Treatment of brain cancer typically includes surgery, radiation therapy, and systemic chemotherapy. Nevertheless, the median survival rate of patients with primary brain tumors after surgery and radiation therapy is nine months, with approximately 10% living two years (Orive, Ali, Anitua, Pedraz, & Emerich, 2010). Ultimately, brain tumors are responsible for approximately 13,000 deaths in the United States each year (Greenlee, Murray, Bolden, & Wingo, 2000).
Limited tumor cell drug uptake, intracellular drug metabolism, and cellular mechanisms of resistance have all stalled the progression of brain cancer therapeutics (Orive, Ali, Anitua, Pedraz, & Emerich, 2010). However, the main obstacle remains the existence of the blood-brain-barrier (BBB), a structure formed by the tight junctions between endothelial cells and astrocytes that strongly limits levels of pinocytosis, thereby restricting the passage of compounds from the blood into the extracellular environment of the brain. Typically most endothelial barriers allow the passive transport of nanoparticles less than 150nm in diameter, however the BBB only permits the diffusion of small (<500Da MW), neutrally charged, lipid-soluble molecules (Pardridge, 2002). As a result, the passage of materials into the cerebral parenchyma is largely inhibited for many of the diagnostic and therapeutic molecules synthesized for treatment of CNS disorders (Farokhzad & Langer, 2006).
While substances that can cross the BBB rely on the paracellular aqueous pathway, transcellular lipophilic pathway, transport proteins, receptor-mediated transcytosis or adsorptive-mediated transcytosis, the last two are the major routes for nanoparticle (NP) delivery across the BBB. Adsorptive-mediated transcyt...
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...ate once in blood, which again, induces rapid clearance from the body. Due to the numerous routes for RES detection, extending circulation time is paramount to developing effective drug therapy to the brain. As a result, nanoparticles have been functionalized with various surface molecules as a means to block RES recognition, prolong circulation time, and prevent agglomeration including dextran and polyvinyl alcohol (PVA) (Moore, Marecos, Bogdanov, & Weissleder, 2000; Cengelli, et al., 2006). However, the most commonly practiced is the covalent attachment of polyethylene glycol (PEG) as a means to prolong circulation time. PEGylation is considered to suppress macrophage recognition via reduced protein adsorption and surface opsonization, likely due to the creation of a steric barrier on the surface of the nanoparticle (Orive, Ali, Anitua, Pedraz, & Emerich, 2010).
Glioblastoma Multiforme (GMB) is the most common form of primary malignant brain tumor in adults. With the current standard therapy, median survival time hovers just over 12 months. This incurable disease is devastating with a median survival time of 6-8 months from time of recurrence (J10). The current standard of therapy at first diagnosis consists of surgery followed by radiotherapy with concommittant and adjuvant chemotherapy using the agent temozolamide (TMZ) (Multiple sources). In 2003, the United States Food and Drug administration approved the Gliadel Wafer (GW) for treatment of newly diagnosed GBM (C3). The monoclonal antibody Bevacizumab (BEV) was first used to treat recurrent GBM in 2005 and has a significant survival benefit for patients with grade IV glioma (E5). Many more promising avenues for new treatment have been and are currently being studied. Such areas include the use of antiepileptic drugs, using Convection-Enhanced Delivery of chemotherapeutic agents, and targeting specific molecular markers and pathways such as the epidermal growth factor receptor (EGFR), O6-methylguanine-DNA-methyltransferase (MGMT), and the PI3K/Akt/mTOR pathway.
Glioblastoma Multiforme is the most aggressive and malignant form of brain cancer, with an average survival of less than 12 months.
According to the Central Brain Tumor Registry of the United States (CBTRUS), the incidence rate of all primary malignant and non-malignant brain and central nervous system tumors (CNS) for 2005 to 2009 was 20.6 cases per 100,00 (7.3 per 100,000 for malignant tumors and 13.3 per 100,000 for non-malignant tumors) (Fig. 1) [1].
The structures of liposomes are spherical and are usually between 15nm and 1000 nm in diameter. They are able to target the ligands that are attached to their surface to direct them to the appropriate sites wi...
...des dissolving of 100mg of PC into 15 ml ethanol and then this solution mixture is added drop-wise into a Vitamin C solution. Continuous stirring is required. The conditions like low temperature and moisture content can be achieved. The organic solvent is then evaporated and by maintaining pH at 7.4 of the phosphate buffer solution (PBS), the solvent traces are removed. The Liposome dispersion is then stored under vacuum overnight. The liposome size can be downsized by sonication. Liposome characterisation i.e. size and surface structure can be observed using cryo-transmission electron microscopy (cryo-TEM) (27).
Due to the brain being protected by the skull, brain tumors have very little room for growth “without pressing on other parts of the brain,” which may cause damage to the nervous system and be life threatening and life altering (Abrahams 120). Some of the possible symptoms to abnormal growths are headaches, intellectual impairment, loss of memory, impaired judgement, confusion, and personality and behavior changes, but on countless occasions the symptoms may go undetected by the carrier (Abrahams
showed that phosphorlyation is not neccessary for Smo translocation but rather inhibition of Smo endocytosis was sufficient to drive Smo to the plasma membrane. This was observed by fluorescently labelling Smo with GFP and tracking its location following either treatment with Hh or Dynasore, a pharmacological inhibitor of dynamin-mediated endocytosis (Macia et al., 2006). In both cases Smo translocated to the plasma membrane. The same was done for a nonphosphorylatable SmoSA-GFP fusion in which the inhibition of endocytosis by treatment with Dynasore caused SmoSA to translocation to the plasma membrane. The observation that SmoSA can also be present at the membrane demonstrates that some exchange between the intracellular and plasma membrane bound pools must also occur for nonphosphorylated
The term nanocarriers includes a wide range of different nanosized drug delivery systems. The oldest and at the same time the most clinically established nanocarriers are liposomes, spheres composed of an aqueous core surrounded by one or more concentric lipid bilayers. They are suited for the encapsulation of both hydrophillic and hydrophobic drugs, respectively in the aqueous core and whitin the lipid membrane (Hafner e.a. 2014). Liposomes increase thus the solubility of hydrophobic compounds, they enable trapping of drug molecules with a high potency, they reduce systemic side effects and toxicity and they attenuate drug clearance (Riehemann e.a. 2009)
According to SEER Statistics, 23,380 people are estimated to get a brain or nervous system cancer diagnosis. Out of those people, 14,320 people are estimated to die from their brain or nervous system cancer diagnosis (National Cancer Institute). Cancer is a type of dangerous tumor, or a buildup of extra cells that form a mass of tissue, that can be life threatening (National Cancer Institute). The term for a tumor that is cancerous is a malignat tumor, whereas a benign tumor does not contain cancer cells (National Cancer Institute). According to the National Cancer Institute, the causes of brain cancer are unknown, but risk factors include family history and excessive radiaton exposure. Although they are not always due to a brain tumor, comon symptoms include headaches, nausea, speech, hearing, vision, and mood changes, problems with balance and mamories, seizures, and numbness in arms and legs (National Cancer Institute). MRI and CT scans as well as surgical biposies (or the removal of part of the tumor to be examined) are used to diagnose brain cancer (National Cancer Institute). Different types of treatment options include radiation therapy, surgery to remove the tumor, and chemotherapy. According to Charles Davis, MD, PhD and Nitin Tandon, MD of WebMD.com, chemotherapy is “ the use of powerful drugs to kill tumor cells”. There are a few different types of chemotherapy, but all of which bring out the same kinds of side effects. Although the physical side effects of chemotherapy are commonly known, few people know of the emotional toll chemotherapy can take on a patient and his or her family as they go though this process.
I was a child when my aunt got sick, and my fascination about the field of medicine began. She had brain cancer. While I watched the disease progress I was flooded, not only with sadness and grief, but with questions. With two psychologists for parents I had a lot of support and understanding of my feelings, but I was left curious about the medical aspect of the disease and why there was no cure. The notion that the brain could change someone’s entire personality and physical function was amazing to me. Spending a lot of time in hospitals, I observed so much about the impact of a cancer diagnosis on patients and their families, and about what happens to people through the disease process. I noticed the enormous influence that the medical professional’s
Lipids and proteins determine the permeability of the membrane, and consequently what gets in and out the cell. Hydrophobic molecules can pass through thanks to the non-polar moieties of lipids that make the
The purpose of this lab is to test how molecular size and diffusion relate and to test the permeability of dialysis tubing using sucrose, glucose, starch and iodine.
To support the claim that endothelial stiffness is influenced by changes in plasma concentration, an atomic force microscopy that measures stiffness of endothelial cells was used to see what occurs in the absence of aldosterone. Endothelial cell samples were kept in two different environments: an eplerenone infusion, which created an aldosterone-free culture medium and another medium that contained aldosterone. Results showed that the stiffness and deformability of the endothelial cells were unchanged in the aldosterone-free environment ...
The cells are the basic building blocks of all living things. One of its significance and unique characteristics is its ability to be selectively permeable with its plasma membrane. The outer membrane mechanisms transports through its bilayer which are important in maintaining homeostasis in the cells and the entire body. To further understand these mechanisms, five experiments were conducted. These experiments were conducted over simple diffusion, facilitated diffusion, osmotic pressure, simulating filtration, and active transport. These studies were obtained by understanding the changing and observing the different variables of how they affect transport through the membrane.
“According to a recent estimate by WHO even though brain cancer occurs quite infrequently, it develops in about 22,000 new people every year along with 13,000 estimated deaths” (News Pointe). The definition of the word cancer is, “a disease in which abnormal cells divide uncontrollably and destroy body tissue.” More specifically brain cancer is a mass growth of abnormal cells in the brain. This is a very interesting disease because it attacks one of the most important and complex organs of the human body. This cancer is very deadly and although it is treatable, it is not curable. “These findings indicate that long-term survivors of brain cancer continue to experience significant quality of life deficits for many years after their primary diagnosis and treatment” (Klein, 240). Patients can however