User:Andrea Trementozzi/sandbox/Nanoparticles for Drug Delivery to the Brain

Nanoparticles for drug delivery to the brain provides an innovative and promising method for crossing the Blood Brain Barrier (BBB) and delivering pharmaceuticals to the brain for therapeutic treatment of neurological disorders. Many of these disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors, and part of the difficulty in finding cures for these central nervous system disorders is that there is not yet a truly efficient delivery method for drugs across the BBB. Antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, particularly neuropeptides, include many of the molecules that cannot pass this barrier alone. With the aid of nanoparticle delivery systems, studies have shown that certain drugs can not only cross the BBB, but they can also exhibit lower toxicity and decreased adverse effects throughout the body, which is an importnat concept for pharmacology because high toxicity levels could be detrimental to the patient. The Blood Brain Barrier, however, is the not the only physiological barrier for drug delivery to the brain, other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Background
Nanoparticles range in size from 10 - 1000 nm (or 1 μm) and they are made from natural or artificial polymers. The majority of polymers used for nanoparticle drug delivery systems are natural, biocompatible, biodegradable polymers to prevent contamination and the introduction of foreign particles into the CNS. Several methods for drug delivery to the brain include the use of liposomes, prodrugs and carrier-mediated transporters, or invasive intracranial delivery. Many different delivery methods exist to transport these drugs into the body, such as oral delivery, intranasal delivery, intravenous injections, and intracranial delivery, though for nanoparticles the majority of studies have shown increasing progress with intravenous delivery, meaning administration into the veins. In addition to delivery methods and transport methods, there are several means of functionalizing the nanoparticle with the drug load, some of which include dissolving the drug within the nanoparticle, encapsulating the drug inside, absorbing the drug onto or in the particle, and attaching the drug on the surface of the particle.

Lipid Based Nanoparticles
Lipid nanoparticles can be manufactured by high pressure homogenization, which is a current method used to produce parenteral emulsions. To formulate Solid Lipid Nanoparticles (SLN), the liquid lipid oil for the emulsion process is simply replaced with a solid lipid.

Polymer-Based Nanoparticles
Polymer based nanoparticles are nanoparticles developed from polymeric materials such as polylactic acid (PLA), poly(D-L-glycolide) (PLG), poly(lactide-co-glycolide) (PLGA), and poly(cyanoacrylate) (PCA). Biodegradability and biocompatibility are important factors to consider in developing polymeric nanoparticles for drug delivery to the brain. Some polymeric substances that were shown to produce effective nanoparticles are poly(butyl cyanoacrylate),polylactic-acid-polyglycolic acid copolymers, albumin, and chitosan.

Mechanisms
The mechanism for transport of polymer-based nanoparticles across the BBB has been characterized as Receptor-mediated endocytosis by the brain capillary endothelial cells. Transcytosis then occurs to transport the nanoparticles across the tight junction of endothelial cells into the brain. Surface coating of the nanoparticles with surfactants such as Polysorbate 80 or Polaxamer 188 and targeting ligands were shown to increase receptor-mediated uptake of the drug into the brain.

Toxicity
Nanoparticles may reduce drug toxicity and adverse effects in the body. Emulsions and surface coating can encapsulate the drug compound and preserve it from getting metabolized in other organs of the body. This allows the drug to reach the brain or target organ at a more potent level.

Research
Discuss Dr. Amiji's research on nanoparticle emulsions and transport of drugs into the CNS for brain tumors.