired and through investigations the individual will have low white blood cell and platelet count (Chia, et al, 2006). To overcome the side effects of Herceptin a detailed history should be taken from the patient about any allergic reaction to the drug or other drugs containing the HER2 protein since further treatment with this drug will worsen the side effects. Information about previous cancer treatment should be taken especially treatment of the chest with radiotherapy since this can produce effects to the normal functioning of the heart. Herceptin makes one prone to infection or worsen an infection, so history concerning any current infection is important before the use of the drug (Spector, & Blackwell 2009). During the use of the drug the patient should avoid close contact with people who have infections which are easily spread like common cold and measles. Since the main side effect of the drug is cardiac toxicity, the drug shouldn’t be administered to individuals with a history of heart disease, heart failure or heart attack. In cases of infusion reaction administration of drug should be stopped and keen observation made on the patients progress to prevent further effects (Lin, 2009). Detailed investigations are done on the type of cancer and the best medication for the patient to prevent further effect. Herceptin Stability and Evaluation Chemotherapeutic drug use has come out as a controversy to the therapy of breast cancer. This is because it has become hard to break the breast cancer stem as scholarly research has proved it to be a strong drug resister (Geyer, et al 2006). Some monoclonal antibodies have potent therapeutic activity, but exhibit instability related to their structure. This poses significant challenges when it comes to their formulation, processing, storage, and administration. These proteins based therapeutics are highly labile molecules which get disrupted easily when subjected to chemical, physical, and thermal stressors. Physical disruption may present as denaturation or aggregation which are common problems during manufacturing and administration of proteins including monoclonal antibodies (Lu, & Mahato, 2009). Encapsulation of monoclonal antibodies such as Herceptin into nano and microparticulate delivery systems has generated much interest in the field of science. These delivery systems confer several benefits. For example, encapsulation of Herceptin protects it from degradation, promotes its ability to target specific cells and tissues, and enhances its controlled release. Furthermore, encapsulation of Herceptin provides it the ability to exploit the enhanced permeability and retention effect that arises in breast cancer cells, leading to increased drug concentrations at the tumour site unlike non-encapsulated drugs (Vogel & Cobleigh, 2002). Encapsulated Herceptin withstands stressors such as lyophilisation, sonication, and freeze-thawing. Therefore, the stability of Trastuzumab enables it to maintain its structure and conformation when exposed to one or more thermal or physical stress when administered (Bruno, et al, 2005). However, there are limitations to these systems in that they manufacture exposes the therapeutic agent to various stressors that may be deleterious to biological actives such as proteins and may render the biological therapeutics inactive or immunogenic. Herceptin drug has for a lengthy period being considered as an anti-oxidant as well as an anti-cancer. In the process of encapsulation, many researchers from different bioengineering and nanotechnology insitiutes have engineered nanocarriers that can provide a drug that can be used to kill the cancer cells in a more efficient way. In research, Herceptin has been used as a material to encapsulate and at the same time deliver drugs to the cells of cancer. The Herceptin drug in the process delivers protein drugs effectively to the cells and at the same time reduces growth of tumour (Cortes, et al 2009). The biggest challenge in chemotherapy is to ensure that the delivery of the drug is done only to the tumour so as to ensure that the surrounding organs and tissues are not affected in the process. To avoid this issue, thus it is important to develop a drug that will act as a homing missiles. Such drug once injected in the body zoom on the targeted cells and once located, they release the drug into the cells thus destroying the target cell alone (Park, et al, 2009). Some of the challenges of most drug delivery systems include; in vivo stability, poor bioavailability, intestinal absorption, therapeutic effectiveness, side effects, and delivery to site of action. However, in drug delivery, nanotechnology is an approach designed to overcome these challenges (Capek, 2006). This is because of the fabrication and development of nanostructures at nanoscale which are mainly polymeric with multiple advantages. Generally, nanostructures can protect drugs that are encapsulated within them from enzymatic and hydrolytic degradation in the gastrointestinal tract and site of delivery for sustained release and thus are able to deliver proteins, genes, and drugs through the peroral route of administration (Kulshreshtha, Singh, & Wall, 2010). They deliver drugs that are highly water- insoluble, can bypass the liver, thereby preventing the first pass metabolism of the incorporated drug. They also increase oral bioavailability of drugs due to their specialized uptake mechanisms such as absorptive endocytosis. Drugs are also able to remain in circulation for a longer time, releasing the incorporated drug in a continuous manner, decreasing plasma fluctuations hence minimizing side effects that are associated with drugs. Due to their small size, they can penetrate through tissues and absorbed into cells, this allows drugs to be delivered efficiently to the target site. Studies have shown the uptake of nanostructures to be 15-250 times faster than that of microparticles in the range of 1-10 micrometer (Aguilar, 2012). Release of drugs can be regulated to attain the desired therapeutic concentration for the desired duration through manipulation of the features of polymers. For instance, for targeted delivery, nanostructures can be conjugated with moieties. Dirote (2006) argues that the linkage between the active substance and the polymer can be conjugated to control duration and site of action of the drug. This linkage can be made successful by incorporating lipids, amino acids, peptides or small chains as spacer molecules. In chemotherapy, Aguilar (2012) states that drug targeting is crucial. Here, he further argues that a drug delivery system can target only the cancerous tumour while protecting the healthy cells from uniform distribution of chemotherapeutics in the body and their harmful effects. Nanostructures such as polymeric nanoparticles can be used in a non-invasive approach of penetrating the blood-brain barrier for management of neurodegenerative disorders, inflammatory, and cerebrovascular diseases. Bibliography 1. Aguilar, Z. P. (2012). Nanomaterials for medical applications. Amsterdam, Elsevier. 2. Baselga J, Carbonell X, Castaneda-Soto NJ, et al 2005. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol. 2005;23:2162–2171. 3. Beano A, Signorino E, Evangelista A, et al 2008. 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