Vivienne H. Tam. (2016). Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier. International Journal of Pharmaceutics. 515 (n/a), 331-342.
Figure 1 – The cerebral capillary of the BBB and an example of the obstacles presented by the structure 
The paper that has been chosen to be critically reviewed was published in 2016 by Vivienne H. Tam, Chris Sosa, and Rui Lui for the International Journal of Pharmaceuticals targeting individuals within the field of drug delivery. The title of this paper is “Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier” and researches invasive and non-invasive strategies for treating the Central Nervous System (CNS) through the Blood Brain Barrier (BBB). The paper is well researched with 70+ references, focusing heavily on nanomedicine as a non-invasive strategy, and the strengths and weaknesses of the types of nanocarriers, types of targeting mechanisms and methods of applications for these nanomedicine therapies .
Background to the BBB
The paper states that the BBB serves a natural protective function to prevent entry of toxic substances into the CNS [1,2], which has shown to be the most tightly regulated and biologically complex structure to penetrate within the drug delivery field [1,3]. The focus of this paper is on the lack of available treatments for neurological diseases, such as Alzheimer’s and Parkinson’s, and how nanomedicines can penetrate the BBB and access the CNS to treat such diseases. Current nanoparticles characteristics that are essential to the implementation within food and medicine products are displayed in Figure 2, with nanomaterials present in food products being monitored and regulated by OSHA and the EPA, while nanomaterials used in nanomedicines are monitored and regulated by the FDA . These organisations are essential for the collaboration between industry and manufacturing agencies to ensure the production of safe and effective nanomedicines and therapies in the future. Currently there is a wide range of materials being employed in the synthesis of nanocarriers, which can be grouped into inorganic, polymer and lipid-based materials  used in the production of invasive and non-invasive nanomedicines.
Figure 2 – Comparative characteristics of nanomaterials used in medicine and foods regulated by the OSHA, EPA and FDA 
The BBB can transport essential nutrients, for the normal metabolism of the brain cells, while providing protection against harmful toxic compounds and bacteria . The BBB is a major obstacle in the field of drug delivery due to its complex structure of endothelial cells, surrounding its microvasculature network of blood vessels, which make it nearly impermeable to drug therapies. The article displays an excellent figure displaying the structure and components of the BBB that can be seen in “figure 1”. Tam states that the main obstacle for the development of therapies related to the brain is the mechanism of transportation of the drugs through and into the BBB matrix which is backed up by numerous papers in the field [1,2,3,5]. Tight junctions in between the endothelial cells prevent the passage of larger molecules, by limiting diffusion of polar molecules, from the blood, through the capillaries, with the additional defence of P-Glycoprotein efflux pumps expelling any foreign substances that gain access to the BBB [1,2]. Compounds that are lipophilic have shown that they can diffuse across the BBB, but endogenous membrane transport proteins, as mentioned before, expel the molecules back into the bloodstream before they can perform their pharmacodynamic functions. The largest molecule able to pass through the BBB is >500 Da, which eliminates nearly 100% of drugs and therapeutics for the treatment of the CNS due to the inability of the compounds to diffuse across the BBB . The development of specific targeting ligands, endogenous proteins, or antibodies against specific receptors (TFRC; INSR) that can cause receptor mediated transcytosis, and can pass the biological therapeutics through the BBB, are some of the new innovative ideas implemented within drug delivery research . [Reference new therapies here]
Figure 3 – Transport routes across the BBB 
Invasive and Non-invasive strategies for Drug Delivery
There are two main strategies for the treatment of the CNS through the BBB that this paper focused on, which are invasive and non-invasive strategies. Invasive methods involve the disruption of the structure of the BBB’s endothelial cells which can temporarily increase permeability and pass macromolecular drugs directly through the BBB, with methods such as injections into the CNS tissue to cause a therapeutic effect, and disruptive techniques; such as Osmotic Shock to shrink the endothelial cells and allow sufficient drug molecules to pass the BBB, and Ultrasound mediated drug delivery (USMD) that uses 1-10µm microbubbles to disrupt the tight junctions and allow for enhanced chemotherapy treatments. Invasive strategies can be accompanied by high neurosurgical costs and increased risk of infections, when the BBB has been exposed, for undesirable elements to enter , so, as invasive strategies are more effective on the removal or treatment of well-defined tumours, they are less desirable in the treatment of less localized diseases such as Alzheimer’s and Parkinson’s disease or multiple sclerosis [1,2]. From November 1999 to May 2005, a clinical trial was conducted on the treatment of cerebral metastases in 38 volunteers using invasive methods, which are the most common intracranial brain tumours among adults, using palliative radio therapy by D. Fortin, in which the trial evaluated the effectiveness of the treatment in enhancement of the survival rate associated with multiple cerebral metastases conditions. The results of the trial determined the mean survival rates of patients with various carcinomas, with ”promising results occurring for multiple brain metastasis of ovarian carcinoma, adeno- carcinoma of lung, small cell lung carcinoma, and systemic lymphoma” .
The paper points out that the adverse consequences of using invasive therapies have led to the development of new non-invasive therapies that can penetrate the BBB without exposing the brain to harmful infections or bacteria. Intranasal mechanisms were designed to permit transport to the brain through non-invasive perineural or perivascular channels through olfactory nerves, but poor absorption across the nasal epithelium has limited the delivery efficacy. The use of Mannitol as a chemical disruption mechanism has also been implemented to cause osmotic-driven movement of fluid out of the cells causing them to shrink leading to fenestration of cerebral cells .
Figure 4 – Nanoparticles and their biophysicochemical characteristics 
The main topic of this paper is nanomedicines, which is discussed in detail to give the reader insights on the delivery of macromolecules to the CNS through the BBB using nanocarriers such as Liposomes, Polymeric nanoparticles, Solid-Lipid Nanoparticles (NPLs), and Magnetic nanoparticles (MNPs). The paper also discusses the targeting mechanisms involved in delivering drugs past the BBB with mechanisms such as Carrier Mediated Transport (CMT), Receptor Mediated Transport (RMT), and Absorptive-Mediated Transport (AMT) . Tam states that the use of nanoparticles in the development of therapeutics and diagnostics, that are functionalized with multiple ligands and probes, gives the ability to produce specific properties in nanomedicines that researchers desire called “Theranostic agents”. In an in-vivo study performed on rats by G.R Reddy in 2006, Reddy showed by using F3 targeted nanoparticles that have both an imaging agent and a photosensitizer (Photofrin), Reddy could make brain gliomas sensitive to laser light irradiation with aims to target the cancer cells with the nanoparticles and the laser light, killing 90% of cancer cells present, which opens the door for possible use of laser light to kill cancer cells after treatment with the nanoparticles .
Overall, final evaluation of this paper by H. Tam; This paper gives great insights into new nanoparticles, targeting therapies, delivery mechanisms and strategies being developed and researched in recent years. Non-invasive methods appear to be the most important strategy for the treatment of CNS related diseases, according to Tam, as they display less adverse health effects and risk to the patient than invasive strategies, although research is still on going. This paper was very informative and gives great insights into the types of nanocarriers and targeting mechanisms in development within the field of drug delivery.
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