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Surface Functionalization of Nanoparticles in Drug Delivery
Nanotechnology has opened up a new area of research for the disease diagnosis as well as therapeutics. Though drug discovery is very essential for the proper treatment of the diseases, drug delivery remains a major concern. The agents used for drug delivery have been found to possess their own properties of cell toxicity, low persistence in the microenvironment of the body as well as impermeability across the cell membranes, which result in inefficient drug delivery within the body. Nanoparticles have emerged, as a better alternative for drug delivery in recent times though further in-depth research is essential to provide concrete evidence for the same.

Nanoparticles are usually made of elements, which are biologically less reactive and hence used for different diagnostic assays as well as therapies. The nanoparticles due to their extreme small size, zeta potential and other favourable factors have added advantage in being used as drug delivery agents. Adsorption of the proteins like antibodies or other bioactive moieties on the surface of the nanoparticles is a method by which the bioactive agents are transported to the target site in-vivo, but this method has some disadvantages because of which surface functionalization has gained importance. The adsorption on the surface technique causes the denaturation of the protein adsorbed in most of the cases and the presence of steric hindrance is one more drawback. Moreover, the nanoparticles must have to be present in the systemic circulation for a longer period. All these factors have initialized the study of surface functionalization of nanoparticles, which has become a greatly researched topic.

Surface functionalization means the introduction of chemical functional groups on the surface of the nanoparticles. The chemical groups are not directly attached to the nanoparticles but are attached using spacer arms or other lipophilic agents. Many studies have been conducted whereby PEG (Polyethylene glycol) has been used for the surface functionalization of the nanoparticles. The surface functionalized nanoparticles become capable of crossing the lipid bio layer of the membranes of the cell and thereby help in the delivery of the drugs and other bioactive agents to the target site in-vivo. The PEG spacer allows the GNPs (Gold nanoparticles) to persist in the systemic circulation within the body protected from the macrophage attack while providing flexibility also to the molecule for proper interaction with the target. Research with other surfactants apart from PEG, which can provide the same advantages as PEG in the drug delivery through nanoparticles is going on.

Surface functionalization is possible for carbon nanotubes (CNTs) also apart from GNPs. The CNTs have two ends and two surfaces (inner and outer). Hence, it provides wide possibility for functionalization on its surface thereby providing a possibility of delivery of bioactive agents within the body. The functionalization of the CNTs occurs usually by the physical adsorption of the surfactants by weakening of the van der Waals interaction within the bundle of CNTs, which may lead to the exfoliation of the CNTs. The exact mechanism of the adsorption and the nature of interaction between the CNTs and the surfactant remain unknown, though, it is suggested that in some cases the polymer coils itself around the CNTs in a helical fashion.

The surface functionalization of the nanoparticles has made tremendous progress in drug delivery through BBB. The potential drugs used for the therapy of the CNS related diseases face an enormous challenge of crossing the BBB due to which much progress in the successful treatment of the CNS related diseases has not been made. This problem has been resolved largely with the use of functionalized nanoparticles. Many possible mechanisms have been reported for the delivery of the drugs through the BBB with the use of nanoparticles. Endocytosis or transcytosis of the endothelial cell layer, dissolution of the membrane lipids of BBB due to surfactant effect, loosening of tight junctions of BBB due to the nanoparticle effect or the modification of the efflux protein in BBB thereby preventing efflux , may be some of the mechanisms by which the drug-coated nanoparticles move across BBB. Many other mechanisms have been suggested, which need proper concrete evidence as proof for the same. In this way, it is seen that surface functionalization of the nanoparticles has broadened the research related to drug delivery.
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Improvements in drug delivery across the BBB

Blood-brain barrier (BBB) is selectively permeable membrane in the central nervous system, designed to protect brain tissue from drugs, infective agents, radioactive ions and other harmful elements. It’s made out of specifically designed microvascular endothelial cells, astrocytic endfeet, basal lamina and pericytes. Tight junctions between the cells are preventing large hydrophilic molecules and bacteria/viruses from entering the extra cerebral fluid, but allowing the small hydrophobic molecules, such as O2, CO2 and hormones to enter by diffusion. Large molecules that are essential for the normal brain functioning, such as glucose, are transported by the protein carriers.

Experiments (at the beginning of the 20th century) with dies injected in the blood or directly into brain tissue proved that some kind of barrier exists between brain and the rest of the body, but it couldn’t be visualized until scanning electron microscope was discovered in 1960s. It was believed that this barrier is undergoing some sort of changes from the birth until the adult age, but after series of tests on rabbits and rats it was confirmed that BBB is operative from the birth.
BBB is important shield against potentially harmful agents (chemical or living ones), but that doesn’t make the brain and neuronal tissue untouchable and universally immune to the diseases. Genetic or acquired diseases of the CNS need to be treated like any other disorder and any solution that could “trick” BBB and allow drug transportation directly to the site where needed is more than valuable. So far, drugs were transported either through the barrier using the glucose or amino acid carriers, or by intracerebral implantation. Attempts to loosen up the barrier were made also by disrupting the osmotic pressure, by applying vasoactive substances or by using high-intensity focused ultrasound. Huge progress in this field is made by designing nanoparticles as drug carriers and cancer treatment methods improved a lot after this discovery.

Brain cancer statistics and survival rates are not bright. When tumor is originating directly in the brain, it’s called primary brain tumor. This type of tumor is more often with children then with adults. It accounts for 25% of all tumors in children, while only 2-3% of all cancers in adult age are result of primary brain tumor. More often is secondary brain tumor, resulting from metastasis, and it’s happening very often: 1 out of 4 cases of any kind of cancer in adult age will result in secondary brain tumor. Despite aggressive treatments and improvements in the cancer therapy, survival rate is dropping with patient age and with disease progression.

Whenever possible, cancer will be surgically removed and chemotherapy will be included in the postoperative course to destroy remaining cancer cells and prevent tumor recurrence. Chemotherapy needs to be delivered at the surgical site, but so far that goal was hard to accomplish for two reasons: to ensure effective penetration through the BBB drug needs to be administered at the highest dose possible and that dose usually adversely affect the rest of the patient’s organism. Using nanoparticles that are releasing drug gradually in time, dosing problem was eliminated. Initially designed nanoparticles didn’t move through the neural tissue after the application. Deeper parts of the tissue were usually “drug free” since nanoparticles remained attached to the cells at the application site. Latest improvements in the brain targeted drug delivery managed to overcome this problem. Using the nanoparticles coated in polyethyleneglycol (PEG), more sophisticated drug delivery technique is achieved, enabling not just to lower the drug dose, but to deliver it to the targeted spot in the brain. Labeling the coats with glowing tags proved that nanoparticles coated in dense layer of PEG can move deep in the tissue. It’s shown that density of the PEG layer is responsible for nanoparticle penetration potential; one with less dense PEG coats will pass shorter distance than one with more dense coats. What makes these nanoparticles more successful in brain targeted drug delivery is reduced interaction with surrounding cells, “slippery” effect of the PEG while penetrating tissue barriers and lack of immune response.

Experiments with rat brain tissue using chemotherapeutic drug Paclitaxel already showed that biodegradable nanopaticles coated in PEG can easily reach deeper parts of the brain. Further investigation will be focused on particle optimization and on the targeted drug delivery for the diseases like multiple sclerosis, stroke, Alzheimer’s disease as well as other brain related disorders.
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