THE ROLE OF CONTROLLED DRUG RELEASE IN CANCER THERAPEUTICS - Essay Example

? THE ROLE OF CONTROLLED DRUG RELEASE IN CANCER THERAPEUTICS The Role of Controlled Drug Release in Cancer Therapeutics Introduction Cancer is a broad classification of diseases involving un-regulated cell growth (Castro, 2011, p.15). The disease is also known as malignant neoplasm since the cells grow continuously without control forming malignant tumours (Wolinsky, Colson and Grinstaff 2012, p.444). Cancer cell fail to follow the normal cell cycle, whereby after sometime the cell needs to die, a process called apoptosis (Blanco Hsiao, Mann, Landry, Meric-Bernstam and Ferrari 2011, p.342). Cancer is known to develop when a gene mutation occurs in the oncogene and suppressor genes. The cell becomes incapable of repairing its damaged DNA and undergoes programmed cell death (Castro 2011, p.12). The cells continue to grow resulting in accumulation of many abnormal cells. These tumours are able to invade the nearby healthy tissues making them cancerous also. Some of the common cancers in the world are liver, lung, prostate, cervix, skin, breast and others. Therefore, there are many types of cancer depending on the organ attacked (Melancon, Zhou and Li 2011, p.12). Cancer has the capability of spreading to other body parts through blood and lymphatic systems. It should be noted that not all tumours are cancerous. For example benign tumours neither invade the neighbouring cells nor spread through the lymphatic or blood systems (Horcajada, Serre, Ferey, Couvreur and Gref 2011, p.102). When cancer is able to spread to other body parts successfully, the process is called metastasis. Scientists research reported in Nature Communications (October, 2012) that spread of cancer is facilitated by the adhesive properties of cancer. Specific molecular interactions between cells and the extracellular matrix cause them to become unstuck at the original tumour site (Toit, Pillay, Choonara, Pillay, and Harilall 2007, p.47). This un-stability causes them to be dispatched and they migrate to new cells where they attach themselves. Many drugs have been formulated in treatment of cancer. However, the effectiveness of these drugs is not as expected since they have serious side effects to the users. (Krol, 2012, p.88). The effectiveness of these drugs is being hindered by the hydrophobic nature of these drugs (Bianchini, Zivi, Sandhu, and Bono, 201). Therefore, development and application of nanotechnology is one of the solutions to these blockages (Gubin, 2009, p. 54). Multi Drug Resistance This leads to most of the drugs to have little efficacy unless used in huge doses which will in turn lead to toxic side effects. The main problem in cancer treatment is the multi-drug resistance of the cancerous cells to chemotherapeutics. This is due to the over expression of the Adenosine Triphosphate (ATP)dependent efflux pump called P-glycoprotein which pumps drugs out of the cells body. Loss of P53 genes that promotes cell apoptosis, over-expression of bd-z genes that blocks cell death, reduced drug uptake due to damage of foliate carriers, and increased DNA repair (Dass and Choong 2008, p.21). Liposomes Liposome is an artificial vesicle with an aqueous space into which drugs are inserted (Jain, Das, Swarnakar and Jain 2011, p.37). They have the ability to target cancer cells. They are being used as vehicles for drug administration. The tight junctions in the endothelium cells do not allow movement of large molecules like liposome out of the blood vessel in a normal cell (Yoshikawa, Okada and Nakagawa 2007, p.33). On the other hand tumour cells have hyper-permeability in their endothelial cells due to a physiological defect hence they allow penetration of liposomes inside them (Natalya, R., Zhonggao, G. And Anne, K. 200). Anti-cancer drugs are being coated with these liposomes creating a reservoir in the blood system. On detection of a cancerous cell, the liposome extravasates from these leaky blood vessels, and accumulates in the tumours and kills the cancerous cells (Malam, Loizidou and Seifalian 2009, p.67).If these macromolecular agents are not used in regulated volumes, they may lead tocardio-toxicitywhereby the cardiac muscles are affected besides damaging myocardium and bone marrows ((Malam et al 2009, p.67). Temperature Sensitive Liposomes Temperature sensitive liposomes (TSL) are stable at normal body temperature thus the drug remains encapsulated. On heating the selected organ at temperature of about 45°C, the drug is released.Low temperature sensitive liposomes (LTSL) are capable of responding to clinical temperature (37oc) and release their drug within a short time (Adair, Parette, Altinogluand Kester 2010, p67). LTSL are made up of three lipid components each with its specific role in permeability and temperature transitions. The drug is incorporated in temperature sensitive liposomes and administered to the patient using a catheter (Yang, Chang, Yang and Lin 2010, p.56). Temperature sensitive liposomes require some 45°Cheating at the tumour site (Renoir, Stella,Ameller, Connault, Opolon and Marsaud 2007, p.67). This temperature of 45oc is so high beyond the physiological temperature of 37°C. The optimum temperature of enzymes is around 37oc. Enzymes are mainly composed of polypeptides. Beyond this the 3D structure of enzymes is distrupted.Therefore; most of the enzymes will be de-activated leading to some important biological processes from taking place. Nanotechnology Nanotechnology is being used in medicine to transport drugs, light, heat or other substances to specific cells especially the cancerous ones (Sultan, Khan, Kumar, Kumar and Ali, 2013. P. 456). Gold nano-particles can be coated within-cancer drugs rendering them the ability to attack the cancer cells on their detection hence killing them a process known as targeted drug therapy (Kamaly, Xiao, Valencia, Radovic-Moreno, Farokhzad 2012, p.333). Nano-particles have unique features like small size, self-assembly, specific drug en-capsulation, large surface area to volume ratio and biocompatibility (Florence 2012, p. 23). Nano-particles are so minute such that they are capable of movement in the human bloodstream and penetration through the cells membranes. Nano-particles' small size enables them to infiltrate cells especially the cancer cells that have an increase phagocytosis (Sanna and Sechi 2012, p.39). Once the cancer cells ingest these nano-particles, apoptosis is induced. A dose of nanoparticles can be modified to release its anti-cancer compounds over a planned duration of time (Yoo, Lee, Shin and Cheon 2011, p.78). Nanoparticles are the size of bio-molecules hence they can be used in vivo or in vitro in medical applications (Jiang, Wang and Wang 2012, p.98). Nowadays it is a major tool in drug delivery especially in cancer treatment (Liechty and Peppas 2011, p.90). The technology is facing many problems due to host’s reaction and the small size of the particle. Nanoparticles have the ability to target specific organs due to their charge and size. A research conducted using mice showed that the positively charged gold particle entered the kidneys while the negatively charged nanoparticles entered the spleen and liver (Shi Xiao, Kamaly and Farokhzad 2011, p.143). Combination of quantum dots and magnetic resonance imaging (MRI) are being used in detection of tumor sites (Melancon, Zhou and Li 2011, p.12). Quantum dots are nanoparticles with emissions of tunable light that are of specific size. The problem that arises that quantum dots are made up of toxic substances hence posing a danger hence the need for controlled usage (Tan and Zhang 2010, p.45). Cadmium selenide which is the main component of quantumdotshas the ability to glow when illuminated with light from an external source. They penetrate the tumour cells enabling the doctor to locate the actual position of the tumor. Photodynamic therapy involves placement of a luminence particle within the body and illuminating it with light from outside the body. The particle absorbs the light and gets heated which results in heating the neighbouring tissue as well. Light is being used to produce high energy molecules like oxygen which reacts with organic materials like tumour cells, killing them leaving no trace of toxic materials (Menei, Benoit, Boisdron-Celle, Fournie, Mercier and Guy 2006, p.56). Nanorobots These are DNA based molecules with computational genes for detecting and repairing damaged cells and healing infected cells especially the cancer cells. These nanorobots are being loaded with molecules containing instructions that order the cells to behave in a particular way. For instance, nanorobots carrying suicidal message which could target leukaemia and lymphoma, cells killing them have been investigated. pH sensitive nanoparticles pH sensitive nanoparticles have been designed for drug delivery in cancer management (Manchun, Dass and Sriamornsak 2012, p.90). Tests were done whereby methotrexate (MTX) loaded-chitosan nanoparticle released more drugs on an acidic medium (Yanes and Tamanoi 2012, p.55). Chitosan is an organic polymer component which is non-toxic and bio-compatible (Liechty and Peppas 2011, p.87). MTX efficiency is overcomed by the action of efflux in the cancer cell. Encapsulation of the drug in this chitosan polymer provides a sufficient drug accumulation within the tumour environment. Lysosomal degradation of the drugs enables the drug to be released to the tumour cells. Sometimes intracellular barriers like endosomes and release of the drug out of the body before action of the lysosome may occur. Drugs are being made that are sensitive to the low pH in the endosome. Drugs are being designed to by-pass the P-glycoprotein and their intake to occur through endocytosis. A response to this problem is to develop mechanisms which will lead to drug releases on response to a stimulus such pH and temperature. The drug may be released in endosomes and lysosomes through pH-controlled endocytosis (Vert 2008, p.23). Drugs that are pH –sensitive conjugated to nano-carriers can enter the cancerous cells through enhanced permeability and retention through the porous blood vessels. The pH triggers the particles to release the drug which is taken by the cancer cells. Sometimes the drugs or the monoclonal antibodies bind to the specific antigens on the surface of the cancerous cells. Mesoporous Silica Nanoparticles (MSN’s) are also advantageous in that they have large interior space that accumulates huge doses of drugs besides having large surface area to volume ratio (Yang, Gai and Lin 2012, p.37). Enzyme Therapy Enzymes are being extensively used in chemotherapy to cure diseases like cancer. Enzyme inhibitors are molecules that interact with the enzyme preventing it from normal functioning. These inhibitors may be specific, non-specific, competitive or non-competitive. The anti-epileptic drugs alter the enzyme activity by activating production of more or less of the enzyme processes known as enzyme induction or enzyme inhibition respectively. These drugs have similar substrate structures hence can bind to the enzyme (ChengMeng, Deng, Klok, and Zhong 2013, p.90). A classic example is the drug methotrexate which substitutes’ folic acid which is a substrate for an enzyme called di-hydrofolate reductase used in the synthesis of nucleotides. Methotrexate binding to this enzyme inhibits production of the nucleotides hence replication of DNA is blocked (Pope-Harman, Cheng, Robertson, Sakamoto and Ferrari 2007, p.87). Cancer cells are known to multiply so rapidly therefore, presence of this drug inhibitor prevents the cancer cells from dividing. Enzymatic degradation of organic compounds like amino acids and folic acids has been used in cancer chemotherapy (Koning and Krijger2006, p.78). These enzyme drugs are foreign in the body hence they will be antigenic leading to production of antibodies against them. Therefore, prolonged use of the drug will lead to hypersensitivity besides decreased absorption of the drug. Scientific studies have shown that enzymes can be administered to cancer patients to prolong their lives by lowering the side effects got after chemotherapy and radiotherapy (Bharali, Mousa and Thanavala 2009, p.32). Enzyme therapy has been extensively used in treatment of pancreatic cancer. The patient is administered a series of enzymes besides being on a controlled special diet. The enzyme digests the cancer cells protective coating. This allows the white blood cells to attack these tumour cells (Shmueli, Anderson and Green 2010, p.34). Enzymes pH Specifity Enzymes being so specific require specific environment for them to function normally. pH sensitive liposomes are manufactured to target specific cells in specific pH. Various enzymes work best at their optimum pH acidic, basic or neutral pHs (Heneweer, Gendy and Penat, 2012, p. 453). Therefore it is an important factor to be considered since the liposome may miss its target if details of the tumour cell are not known (Cobley, Chen and Xia 2010, p.97). If these conditions are not met, the enzymatic activity is lowered. Acidic enzymes require pH values less than 7 while basic enzymes will require pH values of more than 7. Proteolytic enzymes being used in pancreatic treatment require an acidic environment (Lin, Kim, Kim, Dobson and Kim 2010, p.65). Therefore, it is very important for one to have deep information of the enzyme and the target organ. Monoclonal Antibodies An antibody is an immunoglobulin in chemical composition. They have been established as cancer therapeutics due to their ability to target tumour cells. During cancer treatment the main aim is to eliminate the cancerous cells completely. This leads to adverse effects to the user. For the antibody to function it must conjugate with the tumour cell (Kievi and Zhang 2009, p. 45). Nanotechnology requires the interaction of cellular material with the small molecules and atoms which have been engineered. Nano scale devises which are bio-degradable have been made to transport huge doses of anti-cancer drugs into malignant cells while sparing healthy ones (Babincova and Babinec 2009, p.67). Vascular Targeting Agents (VTAs) These have been designed to cause shutdown to blood vessels that supply tumour cells with blood, thus starving them to death due to hemorrhagic necrosis (Coti, Belowich, Liong, Ambrogio, Lau, Khatib and Zink 2009, p.23). VTAs are capable of killing cancer cells in deep areas that drugs penetrations are poor. VTAs are classified into small molecules and ligand-based all which function on vascular shutdown (Wang, Sui and Fan 2010, p.43). The small molecules involve drugs that destabilize microtubulin and flavonoids. Ligand-based uses growth factors, antibodies and peptides that target the tumour vessels. Research showed that these agents are more effective when combined with radiation and other chemotherapeutic drugs. Lipid-Enveloped Nanoparticles They are composed of a hydrophobic phosphoglucan shell with an inorganic core at the centre with a single or double lipid layer between the shell and the inner core (MalamLim and Seifalian2011, p.234).This nanoparticle has vital functionality properties like controlled release, stability long circulation and bio-compatibility. The bio-degradable shell is linked with a poly amino-ester (Constantinides, Chaubal and Shorr 2008, p.33). This makes it so sensitive to pH hence it is capable of disrupting the endosome. (Matsusaki and Akashi 2009, p. 69). The messenger RNA is introduced to these nanoparticles (Cheng, Feng, Meng, Deng, Feijen and Zhong 2011, p.44). The mRNA is absorbed by the dendritic cells and delivered into the cytoplasm with the low effects of toxicity (Ding, He and Li 2008, p.108). The RNA was translated into amino acids after translation. Some of theseamino acids are dysfunctional hence of no help to the cancerous cells (Fattal and Barratt 2009, p. 43). The coded stop codons seized the functioning of the cancer cells by stopping the expression of proteins (translation) hence the cancer cells could not produce viable amino acids (Liu and Deng 2009, p.76). Liposomal Dry Powder Inhalation Liposomal dry powder inhalation is a nanotechnology being used in treatment of lung cancer by use drugs incorporated in form of powders (Willis, Hayes and Mansour 2012, p.123).Liposomalpowders are a combination of proliposomes and lipospheres (Shi, Bedford and Cho 2011, p.34). They have phospholipids which is a lung surfactant as their component (Fergal C. K. Hedgehog.2011). Small doses of the powder are inhaled normally through the nose by aid of special inhalers devices. 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Chicago: Chicago University Press. Yoshikawa, T., Okada, N. and Nakagawa, S. Development of intracellular drug delivery Read More