Overcoming The Blood-Brain Barrier For Delivering Drugs Into The Brain

Treatments of central nervous system (CNS) diseases are limited by the inadequacy in delivering therapeutic agents to the desired locations. The extremely low permeability of blood brain barrier (BBB) is a main reason leading to the compromised brain drug delivery and therapeutic efficiency. For example, over the 7000 drugs analyzed in the comprehensive medicinal chemistry (CMC) database, only 1% of them showed the BBB permeability and be active in the CNS. Therefore, there is great need for a safe and effective method to facilitate brain delivery of drugs for treatment of CNS disorders.Current strategies for brain drug delivery include disrupting BBB via chemical or physical approaches and traversing BBB via biological strategies. Hypertonic chemicals such as mannitol induce the osmotic pressure between the vascular wall, break the TJs and increase BBB permeability. Nevertheless, the chemical strategy carries the risks of neurotoxicity and epileptic seizures due to the uncontrollable TJ leakage. Transcytosis is a biological pathway by which endogenous macromolecules traverse endothelial cells within endocytic vesicles from the luminal side to the abluminal side where exocytosis occurs. However, the transcytosis approach suffers the low receptor expression level, limited endocytic events and the prerequisite for labeling cationic group or receptor targeting ligand on the drug or drug delivery vectors. Therefore, it is necessary to develop brain drug delivery strategy with high efficacy and minimized neurological injury.The present work includes two parts:In the first part of this paper, we investigate the multivalent effect for up-regulating the intracerebral delivery of nanoparticles via receptor mediated transcytosis. We developed a series of nanoparticles that were labeled imaging reporter as well as different numbers of BBB permeable angiopep-2 peptides. The multimetric association between the peptides labeled on the nanoparticles and receptors on the BCECs can increase the local concentration of nanoparticle on the brain capillaries and hence accelerate the receptor-mediated endocytosis. Considering the high expression level of LRP receptors in different types of brain cancer cells and the neurons with up-regulated Aβ peptide, Den-Angio4 as a prototype holds promise for diagnosis or treatment of CNS diseases such as brain tumors and Alzheimer’s disease without the compromise to BBB.In the second part of this paper,.we investigated a new strategy for delivering drugs into the brain by using adenosine receptor nanoagonist. We developed a series of nanoagonists that can not only up-regulated brain delivery of macromolecular model drugs by specifically signaling A2A AR but also demonstrated the capability to temporarily tune the BBB opening time-window under in vivo conditions. This study shows that nano-sized agonists have the ability to enhance brain drug delivery. Meanwhile, labeling the imaging reporter on the NAs and the model drug provides an unprecedented opportunity to noninvasively evaluate the BBB opening time-window, brain drug delivery efficiency, and therapeutic response. The Nanoagonists not only provide a new strategy to enhance brain drug delivery but also show promise to reduce potential risks such as over dosage and uncontrollable BBB leakage by tuning the BBB opening time-window according to the pharmacokinetic behavior of the therapeutics.