Brain cancer treatment typically includes surgery, radiation therapy, and systemic chemotherapy. However, 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 each year in the United States (Greenlee, Murray, Bolden, & Wingo, 2000). Limited drug uptake by tumor cells, intracellular drug metabolism, and cellular resistance mechanisms all blocked tumor progression. brain cancer therapies (Orive, Ali, Anitua, Pedraz, & Emerich, 2010). However, the main obstacle remains the existence of the blood-brain barrier (BBB), a structure formed by tight junctions between endothelial cells and astrocytes that strongly limits the levels of pinocytosis, thus restricting the passage of compounds from the blood to the extracellular environment . brain environment. Typically most endothelial barriers allow the passive transport of nanoparticles less than 150 nm in diameter, however the BBB only allows the diffusion of small (<500 Da MW), neutrally charged, lipid-soluble molecules (Pardridge, 2002). Consequently, the passage of materials into the brain parenchyma is largely inhibited for many of the diagnostic and therapeutic molecules synthesized for the treatment of central nervous system 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 adsorption-mediated transcytosis, the latter two are the major routes for nanoparticle (NP) delivery through the BBB. Adsorption-mediated transit… half the paper… eaten once into the blood, which, again, induces rapid elimination from the body. Due to the numerous pathways for RES detection, extending circulation time is critical to developing effective drug therapy for the brain. Accordingly, 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 method is the covalent attachment of polyethylene glycol (PEG) as a means of prolonging circulation time. PEGylation is believed to suppress macrophage recognition through reduced protein adsorption and surface opsonization, likely due to the creation of a steric barrier on the nanoparticle surface (Orive, Ali, Anitua, Pedraz, and Emerich, 2010).