[BojanaL]

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.