Peptide Drug Delivery into the Central Nervous System
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Hypo- or hypersecretion, alteration in storage, release, catabolism, and post-translational processing of neuropeptides are associated with the etiology of many diseases affecting the central nervous system (CNS). Various peptides native to the brain and the spinal cord, as well as synthetic peptides, peptide analogues and peptidomimetics developed from endogenous neuropeptides could, therefore, be useful in the treatment of these CNS maladies. However, peptides face a formidable obstacle in reaching the intended site of action due to the existence of the blood-brain barrier (BBB)–a vital element in the regulation of the internal environment of the brain and the spinal cord. Although a small portion of peripherally delivered peptide may reach the brain parenchyma, the amount is often insufficient to exert CNS effects. Therefore, methods to deliver these biomolecules into the brain and spinal cord are necessary. Delivering peptides into the CNS has been a difficult task and various approaches have been developed. This presentation discusses the rationale, present state-of-the-art and future trends of various strategies applicable to peptides in order to outwit the BBB as the major obstacle of peptide pharmacotherapy of the CNS. Invasive methods involve either direct intracranial delivery of proteins and peptides, or transient opening of the tight junctions and, alternatively, permeabilizing the endothelial cells separating the systemic circulation from the interstitial fluid of the CNS. However, invasive approaches are associated with many medical risks and their use is justified only for life-threatening maladies such as brain cancer. To avoid problems manifested by invasive strategies to deliver therapeutic peptides into the CNS, various non-invasive methods have been developed. Physiologically based strategies utilize biological carriers such as proteins undergoing receptor-mediated transcytosis across the BBB to gain access to the CNS. Specific peptides (penetratins) may also be utilized as vectors to ferry therapeutic molecules manifesting poor BBB-transportability into the brain and spinal cord. Surfactant-covered polymer nanoparticles that mimic low-density lipoprotein (LDL) particles and, thus, can bind to LDL receptors expressed in the endothelial cells of the BBB have also been implicated as potential peptide drug carriers. Finally, prodrug strategies that aim at “bioreversibly” altering the properties of the peptide to enhance BBB transport will be discussed. |
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MetroCon 2007 |
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“Innovating for Society” |
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Biotechnologies |
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Dr. Prokai received his Ph.D. in Radiochemistry from the University of Veszprem (Hungary) in 1983. In 1987, he joined the University of Florida as a Postdoctoral Research Associate and rose in rank to Professor of Medicinal Chemistry. In addition, he was an Affiliate Professor of Chemistry, Joint Professor of Anesthesiology, Scientific Advisor of the Biotechnology Program and the Member of the McKnight Brain Institute. In the spring of 2002, he was Pro Renovanda Hungariae Visiting Professor at the University of Szeged in Hungary. In 2005, he accepted an offer to become the first Robert A. Welch Professor of Chemistry at the University of North Texas Health Science Center. Dr. Prokai has been recognized nationally and internationally for his work in medicinal chemistry of neuropeptides and estrogens, drug targeting, mass spectrometry of macromolecules and proteomics. He is on the Editorial Board of several journals (such as Current Medicinal Chemistry, Open Journal of Neuroscience and Current Drug Targeting). Dr. Prokai has authored a monograph, edited a book, and written 13 book chapters and published more than 100 papers in scientific journals. He has 12 patents and patent applications on new central nervous system and ophthalmic agents, estrogen therapy, diagnostic brain-imaging agents and methods to evaluate enzyme competency and medication adherence. |
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